El lado oscuro del estrés (la indefensión aprendida)
El lado oscuro del estrés (la indefensión aprendida)
La acetilcolina es el "neurotransmisor" de los nervios colinérgicos, incluido el sistema parasimpático.
La colinesterasa (o acetilcolinesterasa) es una enzima que destruye la acetilcolina, limitando la acción de los nervios colinérgicos.
La unión de un grupo fosfato a la enzima colinesterasa la inactiva, prolongando e intensificando la acción de la estimulación colinérgica.
El sistema nervioso autónomo se ha dividido tradicionalmente en sistema simpático-adrenérgico y sistema parasimpático-colinérgico, con funciones aproximadamente opuestas, intensificando el gasto energético y limitándolo, respectivamente. El sistema hormonal y el sistema conductual interactúan con estos sistemas, y cada uno de ellos es capaz de trastocar a los demás. Los factores disruptivos del entorno han aumentado en las últimas décadas.
Vivir es desarrollarse; las decisiones que tomamos crean nuestra individualidad. Si ratones genéticamente idénticos crecen en un entorno amplio y variado, pequeñas diferencias en su experiencia afectarán al crecimiento celular de sus cerebros, dando lugar a grandes diferencias en su comportamiento exploratorio a medida que envejecen (Freund, et al., 2013). Los genetistas solían decir que "los genes determinan nuestros límites", pero este experimento demuestra que un entorno puede proporcionar tanto limitaciones como oportunidades para ampliar el potencial heredado. Si nuestro entorno restringe nuestras opciones, nuestro devenir humano se ve frustrado, del mismo modo que no se descubrían los potenciales de las ratas cuando se las mantenía encerradas en cajitas de laboratorio. La oportunidad de involucrarnos de manera compleja en un entorno complejo nos permite ser más de lo que somos, más humanamente diferenciados.
Una serie de experimentos que comenzaron en la Universidad de California en 1960 descubrieron que las ratas que vivían en espacios más amplios con diversas cosas que explorar eran mejores aprendiendo y resolviendo problemas que las ratas que se criaban en pequeñas jaulas estándar de laboratorio (Krech, et al., 1960). Al estudiar sus cerebros, descubrieron que la enzima colinesterasa (que destruye el neurotransmisor acetilcolina) había aumentado. Más tarde, descubrieron que las crías de estas ratas eran mejores aprendices que sus padres, y que sus cerebros contenían más colinesterasa. Sus cerebros también eran más grandes, con un considerable engrosamiento del córtex, el área del cerebro considerada como principal responsable del comportamiento complejo, el aprendizaje y la inteligencia.
Estos procesos no se limitan a la infancia. Por ejemplo, los taxistas londinenses que se aprenden todas las calles de la ciudad desarrollan un hipocampo más grande, una zona del cerebro relacionada con la memoria.
La investigación de los años sesenta sobre el enriquecimiento ambiental coincidió con cambios políticos en Estados Unidos, pero iba en contra de las ideas científicas dominantes de la época. A partir de 1945, el gobierno estadounidense había iniciado una serie de proyectos para desarrollar técnicas de modificación del comportamiento o control mental, mediante el uso de fármacos, aislamiento, privación y tortura. En la década de 1950, la psiquiatría recurrió con frecuencia a las lobotomías (unas 80.000, antes de que se suspendieran en la década de los 80) y a la "terapia" electroconvulsiva, y los psicólogos universitarios torturaron animales, a menudo como parte del desarrollo de técnicas para controlar el comportamiento.
La CIA abandonó oficialmente su programa MKultra en 1967, pero ese fue el año en que Martin Seligman, de la Universidad de Pensilvania, popularizó la idea de la "indefensión aprendida". Descubrió que cuando un animal era incapaz de escapar ser torturado, aunque fuera por muy poco tiempo, ni siquiera intentaba escapar la siguiente vez que era sometido a una tortura. A las conferencias de Seligman han asistido psicólogos que trabajaron en Guantánamo, y recientemente recibió una subvención a fondo perdido del Pentágono de 31 millones de dólares para desarrollar un programa de "preparación física integral del soldado", con el fin de entrenar a los marines a no caer en la indefensión aprendida.
En 1957, Curt Richter ya había descrito el fenómeno de la "desesperación" en ratas ("algunas ratas salvajes muestran una reacción de desesperación muy poco después de que se las agarre con la mano y se les impida moverse. Parecen literalmente rendirse") e incluso cómo ponerle remedio: permitiéndoles vivir la experiencia de escapar una vez (Richter, 1957, 1958). Ratas que normalmente serían capaces de mantenerse nadando en un tanque durante dos o tres días, a menudo se rendían y ahogaban en tan sólo unos minutos después de tener una experiencia de "estrés ineludible". Richter hizo el importante descubrimiento de que los corazones de las ratas desesperadas se ralentizaban antes de morir, permaneciendo relajados y llenos de sangre, lo cual revela la actividad dominante del nervio vagal, secretor de acetilcolina.
El sistema nervioso simpático (que segrega noradrenalina) acelera el corazón y suele activarse en situaciones de estrés, en la reacción de "lucha o huida", pero hasta ahora no se había observado que esta otra actividad nerviosa radicalmente distinta (parasimpática) se activara en situaciones de estrés. Se pensaba que el sistema nervioso parasimpático (colinérgico) permanecía inactivo durante el estrés y se activaba para regular procesos como la digestión, el sueño y la reparación. Además de los nervios colinérgicos del sistema parasimpático, muchos nervios del sistema nervioso central también segregan acetilcolina, que activa los músculos lisos, los músculos esqueléticos, las glándulas y otros nervios, y también tiene algunos efectos inhibidores. Los nervios parasimpáticos también segregan la enzima colinesterasa, que destruye la acetilcolina. Sin embargo, muchos otros tipos de células (glóbulos rojos, fibroblastos, nervios simpáticos, células de la médula), tal vez todas las células, pueden secretar colinesterasa.
Debido a que los nervios colinérgicos se han opuesto a los nervios simpáticos (adrenérgicos) se han tendido a descuidar sus funciones excitadoras nerviosas, cuando se analizan las causas de la excitotoxicidad, o la pérdida de células cerebrales inducida por el estrés. Sin embargo, una estimulación colinérgica excesiva puede contribuir a la muerte celular excitotóxica, por ejemplo cuando se combina con un nivel elevado de cortisol y/o hipoglucemia.
Los fármacos que bloquean los efectos estimulantes de la acetilcolina (los anticolinérgicos), así como las sustancias químicas que imitan los efectos de la acetilcolina, como los insecticidas organofosforados, pueden mermar la capacidad de pensar y aprender. Esto sugirió a algunas personas que la demencia relacionada con la edad era el resultado del deterioro de los nervios colinérgicos del cerebro. Los fármacos para aumentar los efectos estimulantes de la acetilcolina en el cerebro (mediante la inactivación de la colinesterasa) se promovieron como tratamiento para la enfermedad de Alzheimer.
Aunque los inhibidores herbales eran bien conocidos, se empezaron a utilizar nuevos fármacos rentables, empezando por la tacrina. Pronto se hizo evidente que la Tacrina causaba graves daños hepáticos, pero no ralentizaba el ritmo del deterioro mental.
Aunque los inhibidores herbales eran bien conocidos, se empezaron a utilizar nuevos fármacos rentables, empezando por la tacrina. Pronto se hizo evidente que la Tacrina causaba graves daños hepáticos, pero no ralentizaba el ritmo del deterioro mental.
A medida que se fue conociendo el fracaso del fármaco colinérgico tacrina, se propuso otro fármaco, la amantadina (y, más tarde, la similar memantina) para el tratamiento combinado. En la década de 1950, el fármaco anticolinérgico atropina se propuso varias veces para tratar la demencia, y la amantadina, que también se consideraba anticolinérgica, se propuso para algunas afecciones mentales, incluida la enfermedad de Creutzfeldt-Jacob (Sanders y Dunn, 1973). Debió de parecer extraño proponer que se utilizara un fármaco anticolinérgico para tratar una afección que se estaba tratando de forma tan provechosa con un fármaco procolinérgico, pero la memantina llegó a clasificarse como un "bloqueante NMDA" antiexcitatorio, para proteger los nervios colinérgicos restantes, de modo que ambos fármacos podían prescribirse lógicamente de forma simultánea. El fármaco adicional parece tener un pequeño efecto beneficioso, pero no se ha sugerido que esto pueda ser el resultado de sus efectos anticolinérgicos previamente conocidos.
A lo largo de los años, algunas personas han sospechado que la enfermedad de Alzheimer podría estar causada en parte por la falta de propósito y estímulo en su vida, y han descubierto que una actividad significativa e interesante podría mejorar su funcionamiento mental. Dado que la idea de un cerebro "genéticamente determinado" ya no se enseña de forma tan dogmática, cada vez hay más interés por esta terapia para todo tipo de deficiencias cerebrales. La analogía con la experiencia de enriquecimiento de Berkeley es clara, por lo que la asociación del aumento de actividad colinesterásica con la mejora de la función cerebral debería despertar interés.
Las secuelas del envenenamiento por gas nervioso o insecticida se han comparado con la demencia de la vejez. En general, se reconoce que los fármacos anticolinérgicos protegen contra esas toxinas. Las lesiones cerebrales traumáticas, incluso con mejoría a corto plazo, suelen iniciar un proceso degenerativo a largo plazo, aumentando enormemente la probabilidad de demencia a una edad más avanzada. Se sabe que en la degeneración traumática de los nervios interviene un proceso excitotóxico colinérgico (Lyeth y Hayes, 1992), y durante muchos años se ha recomendado el uso de fármacos anticolinérgicos para tratar las lesiones cerebrales traumáticas (por ejemplo, Ward, 1950: Ruge, 1954; Hayes, et al., 1986).
En 1976 hubo un experimento (Rosellini, et al.) que estableció un vínculo importante entre los experimentos de enriquecimiento y los de indefensión aprendida. Los animales de control de los experimentos de enriquecimiento se alojaron individualmente, mientras que los demás compartieron un recinto más grande. En el experimento posterior, se descubrió que las ratas "criadas en aislamiento morían repentinamente cuando se las ponía en una situación de natación estresante", mientras que los animales alojados en grupo eran nadadores resistentes y eficaces. El enriquecimiento y la privación tienen un significado biológico muy claro, y el uno es la negación del otro.
El aumento de colinesterasa (la enzima que destruye la acetilcolina) durante el enriquecimiento inactiva los procesos colinérgicos. Si la privación produce sus efectos nocivos aumentando la actividad del sistema colinérgico, cabría esperar que un fármaco colinérgico pudiera sustituir al estrés ineludible como causa de la indefensión aprendida, y que un fármaco anticolinérgico pudiera curarla. Esas pruebas ya se han hecho: "El tratamiento con la anticolinesterasa, fisostigmina, imitó con éxito los efectos del shock inescapable". "El anticolinérgico de acción central bromhidrato de escopolamina antagonizó los efectos de la fisostigmina, y cuando se administró antes de la prueba de escape antagonizó los efectos perturbadores del shock ineludible administrado previamente". (Anisman, et al., 1981.)
Este tipo de experimento sugeriría que los fármacos anticolinesterásicos que aún se utilizan para el tratamiento de la enfermedad de Alzheimer no son biológicamente útiles. En un boletín anterior hablé de los cambios de la hormona del crecimiento y de su antagonista, la somatostatina, en relación con la demencia: La hormona del crecimiento aumenta, la somatostatina disminuye. Los nervios colinérgicos son un factor importante en el cambio de esas hormonas en la dirección de la demencia, y los medicamentos anticolinérgicos tienden a aumentar la proporción de somatostatina con respecto a la hormona del crecimiento. Se ha descubierto que la somatostatina y la colinesterasa coexisten en células nerviosas individuales (Delfs, et al., 1984).
El estrógeno, que se promovió tan intensamente como prevención o tratamiento de la enfermedad de Alzheimer, finalmente se demostró que contribuye a su desarrollo. Uno de los efectos característicos del estrógeno es aumentar el nivel de la hormona del crecimiento en la sangre. Ésta es sólo una de las muchas formas en que el estrógeno se asocia con la activación colinérgica. Durante el embarazo, es importante que el útero no se contraiga. La estimulación colinérgica hace que se contraiga; demasiado estrógeno activa ese sistema y provoca un aborto espontáneo si es excesivo. Una función importante de la progesterona es mantener el útero relajado durante el embarazo. En el útero, y en muchos otros sistemas, la progesterona aumenta la actividad de la colinesterasa, eliminando la acetilcolina que, bajo la influencia del estrógeno, provocaría la contracción del útero.
La progesterona se está utilizando para tratar lesiones cerebrales, y con mucho éxito. Protege contra la inflamación y, en un primer estudio, comparada con placebo, redujo la mortalidad en más de la mitad. Resulta instructivo considerar su papel anticolinérgico en el útero, en relación con sus efectos protectores del cerebro. Cuando el cerebro es envenenado por un insecticida organofosforado, que disminuye la actividad de la colinesterasa, es probable que se produzcan convulsiones, y el tratamiento con progesterona puede prevenir esas convulsiones, revirtiendo la inhibición de la enzima (y aumentando la actividad de la colinesterasa en ratas que no fueron envenenadas) (Joshi, et al., 2010). Efectos similares de la progesterona sobre la colinesterasa se producen en mujeres con ciclos menstruales (Fairbrother, et al., 1989), lo que implica que se trata de una función general de la progesterona, no sólo algo para proteger el embarazo. El estrógeno, con una generalidad similar, disminuye la actividad de la colinesterasa. La DHEA, al igual que la progesterona, aumenta la actividad de la colinesterasa, y es protectora del cerebro (Aly, et al., 2011).
Los traumatismos cerebrales provocan sistemáticamente una disminución de la actividad de esta enzima (Östberg, et al., 2011; Donat, et al., 2007), lo que hace que la acetilcolina producida en el cerebro se acumule, con muchas consecuencias interesantes. En 1997, un grupo (Pike, et al.) creó lesiones cerebrales en ratas para probar la idea de que un inhibidor de la colinesterasa mejoraría su recuperación y su capacidad para moverse por un laberinto. En su lugar, descubrieron que reducía la capacidad cognitiva tanto de las ratas lesionadas como de las normales. Un grupo diferente (Zhu, et al., 2000) descubrió que un fármaco anticolinérgico, la selegelina (Deprenil), que se utiliza para tratar la enfermedad de Parkinson y, de manera informal, como fármaco antienvejecimiento que altera el estado de ánimo, mejoraba la recuperación cognitiva de las lesiones cerebrales.
