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O lado sombrio do estresse (desamparo aprendido)

A acetilcolina é o "neurotransmissor" dos nervos colinérgicos, incluindo o sistema parassimpático.
A colinesterase (ou acetilcolinesterase) é uma enzima que destrói a acetilcolina, limitando a ação dos nervos colinérgicos.
A ligação de um grupo fosfato à enzima colinesterase inativa-a, prolongando e intensificando a ação da estimulação colinérgica.
O sistema nervoso autônomo tem sido tradicionalmente dividido em sistema simpático-adrenérgico e sistema parassimpático-colinérgico, com funções aproximadamente opostas, intensificando o gasto energético e limitando o gasto energético, respetivamente. O sistema hormonal e o sistema comportamental interagem com estes sistemas, e cada um dos sistemas é capaz de perturbar os demais. Os fatores de perturbação do ambiente aumentaram nas últimas décadas.

Viver é desenvolver-se; as escolhas que fazemos criam a nossa individualidade. Se ratos geneticamente idênticos crescerem num ambiente amplo e variado, pequenas diferenças na sua experiência afetarão o crescimento celular nos seus cérebros, levando a grandes diferenças no seu comportamento exploratório à medida que envelhecem (Freund, et al., 2013). Os geneticistas costumavam dizer que "os genes determinam os nossos limites", mas esse experimento mostra que um ambiente pode proporcionar tanto limitações como oportunidades para expandir o potencial herdado. Se o nosso ambiente restringe as nossas escolhas, o nosso tornar-se humano é impedido, da mesma forma que os potenciais dos ratos não foram descobertos quando foram mantidos nas caixinhas padrão de laboratório. A oportunidade de nos envolvermos de forma complexa num ambiente complexo permite-nos ser mais do que somos, mais humanamente diferenciados.

Uma série de experimentos que tiveram início na Universidade da Califórnia, em 1960, descobriu que os ratos que viviam em espaços maiores, com várias coisas para explorar, eram melhores a aprender e a resolver problemas do que os ratos que eram criados nas pequenas gaiolas normais de laboratório (Krech, et al., 1960). Estudando os seus cérebros, descobriram que a enzima colinesterase, que destrói o neurotransmissor acetilcolina, estava aumentada. Mais tarde, verificaram que a descendência destes ratos aprendia melhor do que os seus pais e que os seus cérebros continham mais colinesterase. Os seus cérebros eram também maiores, com um espessamento considerável do córtex, que é considerado a parte principalmente responsável pelo comportamento complexo, pela aprendizagem e pela inteligência.

Estes processos não se limitam à infância. Por exemplo, os taxistas londrinos que aprendem todas as ruas da cidade desenvolvem um hipocampo maior, uma área do cérebro envolvida com a memória.

A investigação dos anos 60 sobre enriquecimento ambiental coincidiu com mudanças políticas nos EUA, mas foi contra as ideias científicas dominantes da época. A partir de 1945, o governo americano iniciou uma série de projetos para desenvolver técnicas de modificação do comportamento ou de controle da mente, utilizando drogas, isolamento, privação e tortura. Na década de 1950, a psiquiatria recorria frequentemente a lobotomias (cerca de 80.000, antes de serem geralmente interrompidas na década de 1980) e à "terapia" eletroconvulsiva, e os psicólogos universitários torturavam animais, muitas vezes como parte do desenvolvimento de técnicas de controle do comportamento.

A CIA abandonou oficialmente o seu programa MK Ultra em 1967, mas foi nesse ano que Martin Seligman, da Universidade da Pensilvânia, popularizou a ideia de "desamparo aprendido". Ele descobriu que quando um animal não conseguia escapar da tortura, mesmo que por um período muito curto, muitas vezes não conseguia nem tentar escapar na próxima vez que fosse torturado. As palestras de Seligman foram assistidas por psicólogos que trabalharam em Guantánamo, e ele recebeu recentemente uma subvenção do Pentágono, sem licitação, no valor de 31 milhões de dólares, para desenvolver um programa de "aptidão abrangente do soldado", para treinar os fuzileiros navais a evitar o desamparo aprendido.

Curt Richter, já em 1957, tinha descrito o fenômeno do "desespero" em ratos ("uma reação de desespero é demonstrada por alguns ratos selvagens logo após serem agarrados na mão e impedidos de se moverem. Parecem literalmente desistir") e até como curar o seu desespero, permitindo-lhes ter uma experiência de fuga uma vez (Richter, 1957, 1958). Os ratos que normalmente seriam capazes de continuar a nadar num tanque durante dois ou três dias, muitas vezes desistiam e afogavam-se em apenas alguns minutos, depois de terem uma experiência de "estresse inevitável". Richter fez a importante descoberta de que os corações dos ratos sem esperança desaceleravam antes de morrerem, permanecendo relaxados e cheios de sangue, revelando a atividade dominante do nervo vago, secretando acetilcolina.