Una de las funciones importantes de la acetilcolina, tanto en el cerebro como en otros lugares, es la relajación de los vasos sanguíneos, y esto se consigue activando la síntesis de NO, óxido nítrico. (Sin NO, la acetilcolina contrae los vasos sanguíneos; Librizzi, et al., 2000.) El control básico del flujo sanguíneo en el cerebro es el resultado de la relajación de la pared de los vasos sanguíneos en presencia de dióxido de carbono, que se produce en proporción al ritmo al que las células activas combinan metabólicamente el oxígeno y la glucosa. Cuando las células no pueden producir CO2 a un ritmo normal, la síntesis de óxido nítrico en los vasos sanguíneos puede provocar su dilatación. Sin embargo, el mecanismo de relajación por NO es muy diferente, ya que implica la inhibición de la producción de energía mitocondrial (Barron, et al., 2001). Es probable que las situaciones que favorecen la producción y retención de una mayor cantidad de dióxido de carbono en los tejidos reduzcan el "tono" básico del sistema nervioso parasimpático, ya que hay menos necesidad de vasodilatación adicional.
El óxido nítrico puede propagarse fuera de los vasos sanguíneos, afectando al metabolismo energético de las células nerviosas (Steinert, et al., 2010). Normalmente, los astrocitos protegen a las células nerviosas del óxido nítrico (Chen, et al., 2001), pero esa función puede verse alterada, por ejemplo, por endotoxina bacteriana absorbida desde el intestino (Solà, et al., 2002) o por beta-amiloide (Tran, 2001), haciéndoles producir óxido nítrico por sí mismos.
El óxido nítrico se considera cada vez más como un factor importante en la degeneración nerviosa (Doherty, 2011). El óxido nítrico activa procesos (Obukuro, et al., 2013) que pueden conducir a la muerte celular. La inhibición de la producción de óxido nítrico protege contra varios tipos de demencia (Sharma y Sharma, 2013; Sharma y Singh, 2013). Los traumatismos cerebrales provocan un gran aumento de la formación de óxido nítrico, y bloquear su síntesis mejora la recuperación (Hüttemann, et al., 2008; Gahm, et al., 2006). Los organofosforados aumentan la formación de óxido nítrico, y los fármacos anticolinérgicos protectores como la atropina la reducen (Chang, et al., 2001; Kim, et al., 1997). El estrés, incluido el miedo (Campos, et al., 2013) y el aislamiento (Zlatković y Filipović, 2013) pueden activar la formación de óxido nítrico, y diversos mediadores de la inflamación también lo activan. El óxido nítrico exhalado por una persona puede utilizarse para diagnosticar algunas enfermedades, y probablemente también refleje su nivel de bienestar emocional.
El aumento de la colinesterasa causado por el enriquecimiento de la vida sirve para proteger los tejidos contra la acumulación de acetilcolina. La activación de la síntesis de óxido nítrico por la acetilcolina tiende a bloquear la producción de energía y a activar los procesos autolíticos o catabólicos, que probablemente estén implicados en el desarrollo de una corteza cerebral más delgada en los animales aislados o estresados. Al descomponer rápidamente la acetilcolina, los procesos de renovación tisular consiguen predominar en los animales enriquecidos.
Las condiciones ambientales favorables para la producción de energía respiratoria protegen contra la indefensión aprendida y la neurodegeneración, así como contra otros problemas biológicos en los que intervienen los mismos mecanismos. La adaptación a la altitud, que estimula la formación de nuevas mitocondrias y el aumento de la actividad tiroidea (T3), se ha utilizado durante muchos años para tratar problemas neurológicos, y su efecto se ha demostrado en experimentos con animales (Manukhina, et al., 2010). La luz brillante puede revertir los efectos colinérgicos del estrés ineludible (Flemmer, et al., 1990).
Cuando se desarrolla la indefensión aprendida, el nivel de T3 en la sangre disminuye (Helmreich, et al., 2006), y la extirpación de la glándula tiroides crea el "déficit de escape", mientras que la administración de suplementos de hormona tiroidea antes de exponer al animal a un shock ineludible previene su desarrollo (Levine, et al., 1990). Una vez creada la indefensión aprendida en ratas, la suplementación con T3 la revierte (Massol, et al., 1987, 1988).
El hipotiroidismo y el exceso de tono colinérgico tienen muchas similitudes, como el aumento de la formación de óxido nítrico, de forma que síntomas similares, como la inflamación muscular, pueden ser producidos por inhibidores de la colinesterasa como la tacrina, por aumento del óxido nítrico o por simple hipotiroidismo (Jeyarasasingam, et al., 2000; Franco, et al., 2006).
Se sospecha que la exposición a insecticidas es un factor en el aumento de la incidencia de la enfermedad de Alzheimer (Zaganas, et al., 2013), pero podría estar contribuyendo a muchos otros problemas, relacionados con la inflamación, el edema y la degeneración. Otra fuente importante de intoxicación por organofosfatos es el aire utilizado para presurizar los aviones de pasajeros, que puede estar contaminado con vapores de organofosfatos procedentes del motor utilizado para comprimirlo.
Posiblemente, el componente más tóxico de nuestro entorno es la forma en que se ha diseñado la sociedad, para eliminar las decisiones significativas para la mayoría de las personas. En el experimento de Freund et al., algunos ratones se volvieron más exploradores gracias a las decisiones que tomaron, mientras que las vidas de otros se volvieron más rutinarias y limitadas. Nuestra cultura refuerza la vida rutinaria. A falta de oportunidades para variar la forma de trabajar y de vivir de acuerdo con los nuevos conocimientos que adquieres, los factores nutricionales, hormonales y físicos cobran especial importancia.
Se ha demostrado que los suplementos de tiroides y progesterona protegen en general contra las amenazas colinérgicas, pero hay muchos otros factores que pueden ajustarse en función de las necesidades particulares. La niacinamida, al igual que la progesterona, inhibe la producción de óxido nítrico, y también como la progesterona, mejora la recuperación de las lesiones cerebrales (Hoane, et al., 2008). En ratones alterados genéticamente con un rasgo de Alzheimer, la niacinamida corrige el defecto (Green, et al., 2008). En situaciones de crisis pueden utilizarse fármacos como la atropina y los antihistamínicos. La luz brillante, sin exceso de ultravioleta, debería estar disponible todos los días.
El sistema colinérgico es mucho más que una parte del sistema nervioso, y está implicado en el metabolismo celular y la renovación de los tejidos. La mayoría de las personas pueden beneficiarse de la reducción de la ingesta de fosfato, hierro y grasas poliinsaturadas (que pueden inhibir la colinesterasa; Willis, et al., 2009), y de la elección de alimentos que reduzcan la producción y absorción de endotoxinas. Y, obviamente, los fármacos destinados a aumentar los efectos del óxido nítrico (asparagina, zildenafilo/Viagra, minoxidil/Rogaine) y la acetilcolina (betanecol, benzpirinio, etc.) deben evitarse.
Texto original traducido por Project Impero
Psychopharmacology (Berl). 1981;74(1):81-7. Cholinergic influences on escape deficits produced by uncontrollable stress. Anisman H, Glazier SJ, Sklar LS.
Biochim Biophys Acta. 2001 Nov 1;1506(3):204-11. Endothelial- and nitric oxide-dependent effects on oxidative metabolism of intact artery. Barron JT, Gu L, Parrillo JE.
Psychiatry Res. 1987 Jul;21(3):267-75. Triiodothyronine potentiation of antidepressant-induced reversal of learned helplessness in rats. Brochet DM, Martin P, Soubrié P, Simon P.
Behav Brain Res. 2013 Aug 12. pii: S0166-4328(13)00482-8. Increased nitric oxide-mediated neurotransmission in the medial prefrontal cortex is associated with the long lasting anxiogenic-like effect of predator exposure. Campos AC, Piorino EM, Ferreira FR, Guimarães FS.
J Biomed Sci. 2001 Nov-Dec;8(6):475-83. Engagement of inducible nitric oxide synthase at the rostral ventrolateral medulla during mevinphos intoxication in the rat. Chang AY, Chan JY, Kao FJ, Huang CM, Chan SH.
Science. 1984 Jan 6;223(4631):61-3. Coexistence of acetylcholinesterase and somatostatin-immunoreactivity in neurons cultured from rat cerebrum. Delfs JR, Zhu CH, Dichter MA.
Neurosci Bull. 2011 Dec;27(6):366-82. Nitric oxide in neurodegeneration: potential benefits of non-steroidal anti-inflammatories. Doherty GH.18.
Brain Inj. 2007 Sep;21(10):1031-7. Alterations of acetylcholinesterase activity after traumatic brain injury in rats. Donat CK, Schuhmann MU, Voigt C, Nieber K, Schliebs R, Brust P.
Environ Res. 1989 Aug;49(2):181-9. Influence of menstrual cycle on serum cholinesterase. Fairbrother A, Wagner SL, Welch S, Smith BB.
Pharmacol Biochem Behav. 1990 Aug;36(4):775-8. Bright light blocks the capacity of inescapable swim stress to supersensitize a central muscarinic mechanism. Flemmer DD, Dilsaver SC, Peck JA.
J Biol Chem. 2006 Feb 24;281(8):4779-86. Hypothyroid phenotype is contributed by mitochondrial complex I inactivation due to translocated neuronal nitric-oxide synthase. Franco MC, Antico Arciuch VG, Peralta JG, Galli S, Levisman D, López LM, Romorini L, Poderoso JJ, Carreras MC.
J Neurotrauma. 2006 Sep;23(9):1343-54. Neuroprotection by selective inhibition of inducible nitric oxide synthase after experimental brain contusion. Gahm C, Holmin S, Wiklund PN, Brundin L, Mathiesen T.
Exp Neurol. 2005 Jun;193(2):522-30. Progesterone suppresses the inflammatory response and nitric oxide synthase-2 expression following cerebral ischemia. Gibson CL, Constantin D, Prior MJ, Bath PM, Murphy SP.
J Neurosci. 2008 Nov 5;28(45):11500-10. Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, LaFerla FM.
Cent Nerv Syst Trauma. 1986 Spring;3(2):163-73. Metabolic and neurophysiologic sequelae of brain injury: a cholinergic hypothesis. Hayes RL, Stonnington HH, Lyeth BG, Dixon CE, Yamamoto T.
Physiol Behav. 2006 Jan 30;87(1):114-9. Peripheral triiodothyronine (T(3)) levels during escapable and inescapable footshock. Helmreich DL, Crouch M, Dorr NP, Parfitt DB.
Neuroscience. 2008 Jun 26;154(3):861-8. Nicotinamide treatment induces behavioral recovery when administered up to 4 hours following cortical contusion injury in the rat. Hoane MR, Pierce JL, Holland MA, Anderson GD.
Neuroscience. 2008 Jan 2;151(1):148-54. Suppression of the inducible form of nitric oxide synthase prior to traumatic brain injury improves cytochrome c oxidase activity and normalizes cellular energy levels. Hüttemann M, Lee I, Kreipke CW, Petrov T.
Neuroreport. 2000 Apr 27;11(6):1173-6. Tacrine, a reversible acetylcholinesterase inhibitor, induces myopathy. Jeyarasasingam G, Yeluashvili M, Quik M.
J Pharmacol Exp Ther. 2000 Oct;295(1):314-20. Nitric oxide is involved in acetylcholinesterase inhibitor-induced myopathy in rats. Jeyarasasingam G, Yeluashvili M, Quik M.
Naunyn Schmiedebergs Arch Pharmacol. 2010 Oct;382(4):311-20. Effect of phosphamidon on convulsive behavior and biochemical parameters: modulation by progesterone and 4'-chlorodiazepam in rats. Joshi V, Arora T, Mehta AK, Sharma AK, Rathor N, Mehta KD, Mahajan P, Mediratta PK, Banerjee BD, Sharma KK.
Environ Toxicol Pharmacol. 1997 Feb 15;3(1):53-6. A role of nitric oxide in organophosphate-induced convulsions. Kim YB, Hur GH, Lee YS, Han BG, Shin S.
J Comp Physiol Psychol. 1960 Dec;53:509-19. Effects of environmental complexity and training on brain chemistry. Krech D, Rosenzweig MR, Bennett EL.
Physiol Behav. 1990 Jul;48(1):165-7. Thyroparathyroidectomy produces a progressive escape deficit in rats. Levine JD, Strauss LR, Muenz LR, Dratman MB, Stewart KT, Adler NT.
Neuroscience. 2000;101(2):283-7. Nitric oxide synthase inhibitors unmask acetylcholine-mediated constriction of cerebral vessels in the in vitro isolated guinea-pig brain. Librizzi L, Folco G, de Curtis M.
J Neurotrauma. 1992 May;9 Suppl 2:S463-74. Cholinergic and opioid mediation of traumatic brain injury. Lyeth BG, Hayes RL.
Neurosci Behav Physiol. 2010 Sep;40(7):737-43. Prevention of neurodegenerative damage to the brain in rats in experimental Alzheimer's disease by adaptation to hypoxia. Manukhina EB, Goryacheva AV, Barskov IV, Viktorov IV, Guseva AA, Pshennikova MG, Khomenko IP, Mashina SY, Pokidyshev DA, Malyshev IY.
Eur J Pharmacol. 1987 Feb 24;134(3):345-8. Triiodothyroacetic acid-induced reversal of learned helplessness in rats. Massol J, Martin P, Soubrié P, Simon P.
Eur J Pharmacol. 1988 Aug 2;152(3):347-51. Triiodothyroacetic acid (TRIAC) potentiation of antidepressant-induced reversal of learned helplessness in rats. Massol J, Martin P, Soubrié P, Puech AJ.
J Neurosci. 2013 Jul 31;33(31):12557-12568. Nitric Oxide Mediates Selective Degeneration of Hypothalamic Orexin Neurons through Dysfunction of Protein Disulfide Isomerase.Obukuro K, Nobunaga M, Takigawa M, Morioka H, Hisatsune A, Isohama Y, Shimokawa H, Tsutsui M, Katsuki H.
Neurology. 2011 Mar 22;76(12):1046-50. Cholinergic dysfunction after traumatic brain injury: preliminary findings from a PET study. Östberg A, Virta J, Rinne JO, Oikonen V, Luoto P, Någren K, Arponen E, Tenovuo O.