O sistema nervoso simpático (que secreta noradrenalina) acelera o coração e é normalmente ativado em situações de estresse, na reação de "luta ou fuga", mas esta atividade nervosa radicalmente diferente (parassimpática) não tinha sido observada anteriormente em situações de estresse. O sistema nervoso parassimpático, colinérgico, era considerado inativo durante o estresse e ativado para regular os processos de digestão, sono e reparação. Além dos nervos colinérgicos do sistema parassimpático, muitos nervos do sistema nervoso central também secretam acetilcolina, que ativa os músculos lisos, os músculos esqueléticos, as glândulas e outros nervos, tendo também alguns efeitos inibitórios. Os nervos parassimpáticos também secretam a enzima colinesterase, que destrói a acetilcolina. No entanto, muitos outros tipos de células (glóbulos vermelhos, fibroblastos, nervos simpáticos, células da medula óssea), talvez todas as células, podem secretar colinesterase.

Uma vez que os nervos colinérgicos se opõem aos nervos simpáticos, adrenérgicos, tem havido uma tendência para negligenciar os seus papéis de excitadores nervosos, quando se analisam as causas da excitotoxicidade, ou a perda de células cerebrais induzida pelo estresse. A estimulação colinérgica excessiva pode, no entanto, contribuir para a morte celular excitotóxica, por exemplo, quando é combinada com cortisol elevado e/ou hipoglicemia.

Os medicamentos que bloqueiam os efeitos estimulantes da acetilcolina (os anticolinérgicos), bem como os produtos químicos que imitam os efeitos da acetilcolina, como os inseticidas organofosforados, podem prejudicar a capacidade de pensar e de aprender. Este fato sugeriu a algumas pessoas que a demência relacionada com a idade era o resultado da deterioração dos nervos colinérgicos no cérebro. Os medicamentos que aumentam os efeitos estimulantes da acetilcolina no cérebro (através da inativação da colinesterase) foram promovidos como tratamento para a doença de Alzheimer.

Embora os inibidores à base de plantas fossem bem conhecidos, foram utilizados novos fármacos rentáveis, a começar pela Tacrina. Rapidamente se tornou evidente que a Tacrina causava graves lesões no fígado, mas não diminuía o ritmo da deterioração mental.

Como o fracasso do fármaco colinérgico Tacrina estava tornando-se conhecido, foi proposto outro fármaco, a Amantadina (e, mais tarde, o similar Memantina) para tratamento combinado. Na década de 1950, o fármaco anticolinérgico Atropina foi proposto algumas vezes para o tratamento da demência e a Amantadina, que também era considerada anticolinérgica, foi proposta para algumas doenças mentais, incluindo a doença de Creutzfeldt-Jakob (Sanders e Dunn, 1973). Deve ter parecido estranho propor a utilização de um medicamento anticolinérgico para tratar uma doença que estava sendo tratada de forma tão rentável com um medicamento pró-colinérgico, mas a Memantina passou a ser classificada como um "antagonista NMDA" anti-excitatório, para proteger os nervos colinérgicos remanescentes, pelo que, logicamente, ambos os medicamentos poderiam ser prescritos em simultâneo. O fármaco adicionado parece ter um pequeno efeito benéfico, mas não foi sugerido que este pudesse ser o resultado dos seus efeitos anticolinérgicos previamente conhecidos.

Ao longo dos anos, algumas pessoas suspeitaram que a doença de Alzheimer poderia ser causada, em parte, por uma falta de objetivo e de estímulo na sua vida, e descobriram que uma atividade significativa e interessante poderia melhorar o seu funcionamento mental. Uma vez que a ideia de um cérebro "geneticamente determinado e programado" já não é ensinada de forma tão dogmática, há um interesse crescente por esta terapia para todos os tipos de deficiências cerebrais. A analogia com a experiência de enriquecimento de Berkeley é clara, então a associação do aumento da atividade da colinesterase com a melhoria do funcionamento do cérebro deve ser de interesse.

O efeito posterior do envenenamento por gás nervoso ou inseticida foi comparado à demência da velhice. Os medicamentos anticolinérgicos são geralmente reconhecidos por protegerem contra estas toxinas. Os traumatismos crânio-encefálicos, mesmo com melhorias a curto prazo, muitas vezes iniciam um processo degenerativo a longo prazo, aumentando consideravelmente a probabilidade de demência numa idade mais avançada. Sabe-se que um processo excitotóxico colinérgico está envolvido na degeneração traumática dos nervos (Lyeth e Hayes, 1992), e o uso de fármacos anticolinérgicos tem sido recomendado há muitos anos para tratar lesões cerebrais traumáticas (por exemplo, Ward, 1950: Ruge, 1954; Hayes, et al., 1986).