1. Eur J Neurosci. 2013 Jan;37(2):181-9. Regulation of acetylcholinesterase activity by nitric oxide in rat neuromuscular junction via N-methyl-D-aspartate receptor activation. Petrov KA, Malomouzh AI, Kovyazina IV, Krejci E, Nikitashina AD, Proskurina SE, Zobov VV, Nikolsky EE.
Brain Res. 2005 Jul 5;1049(1):112-9. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Pettus EH, Wright DW, Stein DG, Hoffman SW.
J Neurotrauma. 1997 Dec;14(12):897-905. Effect of tetrahydroaminoacridine, a cholinesterase inhibitor, on cognitive performance following experimental brain injury. Pike BR, Hamm RJ, Temple MD, Buck DL, Lyeth BG.
Psychosom Med. 1957 May-Jun;19(3):191-8. On the phenomenon of sudden death in animals and man. Richter CP.
Psychosom Med. 1976 Jan-Feb;38(1):55-8. Sudden death in the laboratory rat. Rosellini RA, Binik YM, Seligman MP.
J Neurosurg. 1954 Jan;11(1):77-83. The use of cholinergic blocking agents in the treatment of cranio-cerebral injuries. RUGE D.
J Neurosurg. 1950 Sep;7(5):398-402. Atropine in the treatment of closed head injury.
WARD A Jr.
Toxicol Appl Pharmacol. 2013 Aug 3. pii: S0041-008X(13)00326-8. Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors. Sharma B, Sharma PM.
Pharmacol Biochem Behav. 2013 Feb;103(4):821-30. Pharmacological inhibition of inducible nitric oxide synthase (iNOS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, convalesce behavior and biochemistry of hypertension induced vascular dementia in rats. Sharma B, Singh N.
J Neurol Neurosurg Psychiatry. 1973 Aug;36(4):581-4. Creutzfeldt-Jakob disease treated with amantidine. A report of two cases. Sanders WL, Dunn TL.
Neuroscientist. 2010 Aug;16(4):435-52. Nitric oxide signaling in brain function, dysfunction, and dementia. Steinert JR, Chernova T, Forsythe ID.
FASEB J. 2001 Jun;15(8):1407-9. Amyloid beta-peptide induces nitric oxide production in rat hippocampus: association with cholinergic dysfunction and amelioration by inducible nitric oxide synthase inhibitors. Tran MH, Yamada K, Olariu A, Mizuno M, Ren XH, Nabeshima T.
Genes Nutr. 2009 December; 4(4): 309–314. Dietary polyunsaturated fatty acids improve cholinergic transmission in the aged brain Willis LM, Shukitt-Hale B, Joseph JA.
Toxicology. 2013 May 10;307:3-11. Linking pesticide exposure and dementia: what is the evidence? Zaganas I, Kapetanaki S, Mastorodemos V, Kanavouras K, Colosio C, Wilks MF, Tsatsakis AM.
Exp Neurol. 2000 Nov;166(1):136-52. Postinjury administration of L-deprenyl improves cognitive function and enhances neuroplasticity after traumatic brain injury. Zhu J, Hamm RJ, Reeves TM, Povlishock JT, Phillips LL.
Neurochem Int. 2013 Sep;63(3):172-9. Chronic social isolation induces NF-κB activation and upregulation of iNOS protein expression in rat prefrontal cortex. Zlatković J, Filipović D.
J Biol Chem. 2006 Feb 24;281(8):4779-86. Hypothyroid phenotype is contributed by mitochondrial complex I inactivation due to translocated neuronal nitric-oxide synthase. Franco MC, Antico Arciuch VG, Peralta JG, Galli S, Levisman D, López LM, Romorini L, Poderoso JJ, Carreras MC.
Laboratory of Oxygen Metabolism, University Hospital, Facultad de Medicina,
University of Buenos Aires, 1120-Buenos Aires, Argentina.
Although transcriptional effects of thyroid hormones have substantial influence
on oxidative metabolism, how thyroid sets basal metabolic rate remains obscure.
Compartmental localization of nitric-oxide synthases is important for nitric
oxide signaling. We therefore examined liver neuronal nitric-oxide synthase-alpha
(nNOS) subcellular distribution as a putative mechanism for thyroid effects on
rat metabolic rate. At low 3,3',5-triiodo-L-thyronine levels, nNOS mRNA increased
by 3-fold, protein expression by one-fold, and nNOS was selectively translocated
to mitochondria without changes in other isoforms. In contrast, under thyroid
hormone administration, mRNA level did not change and nNOS remained predominantly
localized in cytosol. In hypothyroidism, nNOS translocation resulted in enhanced
mitochondrial nitric-oxide synthase activity with low O2 uptake. In this context,
NO utilization increased active O2 species and peroxynitrite yields and tyrosine
nitration of complex I proteins that reduced complex activity. Hypothyroidism was
also associated to high phospho-p38 mitogen-activated protein kinase and
decreased phospho-extracellular signal-regulated kinase 1/2 and cyclin D1 levels.
Similarly to thyroid hormones, but without changing thyroid status, nitric-oxide
synthase inhibitor N(omega)-nitro-L-arginine methyl ester increased basal
metabolic rate, prevented mitochondrial nitration and complex I derangement, and
turned mitogen-activated protein kinase signaling and cyclin D1 expression back
to control pattern. We surmise that nNOS spatial confinement in mitochondria is a
significant downstream effector of thyroid hormone and hypothyroid phenotype.
Toxicology. 2013 May 10;307:3-11. Linking pesticide exposure and dementia: what is the evidence? Zaganas I, Kapetanaki S, Mastorodemos V, Kanavouras K, Colosio C, Wilks MF, Tsatsakis AM.
J Pharmacol Exp Ther. 2000 Oct;295(1):314-20. Nitric oxide is involved in acetylcholinesterase inhibitor-induced myopathy in rats. Jeyarasasingam G, Yeluashvili M, Quik M.
Neuroreport. 2000 Apr 27;11(6):1173-6. Tacrine, a reversible acetylcholinesterase inhibitor, induces myopathy. Jeyarasasingam G, Yeluashvili M, Quik M.
Biochem Biophys Res Commun. 2002 Jan 11;290(1):97-104.
NO synthesis, unlike respiration, influences intracellular oxygen tension.
Coste J, Vial JC, Faury G, Deronzier A, Usson Y, Robert-Nicoud M, Verdetti J.
We have developed a new phosphorescent probe, PdTCPPNa(4), whose luminescence properties are affected by local variations of intracellular oxygen tension (PO(2)). Spectrofluorometric measurements on living human umbilical venous endothelial cells loaded with this molecule show that a decrease in extracellular oxygen tension induces a decrease of PO(2), illustrating the phenomenon of oxygen diffusion and validating the use of this probe in living cells. Moreover, KCN- or 2,4-dinitrophenol-induced modifications of respiration do not lead to detectable PO(2) variations, probably because O(2) diffusion is sufficient to allow oxygen supply. On the contrary, activation by acetylcholine or endothelial nitric oxide synthase (eNOS), which produces NO while consuming oxygen, induces a significant decrease in PO(2), whose amplitude is dependent on the acetylcholine dose, i.e., the eNOS activity level. Hence, activated cytosolic enzymes could consume high levels of oxygen which cannot be supplied by diffusion, leading to PO(2) decrease. Other cell physiology mechanisms leading to PO(2) variations can now be studied in living cells with this probe.
Science. 1984 Jan 6;223(4631):61-3. Coexistence of acetylcholinesterase and somatostatin-immunoreactivity in neurons cultured from rat cerebrum. Delfs JR, Zhu CH, Dichter MA.
Genes Nutr. 2009 December; 4(4): 309–314. Dietary polyunsaturated fatty acids improve cholinergic transmission in the aged brain Willis LM, Shukitt-Hale B, Joseph JA.
Toxicology. 2013 May 10;307:3-11. Linking pesticide exposure and dementia: what is the evidence? Zaganas I, Kapetanaki S, Mastorodemos V, Kanavouras K, Colosio C, Wilks MF,
Tsatsakis AM.
s sufficient for oxidative phosphorylation (references in ref. 1). These findings indicate that, in execution of these tasks, the involved brain tissue switches to aerobic glycolysis.
Acta Neurochir Suppl. 1997;70:130-3. Topical application of insulin like growth factor-1 reduces edema and upregulation of neuronal nitric oxide synthase following trauma to the rat spinal cord. Sharma HS, Nyberg F, Gordh T, Alm P, Westman J.
Toxicol Appl Pharmacol. 2013 Aug 3. pii: S0041-008X(13)00326-8. Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors. Sharma B, Sharma PM.
2. Pharmacol Biochem Behav. 2013 Feb;103(4):821-30. Pharmacological inhibition of inducible nitric oxide synthase (iNOS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, convalesce behavior and biochemistry of hypertension induced vascular dementia in rats. Sharma B, Singh N.
CNS and CVS Research Lab., Pharmacology Division, Department of Pharmaceutical
Sciences and Drug Research, Faculty of Medicine, Punjabi University, Patiala
147002, Punjab, India. bhupeshresearch@gmail.com
Cognitive disorders are likely to increase over the coming years (5-10). Vascular
dementia (VaD) has heterogeneous pathology and is a challenge for clinicians.
Current Alzheimer's disease drugs have had limited clinical efficacy in treating
VaD and none have been approved by major regulatory authorities specifically for
this disease. Role of iNOS and NADPH-oxidase has been reported in various
pathological conditions but there role in hypertension (Hypt) induced VaD is
still unclear. This research work investigates the salutiferous effect of
aminoguanidine (AG), an iNOS inhibitor and 4'-hydroxy-3'-methoxyacetophenone
(HMAP), a NADPH oxidase inhibitor in Hypt induced VaD in rats.
Deoxycorticosterone acetate-salt (DOCA-S) hypertension has been used for
development of VaD in rats. Morris water-maze was used for testing learning and
memory. Vascular system assessment was done by testing endothelial function. Mean
arterial blood pressure (MABP), oxidative stress [aortic superoxide anion, serum
and brain thiobarbituric acid reactive species (TBARS) and brain glutathione
(GSH)], nitric oxide levels (serum nitrite/nitrate) and cholinergic activity
(brain acetyl cholinesterase activity-AChE) were also measured. DOCA-S treated
rats have shown increased MABP with impairment of endothelial function, learning
and memory, reduction in serum nitrite/nitrate & brain GSH levels along with
increase in serum & brain TBARS, and brain AChE activity. AG as well as HMAP
significantly convalesce Hypt induced impairment of learning, memory, endothelial
function, and alterations in various biochemical parameters. It may be concluded
that AG, an iNOS inhibitor and HMAP, a NADPH-oxidase inhibitor may be considered
as potential agents for the management of Hypt induced VaD.
Copyright © 2012 Elsevier Inc. All rights reserved.
[Curr Pharm Des. 2010;16(25):2837-50. Nitric oxide: target for therapeutic strategies in Alzheimer's disease. Fernandez AP, Pozo-Rodrigalvarez A, Serrano J, Martinez-Murillo R. "data implicating nitric oxide (NO) in the progression of the disease. The three isoforms of the NO-synthesizing enzyme (NOS) operate as central mediators of amyloid beta-peptide (Aβ) action, giving rise to elevated levels of NO that contributes to the maintenance, self-perpetuation and progression of the disease. "]
J Neuropathol Exp Neurol. 2007 Apr;66(4):272-83. Nitric oxide synthase 3-mediated neurodegeneration after intracerebral gene delivery. de la Monte SM, Jhaveri A, Maron BA, Wands JR. "increased nitric oxide synthase 3 (NOS3) expression correlates with apoptosis in cortical neurons and colocalizes with amyloid precursor protein (APP)-amyloid beta (Abeta) deposits in the brain."
Neuroscience. 2000;101(2):283-7. Nitric oxide synthase inhibitors unmask acetylcholine-mediated constriction of cerebral vessels in the in vitro isolated guinea-pig brain. Librizzi L, Folco G, de Curtis M.
Pharmacology. 2000 Feb;60(2):82-9. Choline is a full agonist in inducing activation of neuronal nitric oxide synthase via the muscarinic M1 receptor. Carriere JL, El-Fakahany EE.
Glia. 2003 Jan 15;41(2):207-11. Alzheimer's disease is associated with a selective increase in alpha7 nicotinic acetylcholine receptor immunoreactivity in astrocytes. Teaktong T, Graham A, Court J, Perry R, Jaros E, Johnson M, Hall R, Perry E.
16. Neuroscientist. 2010 Aug;16(4):435-52.
Nitric oxide signaling in brain function, dysfunction, and dementia.
Steinert JR, Chernova T, Forsythe ID.
Neurotoxicity at the Synaptic Interface, MRC Toxicology Unit, University of
Leicester, Leicester, UK.
Nitric oxide (NO) is an important signaling molecule that is widely used in the
nervous system. With recognition of its roles in synaptic plasticity (long-term
potentiation, LTP; long-term depression, LTD) and elucidation of
calcium-dependent, NMDAR-mediated activation of neuronal nitric oxide synthase
(nNOS), numerous molecular and pharmacological tools have been used to explore
the physiology and pathological consequences for nitrergic signaling. In this
review, the authors summarize the current understanding of this subtle signaling
pathway, discuss the evidence for nitrergic modulation of ion channels and
homeostatic modulation of intrinsic excitability, and speculate about the
pathological consequences of spillover between different nitrergic compartments
in contributing to aberrant signaling in neurodegenerative disorders.
Accumulating evidence points to various ion channels and particularly
voltage-gated potassium channels as signaling targets, whereby NO mediates
activity-dependent control of intrinsic neuronal excitability; such changes could
underlie broader mechanisms of synaptic plasticity across neuronal networks. In
addition, the inability to constrain NO diffusion suggests that spillover from
endothelium (eNOS) and/or immune compartments (iNOS) into the nervous system
provides potential pathological sources of NO and where control failure in these
other systems could have broader neurological implications. Abnormal NO signaling
could therefore contribute to a variety of neurodegenerative pathologies such as
stroke/excitotoxicity, Alzheimer's disease, multiple sclerosis, and Parkinson's
disease.
Neurosci Bull. 2011 Dec;27(6):366-82. Nitric oxide in neurodegeneration: potential benefits of non-steroidal anti-inflammatories. Doherty GH.18.
Neuroscience. 2010 Dec 15;171(3):859-68. Low energy laser light (632.8 nm) suppresses amyloid-β peptide-induced oxidative and inflammatory responses in astrocytes.
Yang X, Askarova S, Sheng W, Chen JK, Sun AY, Sun GY, Yao G, Lee JC.
Neurosci Behav Physiol. 2010 Sep;40(7):737-43. Prevention of neurodegenerative damage to the brain in rats in experimental Alzheimer's disease by adaptation to hypoxia. Manukhina EB, Goryacheva AV, Barskov IV, Viktorov IV, Guseva AA, Pshennikova MG, Khomenko IP, Mashina SY, Pokidyshev DA, Malyshev IY.
Physiol Behav. 1990 Jul;48(1):165-7.
Thyroparathyroidectomy produces a progressive escape deficit in rats.
Levine JD, Strauss LR, Muenz LR, Dratman MB, Stewart KT, Adler NT.
Department of Anatomy, University of Pennsylvania, Philadelphia.
Abnormal thyroid status and affective disorders have been associated in the human
clinical literature. It has recently been shown that pretreatment with thyroid
hormone can prevent escape deficits produced by inescapable shock in an animal
analogue of depression. In this report we provide evidence that hypothyroid
status can produce an escape deficit in rats. While sham-operated rats improved
their performance on a simple escape task over three days of testing,
thyroparathyroidectomized rats showed a pronounced decrease in their responses.
Markov transition analysis was used to obtain conditional probabilities of
escaping given a prior escape or failure to escape for the two groups. This
analysis shows that the structure of the data set may be similar for the two
groups. These results suggest that if intact rats learn to escape, then
hypothyroid rats may learn not to escape.
1. Pharmacol Biochem Behav. 1990 Aug;36(4):775-8.
Bright light blocks the capacity of inescapable swim stress to supersensitize a
central muscarinic mechanism.
Flemmer DD, Dilsaver SC, Peck JA.
Department of Psychiatry, Ohio State University.
Clinical and basic researchers have proposed that muscarinic cholinergic
mechanisms mediate some effects of chronic stress. Chronic inescapable (forced)
swim stress depletes brain biogenic amines and is used to produce learned
helplessness in rats. Behavioral and biochemical characteristics of animals in
the state of learned helplessness lead some investigators to believe this
condition provides a useful animal model of depression. Inescapable swim stress
also produces supersensitivity to the hypothermic effect of the muscarinic
agonist oxotremorine in the rat. The authors previously demonstrated that bright
light potently induces subsensitivity of a central muscarinic mechanism involved
in the regulation of core temperature under a variety of circumstances. They now
report using a repeated measures design that inescapable swim stress of five days
duration produces supersensitivity to oxotremorine (increase in thermic response
of 405%). This supersensitivity is reversed within five days by treatment with
bright light, despite continuation of daily swim stress. Daily inescapable swim
stress was continued beyond cessation of treatment with bright light. Five days
later, supersensitivity to the hypothermic effect of oxotremorine was once again
evident.
Pharmacol Biochem Behav. 1986 Aug;25(2):415-21.
Neurochemical and behavioral consequences of mild, uncontrollable shock: effects
of PCPA.
Edwards E, Johnson J, Anderson D, Turano P, Henn FA.
The present experiments examined the role of the serotonergic system in the
behavioral deficit produced by uncontrollable shock. In Experiment 1:
Establishment of model, the behavioral potential of the Sprague-Dawley rat was
defined. When exposed to mild uncontrollable stress such as a 0.8 mA electric
footshock, a significant percentage of rats developed a shock escape deficit
which was evident when subsequently placed in a shock escape paradigm. Serotonin
depletion was produced by chronic treatment with p-chlorophenylalanine. Biogenic
amine levels and 5-HT levels were monitored in various brain areas using HPLC.
Following chronic treatment with PCPA, the shock escape capability of the
Sprague-Dawley rat was assessed. The severe depletion of 5-HT in various brain
regions was highly correlated with a dramatic improvement in the shock escape
scores. Thus, the detrimental effects of exposure to a mild course of inescapable
shock can be prevented by chronic treatment with PCPA. These experiments
implicate the serotonergic system as a possible mediator of the "learned
helplessness" phenomenon.
Biol Psychiatry. 1985 Sep;20(9):1023-5.
Triiodothyronine-induced reversal of learned helplessness in rats.
Martin P, Brochet D, Soubrie P, Simon P.
Pharmacol Biochem Behav. 1982 Nov;17(5):877-83.
Evidence for a serotonergic mechanism of the learned helplessness phenomenon.
Brown L, Rosellini RA, Samuels OB, Riley EP.
The present experiments examined the role of the serotonergic system in the
learned helplessness phenomenon. In Experiment 1, a 200 mg/kg dose of
1-tryptophan injected 30 min prior to testing disrupted acquisition of Fixed
Ratio 2 shuttle escape behavior. In Experiment 2, a 100 mg/kg dose of 5-HTP
produced interference with the acquisition of the escape response. Furthermore,
this interference was prevented by treatment with the serotonergic antagonist
methysergide. In Experiment 3, animals were pretreated with a subeffective dose
of 1-tryptophan in combination with subeffective exposure to inescapable shock.
These animals showed a deficit in the acquisition of FR-2 shuttle escape. In
Experiment 4, combined exposure to a subeffective dose of 5-HTP and inescapable
shock (40 trials) resulted in an acquisition deficit. This deficit was reversed
by methysergide. Experiment 5 showed that the detrimental effects of exposure to
prolonged (80 trials) of inescapable shock can be prevented by treatment with
methysergide. These studies implicate the serotonergic system as a possible
mediator of the learned helplessness phenomenon.
45. Med Hypotheses. 2004;63(2):308-21. Brain cholinesterases: II. The molecular and cellular basis of Alzheimer's disease. Shen ZX.
2436 Rhode Island Avenue #3, Golden valley, MN 55427-5011, USA.
zhengxshen@yahoo.com
Currently available evidence demonstrates that cholinesterases (ChEs), owing to
their powerful enzymatic and non-catalytic actions, unusually strong
electrostatics, and exceptionally ubiquitous presence and redundancy in their
capacity as the connector, the organizer and the safeguard of the brain, play
fundamental role(s) in the well-being of cells, tissues, animal and human lives,
while they present themselves adequately in quality and quantity. The widespread
intracellular and extracellular membrane networks of ChEs in the brain are also
subject to various insults, such as aging, gene anomalies, environmental hazards,
head trauma, excessive oxidative stress, imbalances and/or deficits of organic
constituents. The loss and the alteration of ChEs on the outer surface membranous
network may initiate the formation of extracellular senile plaques and induce an
outside-in cascade of Alzheimer's disease (AD). The alteration in ChEs on the
intracellular compartments membranous network may give rise to the development of
intracellular neurofibrillary tangles and induce an inside-out cascade of AD. The
abnormal patterns of glycosylation and configuration changes in ChEs may be
reflecting their impaired metabolism at the molecular and cellular level and
causing the enzymatic and pharmacodynamical modifications and neurotoxicity
detected in brain tissue and/or CSF of patients with AD and in specimens in
laboratory experiments. The inflammatory reactions mainly arising from
ChEs-containing neuroglial cells may facilitate the pathophysiologic process of
AD. It is proposed that brain ChEs may serve as a central point rallying various
hypotheses regarding the etio-pathogenesis of AD.
3. Neurology. 2011 Mar 22;76(12):1046-50. doi: 10.1212/WNL.0b013e318211c1c4.
Cholinergic dysfunction after traumatic brain injury: preliminary findings from a
PET study.
Östberg A, Virta J, Rinne JO, Oikonen V, Luoto P, Någren K, Arponen E, Tenovuo O.
Department of Neurology, University of Turku and Turku University Central
Hospital, Turku, Finland.
OBJECTIVE: There is evidence that the cholinergic system is frequently involved
in the cognitive consequences of traumatic brain injury (TBI). We studied whether
the brain cholinergic function is altered after TBI in vivo using PET.
METHODS: Cholinergic function was assessed with
[methyl-(11)C]N-methylpiperidyl-4-acetate, which reflects the
acetylcholinesterase (AChE) activity, in 17 subjects more than 1 year after a TBI
and in 12 healthy controls. All subjects had been without any centrally acting
drugs for at least 4 weeks.
RESULTS: The AChE activity was significantly lower in subjects with TBI compared
to controls in several areas of the neocortex (-5.9% to -10.8%, p=0.053 to
0.004).
CONCLUSIONS: Patients with chronic cognitive symptoms after TBI show widely
lowered AChE activity across the neocortex.
© 2011 by AAN Enterprises, Inc.
9. Brain Inj. 2007 Sep;21(10):1031-7.
Alterations of acetylcholinesterase activity after traumatic brain injury in
rats.
Donat CK, Schuhmann MU, Voigt C, Nieber K, Schliebs R, Brust P.
Institute of Interdisciplinary Isotope Research, Permoserstasse 15, 04318
Leipzig, Germany. donat@iif-leipzig.de
OBJECTIVE: The cholinergic system is highly vulnerable to traumatic brain injury
(TBI). However, limited information is available to what extent the degrading
enzyme acetylcholinesterase (AChE) is involved. The present study addresses this
question.
METHOD: Thirty-six anaesthetized Sprague-Dawley rats were subjected to sham
operation or to TBI using controlled cortical impact (CCI). The AChE activity was
histochemically determined in frozen brain slices at 2, 24 and 72 hours after
TBI.
RESULTS: High enzyme activity was observed in regions rich in cholinergic
innervation such as the olfactory tubercle, basal forebrain, putamen and superior
colliculi. Low activity was found in the cortex, cerebellum and particularly in
the white matter. A decrease of AchE activity (20-35%) was found in the
hippocampus and hypothalamus already at 2 hours after TBI. An increase of
approximately 30% was found in the basal forebrain at 2 and 24 hours. No changes
occurred at 72 hours.
CONCLUSION: The findings are consistent with impairment of the cholinergic
neurotransmission after TBI and suggest the involvement of the AChE in short-term
regulatory mechanisms.
35. Res Commun Chem Pathol Pharmacol. 1990 Jun;68(3):391-4.
Increase of muscarinic receptor following kainic acid lesions of the nucleus
basalis magnocellularis in rat brain: an autoradiographic study.
Katayama S, Kito S, Yamamura Y.
Third Department of Internal Medicine, Hiroshima University School of Medicine,
Japan.
We observed changes in cholinergic markers in rat brain seven days after
lesioning the nucleus basalis magnocellularis (nbm) with kainic acid. In
histochemical preparations stained for acetylcholinesterase (AChE), there was a
marked loss of large AChE reactive neurons within and beneath the nbm on the
injected side, and the AChE positive fibers were greatly decreased particularly
in the IV-VI layers of the frontal and parietal cortices ipsilateral to the
kainate lesion. Using in vitro receptor autoradiography, we found a significant
increase (about 25%) in 3H-QNB binding sites in the I-IV layers of the
ipsilateral frontal and parietal cortices (p 0.05, Student's t-test). The area
with decreased AChE activity and increased density in 3H-QNB binding sites
corresponded to the innervation of the cholinergic system arising from the nbm.
The increase of density in 3H-QNB binding sites was considered to reflect the
postsynaptic denervation supersensitivity.
36. Hum Exp Toxicol. 1992 Nov;11(6):517-23.
Long-term study of brain lesions following soman, in comparison to DFP and
metrazol poisoning.
Kadar T, Cohen G, Sahar R, Alkalai D, Shapira S.
Department of Pharmacology, Israel Institute for Biological Research, Ness-Ziona,
Israel.
The long-term histopathological effects of acute lethal (95 micrograms kg-1) and
sublethal (56 micrograms kg-1) doses of soman were studied in rats and were
compared to lesions caused by equipotent doses of either another cholinesterase
(ChE) inhibitor, DFP (1.8 mg kg-1), or a non-organophosphorus convulsant,
metrazol (100 mg kg-1). Severe toxic signs were noted following one LD50 dose
administration of all the compounds, yet only soman induced brain lesions.
Moreover, even when administered at a sublethal dose (0.5 LD50), soman induced
some histological changes without any clinical signs of intoxication.
Soman-induced brain lesions were assessed quantitatively using a computerized
image analyser. The analysis was carried out for up to 3 months following
administration, and a dynamic pattern of pathology was shown. The cortical
thickness and area of CA1 and CA3 cells declined significantly as early as 1 week
post-exposure. No pathological findings were detected following DFP and metrazol
administration. It is therefore suggested that brain lesions are not common for
all ChE inhibitors and that convulsions per se are not the only factor leading to
brain damage following the administration of soman. The degenerative process
(found also with the sublethal dose of soman) might be due to a secondary effect,
unrelated to soman's clinical toxicity, but leading to long-term brain injuries.
42. J Neurotrauma. 1997 Dec;14(12):897-905. Effect of tetrahydroaminoacridine, a cholinesterase inhibitor, on cognitive performance following experimental brain injury. Pike BR, Hamm RJ, Temple MD, Buck DL, Lyeth BG.
Department of Psychology, Virginia Commonwealth University, Medical College of
Virginia, Richmond 23284-2018, USA.
An emerging literature exists in support of deficits in cholinergic
neurotransmission days to weeks following experimental traumatic brain injury
(TBI). In addition, novel cholinomimetic therapeutics have been demonstrated to
improve cognitive outcome following TBI in rats. We examined the effects of
repeated postinjury administration of a cholinesterase inhibitor,
tetrahydroaminoacridine (THA), on cognitive performance following experimental
TBI. Rats were either injured at a moderate level of central fluid percussion TBI
(2.1+/-0.1 atm) or were surgically prepared but not delivered a fluid pulse (sham
injury). Beginning 24 h after TBI or sham injury, rats were injected (IP) daily
for 15 days with an equal volume (1.0 ml/kg) of either 0.0, 1.0, 3.0, or 9.0
mg/kg THA (TBI: n = 8, 8, 10, and 7, respectively, and Sham: n = 5, 7, 8, 7,
respectively). Cognitive performance was assessed on Days 11-15 after injury in a
Morris water maze (MWM). Analysis of maze latencies over days indicated that
chronic administration of THA produced a dose-related impairment in MWM
performance in both the injured and sham groups, with the 9.0 mg/kg dose
producing the largest deficit. The 1.0 and 3.0 mg/kg doses of THA impaired MWM
performance without affecting swimming speeds. Thus, the results of this
investigation do not support the use of THA as a cholinomimetic therapeutic for
the treatment of cognitive deficits following TBI.
43. Toxicol Lett. 1998 Dec 28;102-103:527-33.
Chronic effects of low level exposure to anticholinesterases--a mechanistic
review.
Ray DE.