Em 1976, houve um experimento (Rosellini, et al.) que estabeleceu uma ligação importante entre as experiências de enriquecimento e as experiências de desamparo aprendido. Os animais de controle nas experiências de enriquecimento estavam alojados individualmente, enquanto os outros partilhavam um recinto maior. Na experiência posterior, verificou-se que os ratos "criados em isolamento morriam subitamente quando colocados numa situação de estresse para nadar", enquanto os animais alojados em grupo eram nadadores resistentes e eficazes. O enriquecimento e a privação têm um significado biológico muito claro, e um é a negação do outro.

O aumento da colinesterase, a enzima que destrói a acetilcolina, durante o enriquecimento, serve para inativar os processos colinérgicos. Se a privação causa danos aumentando a atividade do sistema colinérgico, seria de esperar que um medicamento colinérgico pudesse substituir o estresse inevitável, como causa do desamparo aprendido, e que um medicamento anticolinérgico pudesse curar o desamparo aprendido. Esses testes foram feitos: "O tratamento com o anticolinesterásico, Fisostigmina, imitou com sucesso os efeitos do choque inevitável." "O bromidrato de escopolamina, anticolinérgico de ação central, antagonizou os efeitos da Fisostigmina e, quando administrado antes do teste de fuga, antagonizou os efeitos perturbadores do choque inevitável previamente administrado." (Anisman, et al., 1981.)

Este tipo de experimento sugere que os fármacos anticolinesterásicos que continuam a ser utilizados no tratamento da doença de Alzheimer não são biologicamente úteis. Numa newsletter anterior, discuti as alterações do hormônio do crescimento e do seu antagonista, a somatostatina, em associação com a demência: o hormônio do crescimento aumenta, a somatostatina diminui. Os nervos colinérgicos são um fator importante no deslocamento destes hormônios na direção da demência, e os medicamentos anticolinérgicos tendem a aumentar a proporção de somatostatina em relação ao hormônio do crescimento. Verificou-se que a somatostatina e a colinesterase coexistem em células nervosas individuais (Delfs, et al., 1984).

O estrogênio, que foi tão intensamente promovido como prevenção ou tratamento da doença de Alzheimer, acabou por contribuir para o seu desenvolvimento. Um dos efeitos característicos do estrogênio é o aumento do nível de hormônio do crescimento no sangue. Esta é apenas uma das muitas formas em que o estrogênio está associado à ativação colinérgica. Durante a gravidez, é importante que o útero não se contraia. A estimulação colinérgica faz com que ele se contraia; muito estrogênio ativa esse sistema e provoca aborto espontâneo se for excessivo. Uma função importante da progesterona é manter o útero relaxado durante a gravidez. No útero, e em muitos outros sistemas, a progesterona aumenta a atividade da colinesterase, removendo a acetilcolina que, sob a influência do estrogênio, provocaria a contração do útero.

A progesterona está sendo usada para tratar lesões cerebrais com muito sucesso. Ele protege contra a inflamação e, num estudo inicial, comparado ao placebo, reduziu a mortalidade por mais da metade. É instrutivo considerar o seu papel anticolinérgico no útero, em relação aos seus efeitos protetores do cérebro. Quando o cérebro é envenenado por um inseticida organofosforado, que reduz a atividade da colinesterase, é provável que ocorram convulsões, e o tratamento com progesterona pode prevenir essas convulsões, revertendo a inibição da enzima (e aumentando a atividade da colinesterase em ratos que não foram envenenados) (Joshi, et al., 2010). Efeitos semelhantes da progesterona sobre a colinesterase ocorrem em mulheres com ciclos menstruais (Fairbrother, et al., 1989), sugerindo que esta é uma função geral da progesterona e não apenas algo que protege a gravidez. O estrogênio, com generalidade semelhante, diminui a atividade da colinesterase. A DHEA (dehidroepiandrosterona), tal como a progesterona, aumenta a atividade da colinesterase e protege o cérebro (Aly, et al., 2011).

O trauma cerebral leva consistentemente à diminuição da atividade dessa enzima (Östberg, et al., 2011; Donat, et al., 2007), provocando a acumulação da acetilcolina produzida no cérebro, com muitas consequências interessantes. Em 1997, um grupo (Pike, et al.) criou lesões cerebrais em ratos para testar a ideia de que um inibidor da colinesterase melhoraria sua recuperação e capacidade de se mover por um labirinto. Em vez disso, descobriram que o inibidor reduzia a capacidade cognitiva tanto dos ratos lesionados como dos normais. Um grupo diferente (Zhu, et al., 2000) descobriu que um fármaco anticolinérgico, a Selegilina (Deprenyl), utilizado no tratamento da doença de Parkinson e, informalmente, como fármaco anti-envelhecimento que altera o humor, melhora a recuperação cognitiva de lesões cerebrais.