Medical Research Council Toxicology Unit, Leicester, UK. der2@le.ac.uk
High dose exposure to anticholinesterases which results in symptomatic poisoning
can have lasting consequences due to the trauma of intoxication, excitotoxicity,
secondary hypoxic damage, and (for some agents) a delayed onset polyneuropathy
(OPIDN). The potential effects of low level exposure are less well defined. The
most reliable data comes from controlled clinical trials with specific agents. A
single dose of sarin or repeated doses of metrifonate or mevinphos, have produced
only transient adverse effects at doses causing substantial acetylcholinesterase
inhibition. Other data comes from epidemiological surveys. These have often used
more sensitive indices than the clinical studies, but are less reliable due to
the difficulty of defining exposure and matching control and exposed populations.
Subtle, mainly cognitive, differences between exposed and non-exposed populations
are sometimes seen. Low level exposure can cause a reversible down-regulation of
cholinergic systems, and a range of non-cholinesterase effects that are
structure-specific, and do not always parallel acute toxicity. Novel protein
targets sensitive to low level exposure to some organophosphates are known to
exist in the brain, but their functional significance is not yet understood.
44. Exp Neurol. 2000 Nov;166(1):136-52.
Postinjury administration of L-deprenyl improves cognitive function and enhances
neuroplasticity after traumatic brain injury.
Zhu J, Hamm RJ, Reeves TM, Povlishock JT, Phillips LL.
Department of Anatomy, Medical College of Virginia, Richmond, Virginia
23298-0709, USA.
The rat model of combined central fluid percussion traumatic brain injury (TBI)
and bilateral entorhinal cortical lesion (BEC) produces profound, persistent
cognitive deficits, sequelae associated with human TBI. In contrast to percussive
TBI alone, this combined injury induces maladaptive hippocampal plasticity.
Recent reports suggest a potential role for dopamine in CNS plasticity after
trauma. We have examined the effect of the dopamine enhancer l-deprenyl on
cognitive function and neuroplasticity following TBI. Rats received fluid
percussion TBI, BEC alone, or combined TBI + BEC lesion and were treated once
daily for 7 days with l-deprenyl, beginning 24 h after TBI alone and 15 min after
BEC or TBI + BEC. Postinjury motor assessment showed no effect of l-deprenyl
treatment. Cognitive performance was assessed on days 11-15 postinjury and brains
from the same cases examined for dopamine beta-hydroxylase immunoreactivity
(DBH-IR) and acetylcholinesterase (AChE) histochemistry. Significant cognitive
improvement relative to untreated injured cases was observed in both TBI groups
following l-deprenyl treatment; however, no drug effects were seen with BEC
alone. l-Deprenyl attenuated injury-induced loss in DBH-IR over CA1 and CA3 after
TBI alone. However, after combined TBI + BEC, l-deprenyl was only effective in
protecting CA1 DBH-IR. AChE histostaining in CA3 was significantly elevated with
l-deprenyl in both injury models. After TBI + BEC, l-deprenyl also increased AChE
in the dentate molecular layer relative to untreated injured cases. These results
suggest that dopaminergic/noradrenergic enhancement facilitates cognitive
recovery after brain injury and that noradrenergic fiber integrity is correlated
with enhanced synaptic plasticity in the injured hippocampus.
Copyright 2000 Academic Press.
J Neurotrauma. 1992 May;9 Suppl 2:S463-74. Cholinergic and opioid mediation of traumatic brain injury. Lyeth BG, Hayes RL.
Psychosom Med. 1976 Jan-Feb;38(1):55-8. Sudden death in the laboratory rat. Rosellini RA, Binik YM, Seligman MP.
Vulnerability to sudden death was produced in laboratory rats by manipulating
their developmental history. Rats who were reared in isolation died suddenly when
placed in a stressful swimming situation. Handling of these singly-housed rats
from 25 to 100 days of age potentiated the phenomenon. However, animals who were
group housed did not die even when they had been previously handled.
J Neurol Neurosurg Psychiatry. 1973 Aug;36(4):581-4.
Creutzfeldt-Jakob disease treated with amantidine. A report of two cases.
Sanders WL, Dunn TL.
The treatment of two cases of Creutzfeldt-Jakob disease with amantidine is described. The first case made a remarkable initial improvement which was sustained for two months, but then deteriorated and died. Histological examination of the brain showed changes consistent with early Creutzfeldt-Jakob disease. The second case which was clinically one of Creutzfeldt-Jakob disease has now been followed for 30 months since the start of treatment and appears to be cured. It is considered that amantidine has a definite effect in this disease and it is suggested that its mode of action, though unknown, is more likely to be metabolic than antiviral.
Free PMC Article
Arch Int Pharmacodyn Ther. 1986 Mar;280(1):136-44. Effect of stress and glucocorticoids on the gastrointestinal cholinergic enzymes. Oriaku ET, Soliman KF. (Glucocorticoids lower AChE)
Cardiovasc Res. 1990 Apr;24(4):335-9. Sympathectomy alters acetylcholinesterase expression in adult rat heart. Nyquist Battie C, Moran N.
Harris LW, Garry VF, Jr, Moore RD. Biosynthesis of cholinesterase in rabbit bone marrow cells in culture. Biochem Pharmacol. 1974 Aug;23(15):2155–2163.
Heller M, Hanahan DJ. Human erythrocyte membrane bound enzyme acetylcholinesterase. Biochim Biophys Acta. 1972 Jan 17;255(1):251–272.
J Cell Biol. 1976 June 1; 69(3): 638–646. Bartos EM. Properties of growth-related acetylcholinesterase in a cell line of fibroblastic origin
Behav Brain Res 2000 Jul;112(1-2):33-41
Impaired escape performance and enhanced conditioned fear in rats following
exposure to an uncontrollable stressor are mediated by glutamate and nitric
oxide in the dorsal raphe nucleus.
Grahn RE, Watkins LR, Maier SF.
Department of Psychology, Connecticut College, Box 5275, 270 Mohegan Avenue,
06320-4196, New London, CT 06320-4196, USA. regra@conncoll.edu
Exposure to uncontrollable aversive events produces a variety of behavioral
consequences that do not occur if the aversive event is controllable.
Accumulating evidence suggests that exaggerated excitation of serotonin (5-HT)
neurons in the dorsal raphe nucleus (DRN) is sufficient to cause these same
behaviors, such as poor shuttlebox escape performance and enhanced conditioned
fear that occur 24 h after exposure to inescapable tailshock (IS). The aim of
the present studies was to explore the possibility that N-methyl-D-aspartate
(NMDA) receptor activation and nitric oxide (NO) formation within the DRN might
be involved in mediating the behavioral consequences of IS. To this end, either
the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV) or the nitric
oxide synthase inhibitor Nw-nitro-L-arginine methyl ester (L-NAME), was
microinjected into the DRN before IS or before testing 24 h later. Blocking NMDA
receptors with APV in the DRN during IS prevented the usual impact of IS on
escape responding and conditioned fear. However, injection of APV at the time of
testing only reduced these effects. The DRN was shown to be the critical site
mediating blockade of these behavioral changes since injection of APV lateral to
the DRN did not alter the behavioral consequences of IS. Conversely, L-NAME was
most effective in reversing the effects of IS when administered at the time of
testing. These results suggest that there is glutamatergic input to the DRN at
the time of IS that produces long-lasting changes in DRN sensitivity. This
plasticity in the DRN is discussed as a possible mechanism by which IS leads to
changes in escape performance and conditioned fear responding.
and prolonged depression causes shrinkage of this area. The high cortisol associated with depression is undoubtedly one of the factors causing brain shrinkage during stress. Cushing's disease, in which the adrenal glands produce far too much cortisol, causes shrinkage of the brain, and when the disease is cured by normalizing the level of cortisol, the brain size is restored.
There are two very different kinds of stress reaction. The best known "fight or flight reaction" could be called more accurately "struggle to adapt." Another, less discussed kind, might appear to be a "give up and die or get depressed" reaction, but it involves many processes that are protective and adaptive in certain circumstances.
tone and heart rate;
drown easily. The role of acetylcholine, (Anisman, et al., 1981).
A situation of extreme restraint causes very rapid damage to the tissues, with bleeding ulcers of the stomach and intestine, shrinking of the thymus gland, and, if the animal survives for a while, atrophy of the brain. (Doi, et al., 1991; Gatón, et al., 1993)
LH, somatotropin, GH, Ach. caffeine progest
Behav Brain Res. 2012 Mar 17;228(2):294-8. doi: 10.1016/j.bbr.2011.11.036. Epub
2011 Dec 8.
Parental enrichment and offspring development: modifications to brain, behavior
and the epigenome.
Mychasiuk R, Zahir S, Schmold N, Ilnytskyy S, Kovalchuk O, Gibb R.
University of Lethbridge, Canadian Centre for Behavioural Neuroscience, Canada.
r.mychasiuk@uleth.ca
4. Biomed Pharmacother. 2012 Jun;66(4):249-55. doi: 10.1016/j.biopha.2011.11.005.
Epub 2011 Dec 21.
Cholinesterase activities and biochemical determinations in patients with
prostate cancer: influence of Gleason score, treatment and bone metastasis.
Battisti V, Bagatini MD, Maders LD, Chiesa J, Santos KF, Gonçalves JF, Abdalla
FH, Battisti IE, Schetinger MR, Morsch VM.
Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade
Federal de Santa Maria, Campus Universitário, 97105-900 Santa Maria, RS, Brazil.
battistivanessa@gmail.com
Prostate cancer (PCa) is the sixth most common type of cancer worldwide.
Cholinesterase is well known as having non-cholinergic functions such as cellular
proliferation and differentiation, suggesting a possible influence of
cholinesterase in tumorogenesis. Thus, the aim of this study was to investigate
the whole blood acetylcholinesterase (AChE) and plasma butyrylcholinesterase
(BChE) activities and some biochemical parameters in PCa patients. This study was
performed in 66 PCa patients and 40 control subjects. AChE and BChE activities
were determined in PCa patients and the influence of the Gleason score; bone
metastasis and treatment in the enzyme activities were also verified.
Furthermore, we also analyzed possible biochemical alterations in these patients.
AChE and BChE activities decreased in PCa patients in relation to the control
group and various biochemical changes were observed in these patients. Moreover,
Gleason score, metastasis and treatment influenced cholinesterase activities and
biochemical determinations. Our results suggest that cholinesterases activities
and biochemical parameters are altered in PCa. These facts support the idea that
the drop in the cholinesterase activity and the consequent increased amount of
acetylcholine could lead to a cholinergic overstimulation and increase the cell
proliferation in PCa.
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
4. Biomed Pharmacother. 2012 Jun;66(4):249-55. doi: 10.1016/j.biopha.2011.11.005.
Epub 2011 Dec 21.
Cholinesterase activities and biochemical determinations in patients with
prostate cancer: influence of Gleason score, treatment and bone metastasis.
Battisti V, Bagatini MD, Maders LD, Chiesa J, Santos KF, Gonçalves JF, Abdalla
FH, Battisti IE, Schetinger MR, Morsch VM.
Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade
Federal de Santa Maria, Campus Universitário, 97105-900 Santa Maria, RS, Brazil.
battistivanessa@gmail.com
Prostate cancer (PCa) is the sixth most common type of cancer worldwide.
Cholinesterase is well known as having non-cholinergic functions such as cellular
proliferation and differentiation, suggesting a possible influence of
cholinesterase in tumorogenesis. Thus, the aim of this study was to investigate
the whole blood acetylcholinesterase (AChE) and plasma butyrylcholinesterase
(BChE) activities and some biochemical parameters in PCa patients. This study was
performed in 66 PCa patients and 40 control subjects. AChE and BChE activities
were determined in PCa patients and the influence of the Gleason score; bone
metastasis and treatment in the enzyme activities were also verified.
Furthermore, we also analyzed possible biochemical alterations in these patients.
AChE and BChE activities decreased in PCa patients in relation to the control
group and various biochemical changes were observed in these patients. Moreover,
Gleason score, metastasis and treatment influenced cholinesterase activities and
biochemical determinations. Our results suggest that cholinesterases activities
and biochemical parameters are altered in PCa. These facts support the idea that
the drop in the cholinesterase activity and the consequent increased amount of
acetylcholine could lead to a cholinergic overstimulation and increase the cell
proliferation in PCa.
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
1. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2012 May;28(3):253-4, 262.
[Progesterone exerts neuroprotective effect on hypoxic-ischemic
encephalopathy-induced brain damage via inhibition expression of inducible nitric
oxide synthase and nitric oxide production].
[Article in Chinese]
Wang XY, Li XJ, Li DL, Wang CR, Guo XP.
wxyinwxyin@163.com
2. Mol Reprod Dev. 2012 Oct;79(10):689-96. doi: 10.1002/mrd.22075. Epub 2012 Sep 11.
Roles of cytokines and progesterone in the regulation of the nitric oxide
generating system in bovine luteal endothelial cells.
Yoshioka S, Acosta TJ, Okuda K.
Laboratory of Reproductive Physiology, Graduate School of Natural Science and
Technology, Okayama University, Okayama, Japan.
Nitric oxide (NO) produced by luteal endothelial cells (LECs) plays important
roles in regulating corpus luteum (CL) function, yet the local mechanism
regulating NO generation in bovine CL remains unclear. The purpose of the present
study was to elucidate if tumor necrosis factor-α (TNF), interferon γ (IFNG),
and/or progesterone (P4) play roles in regulating NO generating system in LECs.
Cultured bovine LECs obtained from the CL at the mid-luteal stage (Days 8-12 of
the cycle) were treated for 24 hr with TNF (2.9 nM), IFNG (2.5 nM), or P4
(0.032-32 µM). NO production was increased by TNF and IFNG, but decreased by P4
(P < 0.05). TNF and IFNG stimulated the relative steady-state amounts of
inducible nitric oxide synthase (iNOS) mRNA and iNOS protein expression
(P < 0.05), whereas P4 inhibited relative steady-state amounts of iNOS mRNA and
iNOS protein expression (P < 0.05). In contrast, endothelial nitric oxide
synthase (eNOS) expression was not affected by any treatment. TNF and IFNG
stimulated NOS activity (P < 0.05) and 1400W, a specific inhibitor of iNOS,
reduced NO production stimulated by TNF and IFNG in LECs (P < 0.05). Onapristone,
a specific P4 receptor antagonist, blocked the inhibitory effect of P4 on NO
production in LECs (P < 0.05). The overall findings suggest that TNF and IFNG
accelerate luteolysis by increasing NO production via stimulation of iNOS
expression and NOS activity in bovine LECs. P4, on the other hand, may act in
maintaining CL function by suppressing iNOS expression in bovine LECs. Mol.
Reprod. Dev. 79: 689-696, 2012. © 2012 Wiley Periodicals, Inc.
Copyright © 2012 Wiley Periodicals, Inc.
3. J Neurochem. 2012 Jul;122(1):185-95. doi: 10.1111/j.1471-4159.2012.07753.x.
Progesterone prevents mitochondrial dysfunction in the spinal cord of wobbler
mice.
Deniselle MC, Carreras MC, Garay L, Gargiulo-Monachelli G, Meyer M, Poderoso JJ,
De Nicola AF.
Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina
Experimental-CONICET, Buenos Aires, Argentina.
In the Wobbler mouse, a mutation of the Vps54 protein increases oxidative stress
in spinal motoneurons, associated to toxic levels of nitric oxide and
hyperactivity of nitric oxide synthase (NOS). Progesterone neuroprotection has
been reported for several CNS diseases, including the Wobbler mouse
neurodegeneration. In the present study, we analyzed progesterone effects on
mitochondrial-associated parameters of symptomatic Wobbler mice. The activities
of mitochondrial respiratory chain complexes I, II-III and IV and protein levels
of mitochondrial and cytosolic NOS were determined in cervical and lumbar cords
from control, Wobbler and Wobbler mice receiving a progesterone implant for 18
days. We found a significant reduction of complex I and II-III activities in
mitochondria and increased protein levels of mitochondrial, but not cytosolic
nNOS, in the cervical cord of Wobbler mice. Progesterone treatment prevented the
reduction of complex I in the cervical region and the increased level of
mitochondrial nNOS. Wobbler motoneurons also showed accumulation of amyloid
precursor protein immunoreactivity and decreased activity and immunostaining of
MnSOD. Progesterone treatment avoided these abnormalities. Therefore,
administration of progesterone to clinically afflicted Wobblers (i) prevented the
abnormal increase of mitochondrial nNOS and normalized respiratory complex I;
(ii) decreased amyloid precursor protein accumulation, a sign of axonal
degeneration, and (iii) increased superoxide dismutation. Thus, progesterone
neuroprotection decreases mitochondriopathy of Wobbler mouse cervical spinal
cord.
© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for
Neurochemistry.
Comp Biochem Physiol C. 1993 Sep;106(1):125-9. The role of the neurotransmitters acetylcholine and noradrenaline in the pathogenesis of stress ulcers. Gatón J, Fernández de la Gándara F, Velasco A.
People with Cloninger's "harm avoidance" personality trait, which is closely associated with serotonin (Hansenne, et al., 1999), are more likely to develop dementia (Clément, et al., 2010). These observations are consistent with the stress-susceptibility of people with high serotonin exposure, and to the effects of cortisol on nerves and glucose-derived energy production.
Jpn J Surg. 1991 Jan;21(1):43-9.
Participation of the parasympathetic nervous system in the development of
activity-stress ulcers.
Doi K, Iwahashi K, Tsunekawa K.17. J Auton Nerv Syst. 1987 Oct;20(3):265-8.
Adrenergic modulation of gastric stress pathology in rats: a cholinergic link.
Ray A, Sullivan RM, Henke PG.
Department of Psychology, St. Francis Xavier University, Antigonish, Nova Scotia,
Canada.
The effects of some adrenergic drugs were evaluated on cold restraint-induced
gastric ulcers in rats. The beta-adrenergic antagonist, (+/-)-propranolol (1 and
10 mg/kg), as well as the beta-agonist, isoproterenol (0.05 and 0.5 mg/kg)
potentiated the gastric pathology. On the other hand, the alpha-agonist,
clonidine (0.5 mg/kg) attenuated and the alpha-antagonist, yohimbine (1 mg/kg)
aggravated stress ulcer development. The anticholinergic agent, atropine
methylnitrate (1 mg/kg), reduced both the frequency and severity of stress ulcers
and also antagonized the potentiating effects of (+/-)-propranolol, isoproterenol
and yohimbine. The results suggest a cholinergic role in the adrenergic
modulation of gastric stress pathology.
Psychopharmacology (Berl). 1981;74(1):81-7.
Cholinergic influences on escape deficits produced by uncontrollable stress.
Anisman H, Glazier SJ, Sklar LS.
A series of experiments assessed the potential role of acetylcholine (ACh) in the
escape interference produced by inescapable shock. Treatment with the
anticholinesterase, physostigmine, successfully mimicked the effects of
inescapable shock. That is, the drug disrupted performance when escape was
prevented for 6 s on any given trial, thereby necessitating sustained active
responding. When escape was possible upon shock onset, the drug treatment did not
influence performance. The centrally acting anticholinergic scopolamine
hydrobromide antagonized the effects of physostigmine, and when administered
prior to escape testing antagonized the disruptive effects of previously
administered inescapable shock. In contrast, the peripherally acting agent
scopolamine methylbromide did not influence the effects of these treatments,
suggesting that the effects of physostigmine and inescapable shock involved
central ACh changes. Scopolamine hydrobromide administered prior to inescapable
shock did not prevent the escape interference from subsequently appearing, but
this effect could not be attributed to state dependence. It was argued that the
interference of escape following uncontrollable stress was due to non-associative
motor deficits. Alterations of the escape deficits by scopolamine were due to
elimination of the motor disruption.
Curr Opin Oncol. 2005 Jan;17(1):55-60.
DNA methylation and cancer therapy: new developments and expectations.
Esteller M.
Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO) Madrid,
Spain. mesteller@cnio.es
PURPOSE OF REVIEW: In addition to having genetic causes, cancer can also be
considered an epigenetic disease. The main epigenetic modification is DNA
methylation, and patterns of aberrant DNA methylation are now recognized to be a
common hallmark of human tumors. One of the most characteristic features is the
inactivation of tumor-suppressor genes by CpG-island hypermethylation of the CpG
islands located in their promoter regions. These sites, among others, are the
targets of DNA-demethylating agents, the promising chemotherapeutic drugs that
are the focus of this article.
RECENT FINDINGS: Four exciting aspects have recently arisen at the forefront of
the advancements in this field: first, the development of new compounds with
DNA-demethylating capacity that are less toxic (for example, procaine) and may be
administered orally (for example, zebularine);
Science. 2013 May 10;340(6133):756-9.
Emergence of individuality in genetically identical mice.
Freund J, Brandmaier AM, Lewejohann L, Kirste I, Kritzler M, Krüger A, Sachser N,
Lindenberger U, Kempermann G.
CRTD-DFG Research Center for Regenerative Therapies Dresden, Technische
Universität Dresden, Dresden, Germany.
Comment in
Science. 2013 May 10;340(6133):695-6.
Brain plasticity as a neurobiological reflection of individuality is difficult to
capture in animal models. Inspired by behavioral-genetic investigations of human
monozygotic twins reared together, we obtained dense longitudinal activity data
on 40 inbred mice living in one large enriched environment. The exploratory
activity of the mice diverged over time, resulting in increasing individual
differences with advancing age. Individual differences in cumulative roaming
entropy, indicating the active coverage of territory, correlated positively with
individual differences in adult hippocampal neurogenesis. Our results show that
factors unfolding or emerging during development contribute to individual
differences in structural brain plasticity and behavior. The paradigm introduced
here serves as an animal model for identifying mechanisms of plasticity
underlying nonshared environmental contributions to individual differences in
behavior.
Neurobiol Aging. 1995 Jul-Aug;16(4):523-30.
Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and
histamine H2 blocking drugs.
Breitner JC, Welsh KA, Helms MJ, Gaskell PC, Gau BA, Roses AD, Pericak-Vance MA,
Saunders AM.
If each opportunity we have to choose expands our curiosity,
we go beyond our inheritance to become something unique but also universal, that is, more fully human.
J Neurobiol. 1976 Jan;7(1):75-85. Effects of environment on morphology of rat cerebral cortex and hippocampus. Diamond MC, Ingham CA, Johnson RE, Bennett EL, Rosenzweig MR.
…
strains of rats. KRECH D, ROSENZWEIG MR, BENNETT EL.…
19. Pharmacol Biochem Behav. 1986 Sep;25(3):521-6.
Cholinergic function and memory: extensive inhibition of choline
acetyltransferase fails to impair radial maze performance in rats.
Wenk G, Sweeney J, Hughey D, Carson J, Olton D.
The present study investigated the effects of a potent inhibitor of choline
acetyltransferase (ChAT), BW813U, on the choice accuracy of rats in the radial
arm maze. BW813U (100 mg/kg, IP) produced a rapid (within 1 hour) and substantial
decrease in ChAT activity throughout the brain, ranging from 66% (hippocampus) to
80% (caudate nucleus) that lasted up to 5 days. A single injection (50 mg/kg, IP)
into rats with lesions (using ibotenic acid) in the nucleus basalis
magnocellularis and medial septal area, decreased ChAT activity by 75% and 60% in
the cortex and hippocampus, respectively. Lesioned and unlesioned rats were
trained on the radial arm maze until they reached a criterion level of
performance. Each rat then received an injection of BW813U (50 or 100 mg/kg, IP).
Choice accuracy was not impaired at any time following the injection. The lack of
effect on performance may be due to 2 possible factors: The radial maze retention
paradigm chosen may not be sufficiently difficult, or the decrease in
acetylcholine production was not sufficient to affect behavior. Compensation by
non-cholinergic neural systems might account for the insensitivity of the rats to
significant cholinergic depletion.
Psychol Aging. 1988 Dec;3(4):399-406.
Genotype-environment interaction in personality development: identical twins reared apart.
Bergeman CS, Plomin R, McClearn GE, Pedersen NL, Friberg LT.
Center for Developmental and Health Genetics, Pennsylvania State University, University Park 16802.
The focus of this study is to identify specific genotype-environment (GE) interactions as they contribute to individual differences in personality in later life. In behavioral genetics, GE interaction refers to the possibility that individuals of different genotypes may respond differently to specific environments. A sample of 99 pairs of identical twins reared apart, whose average age is 59 years, has been studied as part of the Swedish Adoption/Twin Study of Aging (SATSA). Hierarchical multiple regression was used to detect interactions between personality and environmental measures after the main effects of genotype and environment were removed. Analyses yield evidence for 11 significant interactions that provide the first evidence for GE interaction in human development using specific environmental measures. Thus, in addition to the main-effect contributions of heredity and environment, GE interactions contribute to individual differences in personality as measured in the second half of the life course.
Wikipedia:Excitability and inhibition[edit source | editbeta]
Acetylcholine also has other effects on neurons. One effect is to cause a slow depolarization[citation needed] by blocking a tonically active K+
current, which increases neuronal excitability. Alternatively, acetylcholine can activate non-specific cation conductances to directly excite neurons.[10] An effect upon postsynaptic M4-muscarinic ACh receptors is to open inward-rectifier potassium ion channel (Kir) and cause inhibition.[11] The influence of acetylcholine on specific neuron types can be dependent upon the duration of cholinergic stimulation. For instance, transient exposure to acetylcholine (up to several seconds) can inhibit cortical pyramidal neurons via M1 type muscarinic receptors that are linked to Gq-type G-protein alpha subunits. M1 receptor activation can induce calcium-release from intracellular stores, which then activate a calcium-activated potassium conductance which inhibits pyramidal neuron firing.[12] On the other hand, tonic M1 receptor activation is strongly excitatory. Thus, ACh acting at one type of receptor can have multiple effects on the same postsynaptic neuron, depending on the duration of receptor activation.[13] Recent experiments in behaving animals have demonstrated that cortical neurons indeed experience both transient and persistent changes in local acetylcholine levels during cue-detection behaviors.[14]
In the cerebral cortex, tonic ACh inhibits layer 4 medium spiny neurons, the main targets of thalamocortical inputs while excitingpyramidal cells in layers 2/3 and layer 5.[11] This filters out weak sensory inputs in layer 4 and amplifies inputs that reach the layers 2/3 and layer L5 excitatory microcircuits. As a result, these layer-specific effects of ACh might function to improve the signal noise ratio of cortical processing.[11] At the same time, acetylcholine acts through nicotinic receptors to excite certain groups of inhibitory interneurons in the cortex, which further dampen down cortical activity.[15]
Role in decision making[edit source | editbeta]
One well-supported function of acetylcholine (ACh) in cortex is increased responsiveness to sensory stimuli, a form of attention.Phasic increases of ACh during visual,[16] auditory [17] and somatosensory [18] stimulus presentations have been found to increase the firing rate of neurons in the corresponding primary sensory cortices. When cholinergic neurons in the basal forebrain are lesioned, animals' ability to detect visual signals was robustly and persistently impaired.[19] In that same study, animals' ability to correctly reject non-target trials was not impaired, further supporting the interpretation that phasic ACh facilitates responsiveness to stimuli. Looking at ACh's effect on thalamocortical connections, a known pathway of sensory information, in vitro application of cholinergic agonist carbachol to mouse auditory cortex enhanced thalamocortical activity.[20] In addition, Gil et al. (1997) applied a different cholinergic agonist, nicotine, and found that activity was enhanced at thalamocortical synapses.[21]This finding provides further evidence for a facilitative role of ACh in transmission of sensory information from the thalamus to selective regions of cortex.
An additional suggested function of ACh in cortex is suppression of intracortical information transmission. Gil et al. (1997) applied the cholinergic agonist muscarine to neocortical layers and found that excitatory post-synaptic potentials between intracortical synapses were depressed.[21] In vitro application of cholinergic agonist carbachol to mouse auditory cortex suppressed intracortical activity as well.[20] Optical recording with a voltage-sensitive dye in rat visual cortical slices demonstrated significant suppression in intracortical spread of excitement in the presence of ACh.[22]
Some forms of learning and plasticity in cortex appear dependent on the presence of acetylcholine. Bear et al. (1986) found that the typical synaptic remapping in striate cortex that occurs during monocular deprivation is reduced when there is a depletion of cholinergic projections to that region of cortex.[23] Kilgard et al. (1998) found that repeated stimulation of the basal forebrain, a primary source of ACh neurons, paired with presentation of a tone at a specific frequency, resulted in remapping of the auditory cortex to better suit processing of that tone.[24]Baskerville et al. (1996) investigated the role of ACh in experience-dependent plasticity by depleting cholinergic inputs to the barrel cortex of rats.[25] The cholinergic depleted animals had a significantly reduced amount of whisker-pairing plasticity. Apart from the cortical areas, Crespo et al. (2006) found that the activation of nicotinic and muscarinic receptors in the nucleus accumbens is necessary for the acquisition of an appetitive task.[26]
ACh has been implicated in the reporting of expected uncertainty in the environment [27] based both on the suggested functions listed above and results recorded while subjects perform a behavioral cuing task. Reaction time difference between correctly cued trials and incorrectly cued trials, called the cue validity, was found to vary inversely with ACh levels in primates with pharmacologically (e.g. Witte et al., 1997) and surgically (e.g. Voytko et al., 1994) altered levels of ACh.[28][29] The result was also found in Alzheimer's disease patients (Parasuraman et al., 1992) and smokers after nicotine (an ACh agonist) consumption.[30][31] The inverse covariance is consistent with the interpretation of ACh as representing expected uncertainty in the environment, further supporting this claim.
12•.^ Gulledge, AT; Stuart, GJ (2005). "Cholinergic inhibition of neocortical pyramidal neurons". Journal of Neuroscience 25 (44): 10308–20. doi:10.1523/JNEUROSCI.2697-05.2005. PMID 16267239.
^ Gulledge, AT; Bucci, DJ; Zhang, SS; Matsui, M; Yeh, HH (2009). "M1 Receptors Mediate Cholinergic Modulation of Excitability in Neocortical Pyramidal Neurons". Journal of Neuroscience 29 (31): 9888–902. doi:10.1523/JNEUROSCI.1366-09.2009.PMC 2745329. PMID 19657040.
^ Parikh, V; Kozak, R; Martinez, V; Sarter, M (2007). "Prefrontal acetylcholine release controls cue detection on multiple time scales". Neuron 56 (1): 141–54. doi:10.1016/j.neuron.2007.08.025.PMC 2084212. PMID 17920021.
^ Gulledge, AT; Park, SB; Kawaguchi, Y; Stuart, GJ (2007). "Heterogeneity of phasic cholinergic signaling in neocortical neurons".Journal of neurophysiology 97 (3): 2215–29. doi:10.1152/jn.00493.2006.PMID 17122323.
^ Spehlmann R, Daniels JC, Smathers CC (1971). "Acetylcholine and the synaptic transmission of specific impulses to the visual cortex". Brain 94 (1): 125–38. doi:10.1093/brain/94.1.125. PMID 4324030.
^ Foote SL, Freedman R, Oliver AP (March 1975). "Effects of putative neurotransmitters on neuronal activity in monkey auditory cortex". Brain Res. 86 (2): 229–42. doi:10.1016/0006-8993(75)90699-X.PMID 234774.
^ Stone TW (September 1972). "Cholinergic mechanisms in the rat somatosensory cerebral cortex". J. Physiol. (Lond.) 225 (2): 485–99. PMC 1331117. PMID 5074408.
^ McGaughy J, Kaiser T, Sarter M (April 1996). "Behavioral vigilance following infusions of 192 IgG-saporin into the basal forebrain: selectivity of the behavioral impairment and relation to cortical AChE-positive fiber density". Behav. Neurosci. 110 (2): 247–65.doi:10.1037/0735-7044.110.2.247. PMID 8731052.
^ a b Hsieh CY, Cruikshank SJ, Metherate R (October 2000). "Differential modulation of auditory thalamocortical and intracortical synaptic transmission by cholinergic agonist". Brain Res. 880 (1–2): 51–64.doi:10.1016/S0006-8993(00)02766-9.PMID 11032989.
^ a b Gil Z, Connors BW, Amitai Y (September 1997). "Differential regulation of neocortical synapses by neuromodulators and activity". Neuron 19 (3): 679–86. doi:10.1016/S0896-6273(00)80380-3.PMID 9331357.
^ Kimura F, Fukuda M, Tsumoto T (October 1999). "Acetylcholine suppresses the spread of excitation in the visual cortex revealed by optical recording: possible differential effect depending on the source of input". Eur. J. Neurosci. 11 (10): 3597–609.doi:10.1046/j.1460-9568.1999.00779.x. PMID 10564367.
^ Bear MF, Singer W (1986). "Modulation of visual cortical plasticity by acetylcholine and noradrenaline". Nature 320 (6058): 172–6.doi:10.1038/320172a0. PMID 3005879.
^ Kilgard MP, Merzenich MM (March 1998). "Cortical map reorganization enabled by nucleus basalis activity". Science 279 (5357): 1714–8. doi:10.1126/science.279.5357.1714. PMID 9497289.
^ Baskerville KA, Schweitzer JB, Herron P (October 1997). "Effects of cholinergic depletion on experience-dependent plasticity in the cortex of the rat". Neuroscience 80 (4): 1159–69. doi:10.1016/S0306-4522(97)00064-X. PMID 9284068.
^ Crespo JA, Sturm K, Saria A, Zernig G (May 2006). "Activation of muscarinic and nicotinic acetylcholine receptors in the nucleus accumbens core is necessary for the acquisition of drug reinforcement".J. Neurosci. 26 (22): 6004–10.doi:10.1523/JNEUROSCI.4494-05.2006. PMID 16738243.
^ Witte EA, Marrocco RT (August 1997). "Alteration of brain noradrenergic activity in rhesus monkeys affects the alerting component of covert orienting". Psychopharmacology (Berl.) 132 (4): 315–23.doi:10.1007/s002130050351. PMID 9298508.
^ Voytko ML, Olton DS, Richardson RT, Gorman LK, Tobin JR, Price DL (January 1994). "Basal forebrain lesions in monkeys disrupt attention but not learning and memory". J. Neurosci. 14 (1): 167–86.PMID 8283232.
1. Pharmacol Res. 2011 Jun;63(6):525-31.
Endothelin receptor antagonists: potential in Alzheimer's disease.
Palmer J, Love S.
Dementia Research Group, Institute of Clinical Neurosciences, School of Clinical
Sciences, University of Bristol, Frenchay Hospital, Bristol BS16 1LE, United
Kingdom. jen.palmer@bristol.ac.uk
Alzheimer's disease (AD) is believed to be initiated by the accumulation of
neurotoxic forms of Aβ peptide within the brain. AD patients show reduction of
cerebral blood flow (CBF), the extent of the reduction correlating with the
impairment of cognition. There is evidence that cerebral hypoperfusion precedes
and may even trigger the onset of dementia in AD. Cerebral hypoperfusion impairs
neuronal function, reduces the clearance of Aβ peptide and other toxic
metabolites from the brain, and upregulates Aβ production. Studies in animal
models of AD have shown the reduction in CBF to be more than would be expected
for the reduction in neuronal metabolic activity. Aβ may contribute to the
reduction in CBF in AD, as both Aβâ‚â‚‹â‚„â‚€ and Aβâ‚â‚‹â‚„â‚‚ induce cerebrovascular
dysfunction. Aβâ‚â‚‹â‚„â‚€ acts directly on cerebral arteries to cause cerebral smooth
muscle cell contraction. Aβâ‚â‚‹â‚„â‚‚ causes increased neuronal production and release
of endothelin-1 (ET-1), a potent vasoconstrictor, and upregulation of
endothelin-converting enzyme-2 (ECE-2), the enzyme which cleaves ET-1 from its
inactive precursor. ET-1 and ECE-2 are also elevated in AD, making it likely that
upregulation of the ECE-2-ET-1 axis by Aβâ‚â‚‹â‚„â‚‚ contributes to the chronic
reduction of CBF in AD. At present, only a few symptomatic treatment options
exist for AD. The involvement of ET-1 in the pathogenesis of endothelial
dysfunction associated with elevated Aβ indicates the potential for endothelin
receptor antagonists in the treatment of AD. It has already been demonstrated
that the endothelin receptor antagonist bosentan, preserves aortic and carotid
endothelial function in Tg2576 mice, and our findings suggest that endothelin
receptor antagonists may be beneficial in maintaining CBF in AD.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Fiziol Zh SSSR Im I M Sechenova. 1975 Oct;61(10):1466-72.
[Amine receptors in brain vessels].
[Article in Russian]
Edvinsson L, Owman Ch.
Isolated middle cerebral arteries from cats and pial arteries from humans
(obtained during lobe resection) were studied in a sensitive in vitro system
allowing a detailed pharmacological characterization of various amine receptors
and related dissociation constants. It was found that the adrenergic receptors
comprise contractile (alpha) and dilatory (beta) receptors. Acetylcholine induced
dilation (at low doses) as well as constriction (at high doses) both responses
being inhibited in a comparative way by atropine. Experiments with selective
inhibitors showed the presence of specific histamine H2 (dilatory) receptors; at
high doses histamine contracted the vessels in a non-specific way.
5-Hydroxytryptamine was the most efficient vasoconstrictor agent, and the
response could be blocked by the serotonin-antagonist, methysergide.
Behav Neurosci. 2007 Jun;121(3):491-500.
Exposure to enriched environment improves spatial learning performances and enhances cell density but not choline acetyltransferase activity in the hippocampus of ventral subicular-lesioned rats.
Dhanushkodi A, Bindu B, Raju TR, Kutty BM.
Department of NeurophysiologyNational Institute of Mental Health and Neuro Sciences (NIMHANS Deemed University), Bangalore, India.
The authors demonstrated the efficacy of enriched housing conditions in promoting the behavioral recovery and neuronal survival following subicular lesion in rats. Chemical lesioning of the ventral subiculum impaired the spatial learning performances in rats. The lesion also induced a significant degree of neurodegeneration in the CA1 and CA3 areas of the hippocampus and entorhinal cortex. Exposure to enriched housing conditions improved the behavioral performance and partially attenuated the neurodegeneration in the hippocampus. The choline acetyl transferase (ChAT) activity in the hippocampus remained unchanged following ventral subicular lesion and also following exposure to an enriched environment. The study implicates the effectiveness of activity-dependent neuronal plasticity induced by environmental enrichment in adulthood following brain insult.
Copyright (c) 2007 APA, all rights reserved.
Horm Behav. 2013 Jul 27. pii: S0018-506X(13)00139-6.
Progesterone and vitamin D: Improvement after traumatic brain injury in middle-aged rats.
Tang H, Hua F, Wang J, Sayeed I, Wang X, Chen Z, Yousuf S, Atif F, Stein DG.
Department of Emergency Medicine, Emory University, Atlanta, GA 30322, USA.
Progesterone (PROG) and vitamin D hormone (VDH) have both shown promise in treating traumatic brain injury (TBI). Both modulate apoptosis, inflammation, oxidative stress, andexcitotoxicity. We investigated whether 21days of VDH deficiency would alter cognitive behavior after TBI and whether combined PROG and VDH would improve behavioral and morphological outcomes more than either hormone alone in VDH-deficient middle-aged rats given bilateral contusions of the medial frontal cortex. PROG (16mg/kg) and VDH (5μg/kg) were injected intraperitoneally 1h post-injury. Eight additional doses of PROG were injected subcutaneously over 7days post-injury. VDH deficiency itself did not significantly reduce baseline behavioral functions or aggravate impaired cognitive outcomes. Combination therapy showed moderate improvement in preserving spatial and reference memory but was not significantly better than PROG monotherapy. However, combination therapy significantly reduced neuronal loss and the proliferation of reactive astrocytes, and showed better efficacy compared to VDH or PROG alone in preventing MAP-2 degradation. VDH+PROG combination therapy may attenuate some of the potential long-term, subtle, pathophysiological consequences of brain injury in older subjects.
© 2013.
KEYWORDS:
Yang, glutamate stimulates DNA repair; methylation of dna during stress, hydrophobic
Life Sci 1998;62(17-18):1717-21
Induction of inducible nitric oxide synthase and heme oxygenase-1 in
rat glial cells.
Kitamura Y, Matsuoka Y, Nomura Y, Taniguchi T
Department of Neurobiology, Kyoto Pharmaceutical University, Japan.
Recent observations suggest a possible interaction between the nitric oxide (NO)/NO synthases and carbon monoxide (CO)/heme oxygenases systems. We examined the effects of lipopolysaccharide (LPS), interferon-gamma (IFN-gamma), and NO donor such as S-nitroso-N-acetylpenicillamine (SNAP) on induction of inducible NO synthase (iNOS) and heme oxygenase-1 (HO-1) in mixed glial cells and in rat hippocampus. In in vitro glial cells, treatment with LPS induced the expression of 130-kDa iNOS after 6
h, and NO2- accumulation and enhancement of the protein level of 33-kDa HO-1 after 12 h. In addition, treatment with SNAP induced HO-1 expression after 6 h. Although a NOS inhibitor, such as N(G)-nitro-L-arginine (NNA), did not change LPS-induced iNOS expression, the inhibitor suppressed both NO2- accumulation and the enhancement of HO-1. Immunocytochemistry showed that LPS-treatment induced iNOS-immunoreactivity predominantly in microglia, while this treatment induced HO-1-immunoreactivity in both microglia and astrocytes. These results suggest that endogenous NO production by iNOS in microglia causes autocrine- and paracrine-induction of HO-1 protein in microglia
and astrocytes in rat brain.
4. Proc Soc Exp Biol Med. 1994 Oct;207(1):43-7.
Dietary restriction modulates the norepinephrine content and uptake of the heart
and cardiac synaptosomes.
Kim SW, Yu BP, Sanderford M, Herlihy JT.
Department of Physiology, University of Texas Health Science Center at San
Antonio 78284.
The present study was designed to examine the effects of long-term dietary
restriction on cardiac sympathetic nerves and neurotransmitter. The food intake
of male, 6-week-old Fischer 344 rats was reduced to 60% of the intake of control
rats fed ad libitum. The body and heart weights of rats diet restricted for 4.5
months were less than those of the ad libitum fed animals, while the heart weight
to body weight ratios were higher. The norepinephrine (NE) content of hearts from
restricted rats (1073 +/- 84 ng/g wet wt) was higher than controls (774 +/- 38
ng/g wet wt), although the total amount of NE per heart was unchanged. Similarly,
the cardiac synaptosomal P2 fraction from restricted rats possessed a higher NE
content (24.1 +/- 2.4 ng/mg protein) than the P2 fraction of ad libitum fed
controls (13.7 +/- 1.3 ng/mg protein). The desmethylimipramine-sensitive
norepinephrine uptake of the P2 fraction from restricted rats was significantly
higher than that of control rats (9.44 +/- 1.33 vs 4.75 +/- 0.35 ng/mg
protein/hr). The NE uptakes of the two groups were similar when uptake was
normalized to endogenous NE levels. These results demonstrate that long-term
dietary restriction affects cardiac sympathetic nerve endings and suggest that
part of the beneficial action of life-long dietary restriction on the age-related
decline in cardiovascular regulation may be related to changes in cardiac
sympathetic nerves.
Int J Cancer. 1985 Apr 15;35(4):493-7.
Muscarinic cholinergic receptors in pancreatic acinar carcinoma of rat.
Taton G, Delhaye M, Swillens S, Morisset J, Larose L, Longnecker DS, Poirier GG.
The active enantiomer of tritiated quinuclidinyl benzilate (3H(-)QNB) was used as
a ligand to evaluate the muscarinic receptors. The 3H(-)QNB binding
characteristics of muscarinic cholinergic receptors obtained from normal and
neoplastic tissues were studied to determine changes in receptor properties
during neoplastic transformation. Saturable and stereospecific binding sites for
3H(-)QNB are present in homogenates of rat pancreatic adenocarcinoma. The
proportions of high- and low-affinity agonist binding sites are similar for
neoplastic and normal tissues. The density of muscarinic receptors is higher in
neoplastic (200 femtomoles/mg protein) than in normal pancreatic homogenates (80
femtomoles/mg protein). The muscarinic binding sites of the neoplastic and fetal
pancreas show similar KD values which are higher than those observed for normal
pancreas.
17: Cancer Res. 1986 Nov;46(11):5706-14.
Muscarinic receptor coupling to intracellular calcium release in rat pancreatic
acinar carcinoma.
Chien JL, Warren JR.
Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of
cholinergic receptor protein affinity labeled with the muscarinic antagonist
[3H]propylbenzilylcholine mustard revealed a major polypeptide with molecular
weight of 80,000-83,000 in both acinar carcinoma and normal acinar cells of rat
pancreas. Muscarinic receptor protein is therefore conserved in pancreatic acinar
carcinoma. A small but significant difference was detected in the affinity of
carcinoma cell receptors (Kd approximately 0.6 nM) and normal cell receptors (Kd
approximately 0.3 nM) for reversible binding of the muscarinic antagonist drug,
N-methylscopolamine. In addition, carcinoma cell muscarinic receptors displayed
homogeneous binding of the agonist drugs carbamylcholine (Kd approximately 31
microM) and oxotremorine (Kd approximately 4 microM), whereas normal cell
receptors demonstrated heterogeneous binding, with a minor receptor population
showing high affinity binding for carbamylcholine (Kd approximately 3 microM) and
oxotremorine (Kd approximately 160 nM), and a major population showing low
affinity binding for carbamylcholine (Kd approximately 110 microM) and
oxotremorine (Kd approximately 18 microM). Both carcinoma and normal cells
exhibited concentration-dependent carbamylcholine-stimulated increases in
cytosolic free Ca2+, as measured by 45Ca2+ outflux assay and intracellular quin 2
fluorescence. However, carcinoma cells were observed to be more sensitive to Ca2+
mobilizing actions of submaximal carbamylcholine concentrations, demonstrating
50% maximal stimulation of intracellular Ca2+ release at a carbamylcholine
concentration (approximately 0.4 microM) approximately one order of magnitude
below that seen for normal cells. These results indicate altered muscarinic
receptor coupling to intracellular Ca2+ release in acinar carcinoma cells, which
manifests as a single activated receptor state for agonist binding, and increased
sensitivity of Ca2+ release in response to muscarinic receptor stimulation.
1: Anticancer Drugs. 2008 Aug;19(7):655-71.
Neurotransmission and cancer: implications for prevention and therapy.
Schuller HM.
Experimental Oncology Laboratory, Department of Pathobiology, College of
Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN
37996, USA. hmsch@utk.edu
Published evidence compiled in this review supports the hypothesis that the
development, progression, and responsiveness to prevention and therapy of the
most common human cancers is strongly influenced, if not entirely orchestrated,
by an imbalance in stimulatory and inhibitory neurotransmission. The
neurotransmitters acetylcholine, adrenaline, and noradrenaline of the autonomic
nervous system act as powerful upstream regulators that orchestrate numerous cell
and tissue functions, by releasing growth factors, angiogenesis factors and
metastasis factors, arachidonic acid, proinflammatory cytokines, and local
neurotransmitters from cancer cells and their microenvironment. In addition, they
modulate proliferation, apoptosis, angiogenesis, and metastasis of cancer
directly by intracellular signaling downstream of neurotransmitter receptors.
Nicotine and the tobacco-specific nitrosamines have the documented ability to
hyperstimulate neurotransmission by both branches of the autonomic nervous
system. The expression and function of these neurotransmitter pathways are cell
type specific. Lifestyle, diet, diseases, stress, and pharmacological treatments
modulate the expression and responsiveness of neurotransmitter pathways. Current
preclinical testing systems fail to incorporate the modulating effects of
neurotransmission on the responsiveness to anticancer agents and should be
amended accordingly. The neurotransmitter gamma-aminobutyric acid has a strong
inhibitory function on sympathicus-driven cancers whereas stimulators of cyclic
adenosine monophosphate/protein kinase A signaling have strong inhibitory
function on parasympathicus-driven cancers. Marker-guided restoration of the
physiological balance in stimulatory and inhibitory neurotransmission represents
a promising and hitherto neglected strategy for the prevention and therapy of
neurotransmitter-responsive cancers.
Psychological stress in IBD: new insights into pathogenic and ...
www.ncbi.nlm.nih.gov › Journal List › Gut › v.54(10); Oct 2005
by JE Mawdsley - 2005 - Cited by 255 - Related articles
Psychological stress has long been reported anecdotally to increase disease ..... atropine and was more marked in cholinesterase deficient Wistar-Kyoto rats.
Neuropsychopharmacology. 2002 May;26(5):672-81.
Sexual diergism of hypothalamo-pituitary-adrenal cortical responses to low-dose
physotigmine in elderly vs. young women and men.
Rubin RT, Rhodes ME, O'Toole S, Czambel RK.
Center for Neurosciences Research, MCP Hahnemann University School of Medicine,
Allegheny General Hospital, Pittsburgh, PA 15212, USA. rubin@wpahs.org
We previously demonstrated that the reversible cholinesterase inhibitor,
physostigmine (PHYSO), administered to normal young adult women and men (average
age 35 years) at a dose that produced few or no side effects, resulted in a sex
difference (sexual diergism) in hypothalamo-pituitary-adrenal cortical (HPA)
axis responses: Plasma ACTH(1-39), cortisol, and arginine vasopressin (AVP)
concentrations increased to a significantly greater extent in the men than in
the women. To explore the effect of age on these sexually diergic hormone
responses, in the present study we used the same dose of PHYSO (8 microg/kg IV)
to stimulate ACTH(1-39), cortisol, and AVP secretion in normal elderly,
non-estrogen-replaced women and elderly men (average ages 73 years and 70 years,
respectively). The subjects underwent three test sessions 5-7 days apart: PHYSO,
saline control, and a second session of PHYSO. Serial blood samples were taken
for hormone analyses before and after pharmacologic challenge.As with the
previously studied younger subjects, PHYSO administration produced no side
effects in about half the elderly subjects and mild side effects in the other
half, with no significant female-male differences. The hormone responses were
2-5 fold greater in the elderly subjects than in the younger subjects, but in
contrast to the younger subjects, the elderly men did not have significantly
greater hormone responses to PHYSO administration than did the elderly women.
The ACTH(1-39) and AVP responses to PHYSO for the two sessions were
significantly positively correlated in the men (+0.96, +0.91) but not in the
women. None of the hormone responses was significantly correlated with the
presence or absence of side effects in either group of subjects.These results
indicate a greater sensitivity of the HPA axis to low-dose PHYSO, and a loss of
overall sex differences in hormone responses, in elderly compared with younger
subjects. The lack of a difference in side effects between the elderly women and
men and the lack of significant correlations between presence or absence of side
effects and hormone responses suggest that the increase in hormone responses
with aging is due to correspondingly increased responsiveness of central
cholinergic systems and/or the HPA axis, and not to a nonspecific stress
response.
Horm Behav. 2013 Feb;63(2):284-90.
Progesterone and neuroprotection.
Singh M, Su C.
Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, Center FOR HER, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA. meharvan.singh@unthsc.edu
Numerous studies aimed at identifying the role of estrogen on the brain have used the ovariectomized rodent as the experimental model. And while estrogen intervention in these animals has, at least partially, restored cholinergic, neurotrophin and cognitive deficits seen in the ovariectomized animal, it is worth considering that the removal of the ovaries results in the loss of not only circulating estrogen but of circulating progesterone as well. As such, the various deficits associated with ovariectomy may be attributed to the loss of progesterone as well. Similarly, one must also consider the fact that the human menopause results in the precipitous decline of not just circulating estrogens, but in circulating progesterone as well and as such, the increased risk for diseases such as Alzheimer's disease during the postmenopausal period could also be contributed by this loss of progesterone. In fact, progesterone has been shown to exert neuroprotective effects, both in cell models, animal models and in humans. Here, we review the evidence that supports the neuroprotective effects of progesterone and discuss the various mechanisms that are thought to mediate these protective effects. We also discuss the receptor pharmacology of progesterone's neuroprotective effects and present a conceptual model of progesterone action that supports the complementary effects of membrane-associated and classical intracellular progesterone receptors. In addition, we discuss fundamental differences in the neurobiology of progesterone and the clinically used, synthetic progestin, medroxyprogesterone acetate that may offer an explanation for the negative findings of the combined estrogen/progestin arm of the Women's Health Initiative-Memory Study (WHIMS) and suggest that the type of progestin used may dictate the outcome of either pre-clinical or clinical studies that addresses brain function.
Brain Res. 2005 Jul 5;1049(1):112-9. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Pettus EH, Wright DW, Stein DG, Hoffman SW.
Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
Progesterone given after traumatic brain injury (TBI) has been shown to reduce
the initial cytotoxic surge of inflammatory factors. We used Western blot
techniques to analyze how progesterone might affect three inflammation-related
factors common to TBI: complement factor C3 (C3), glial fibrillary acidic
protein (GFAP), and nuclear factor kappa beta (NFkappaB). One hour after
bilateral injury to the medial frontal cortex, adult male rats were given
injections of progesterone (16 mg/kg) for 2 days. Brains were harvested 48 h
post-TBI, proteins were extracted from samples, each of which contained tissue
from both the contused and peri-contused areas, then measured by Western blot
densitometry. Complete C3, GFAP, and NFkappaB p65 were increased in all injured
animals. However, in animals given progesterone post-TBI, NFkappaB p65 and the
inflammatory metabolites of C3 (9 kDa and 75 kDa) were decreased in comparison
to vehicle-treated animals.
J Leukoc Biol 1996 Mar;59(3):442-50
Progesterone inhibits inducible nitric oxide synthase gene
expression and nitric oxide production in murine
macrophages.
Miller L, Alley EW, Murphy WJ, Russell SW, Hunt JS
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, USA.
The purpose of this study was to determine whether the female hormones estradiol-l7 beta (E2) and progesterone (P4) influence inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) by interferon-gamma(IFN-gamma)-and lipopolysaccharide (LPS)-activated mouse macrophages. Treatment with P4 alone caused a time- and dose-dependent inhibition of NO production by macrophage cell lines (RAW 264.7, J774) and mouse bone marrow culture-derived macrophages as assessed by nitrite accumulation. RAW 264.7 cells transiently transfected with an iNOS gene promoter/luciferase reporter-gene construct that were stimulated with IFN-gamma/LPS in the presence of P4 displayed reduced luciferase activity and NO production. Analysis of RAW 264.7 cells by Northern blot hybridization revealed concurrent P4-mediated reduction in iNOS mRNA. These observations suggest that P4-mediated inhibition of NO may be an important gender-based difference within females and males that relates to macrophage-mediated host defense.
J Reprod Immunol 1997 Nov 15;35(2):87-99
Female steroid hormones regulate production of
pro-inflammatory molecules in uterine leukocytes.
Hunt JS, Miller L, Roby KF, Huang J, Platt JS, DeBrot BL
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City 66160-7400, USA. jhunt@kumc.edu
Estrogens and progesterone could be among the environmental signals that govern uterine immune cell synthesis of pro-inflammatory substances. In order to investigate this possibility, we first mapped expression of the inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) genes in the leukocytes of cycling and pregnant mouse uteri, then tested the ability of estradiol-17 beta (E2) and progesterone to influence gene expression. Immunohistochemistry, in situ hybridization, and other experimental approaches, revealed that the iNOS and TNF-alpha genes are expressed in mouse uterine mast cells, macrophages and natural killer cells (uNK). Gene expression in each cell type was noted to be dependent upon stage of the cycle or stage of gestation, implying potential relationships with levels of female hormones and state of cell differentiation or activation. Further in vivo and in vitro experiments showed that individual hormones have cell type-specific effects on synthesis of iNOS and TNF-alpha that are exerted at the level of transcription. In uterine mast cells, iNOS and TNF-alpha are promoted by E2 whereas preliminary studies in macrophages suggest that transcription and translation
of the two genes are unaffected by E2 but are inhibited by progesterone.
Hypothyroidism increases NO; T3, vs helpless; hypothyroid, escape deficit, Levine, et 1990.
choline is increased in AD CSF Elble R;, Carriere;
Genes Nutr. 2009 December; 4(4): 309–314. Dietary polyunsaturated fatty acids improve cholinergic transmission in the aged brain Willis LM, Shukitt-Hale B, Joseph JA.
28. Bloj B, Morero RD, Farias RN, Trucco RE (1973) Membrane lipid fatty acids and regulation of membrane-bound enzymes. Allosteric behaviour of erythrocyte Mg 2+-ATPase (Na++ K+)-ATPase and acetylcholinesterase from rats fed different fat-supplemented diets. Biochim Biophys Acta 311:67–79. [PubMed]
29. Vajreswari A, Narayanareddy K (1992) Effect of dietary fats on erythrocyte membrane lipid composition and membrane-bound enzyme activities. Metabolism 41:352–358. [PubMed]
30. Vajreswari A, Rupalatha M, Rao PS (2002) Effect of altered dietary n-6-to-n-3 fatty acid ratio on erythrocyte lipid composition and membrane-bound enzymes. J Nutr Sci Vitaminol 48:365–370. [PubMed]
31. Foot M, Cruz TF, Clandinin MT (1983) Effect of dietary lipid on synaptosomal acetylcholinesterase activity. Biochem J 211:507–509. [PMC free article] [PubMed]
33. Srinivasarao P, Narayanareddy K, Vajreswari A, Rupalatha M, Prakash PS, Rao P (1997) Influence of dietary fat on the activities of subcellular membrane-bound enzymes from different regions of the brain. Neuochem Int 31:789–794. [PubMed]