Uma das funções importantes da acetilcolina, tanto no cérebro como em outros locais, é o relaxamento dos vasos sanguíneos, o que é feito através da ativação da síntese de NO, óxido nítrico. (Sem NO, a acetilcolina contrai os vasos sanguíneos; Librizzi, et al., 2000.) O controle básico do fluxo sanguíneo no cérebro é o resultado do relaxamento da parede dos vasos sanguíneos na presença de dióxido de carbono, que é produzido em proporção à taxa na qual o oxigênio e a glicose estão sendo metabolicamente combinados pelas células ativas. Na incapacidade de as células produzirem CO2 a um ritmo normal, a síntese de óxido nítrico nos vasos sanguíneos pode provocar a sua dilatação. O mecanismo de relaxamento pelo NO é, no entanto, muito diferente, envolvendo a inibição da produção de energia mitocondrial (Barron, et al., 2001). As situações que favorecem a produção e retenção de uma maior quantidade de dióxido de carbono nos tecidos tendem a reduzir o "tônus" básico do sistema nervoso parassimpático, uma vez que há menor necessidade de vasodilatação adicional.

O óxido nítrico pode difundir-se para fora dos vasos sanguíneos, afetando o metabolismo energético das células nervosas (Steinert, et al., 2010). Normalmente, os astrócitos protegem as células nervosas do óxido nítrico (Chen, et al., 2001), mas essa função pode ser alterada, por exemplo, pela endotoxina bacteriana absorvida pelo intestino (Solà, et al., 2002) ou pela beta-amilóide (Tran, 2001), levando-os a produzir óxido nítrico.

O óxido nítrico é cada vez mais considerado como um fator importante na degeneração dos nervos (Doherty, 2011). O óxido nítrico ativa processos (Obukuro, et al., 2013) que podem levar à morte celular. A inibição da produção de óxido nítrico protege contra vários tipos de demência (Sharma & Sharma, 2013; Sharma & Singh, 2013). O trauma cerebral causa um grande aumento da formação de óxido nítrico, e o bloqueio da sua síntese melhora a recuperação (Hüttemann, et al., 2008; Gahm, et al., 2006). Os organofosforados aumentam a formação de óxido nítrico e os fármacos anticolinérgicos protetores, como a atropina, reduzem-na (Chang, et al., 2001; Kim, et al., 1997). O estresse, incluindo o medo (Campos, et al., 2013) e o isolamento (Zlatković & Filipović, 2013) podem ativar a formação de óxido nítrico, e vários mediadores da inflamação também o ativam. O óxido nítrico na respiração exalada de uma pessoa pode ser usado para diagnosticar algumas doenças e provavelmente também reflete o nível do seu bem-estar emocional.

O aumento da colinesterase pela vida enriquecida serve para proteger os tecidos contra o acúmulo de acetilcolina. A ativação da síntese de óxido nítrico pela acetilcolina tende a bloquear a produção de energia e a ativar processos autolíticos ou catabólicos, que provavelmente estão envolvidos no desenvolvimento de um córtex cerebral mais fino em animais isolados ou estressados. Ao decompor rapidamente a acetilcolina, os processos de renovação dos tecidos podem predominar nos animais enriquecidos.

As condições ambientais favoráveis à produção de energia respiratória são protetoras contra o desamparo aprendido e a neurodegeneração, bem como contra outros problemas biológicos que envolvem os mesmos mecanismos. A adaptação à altitude elevada, que estimula a formação de novas mitocôndrias e o aumento da atividade da tireoide (T3), é utilizada há muitos anos para tratar problemas neurológicos, tendo o efeito sido demonstrado em experiências com animais (Manukhina, et al., 2010). A luz brilhante pode reverter os efeitos colinérgicos do estresse inevitável (Flemmer, et al., 1990).

Durante o desenvolvimento do desamparo aprendido, o nível de T3 no sangue diminui (Helmreich, et al., 2006), e a remoção da glândula tireoide cria o "déficit de fuga", enquanto a suplementação com hormônio tireoide antes de expor o animal a um choque inevitável evita seu desenvolvimento (Levine, et al., 1990). Depois de ter sido criado o desamparo aprendido nos ratos, a suplementação com T3 o reverte (Massol, et al., 1987, 1988).

O hipotireoidismo e o excesso de tônus colinérgico têm muitas semelhanças, incluindo o aumento da formação de óxido nítrico, de modo que sintomas semelhantes, como a inflamação muscular, podem ser produzidos por inibidores da colinesterase, como a tacrina, pelo aumento do óxido nítrico ou pelo simples hipotireoidismo (Jeyarasasingam, et al., 2000; Franco, et al., 2006).

Suspeita-se que a exposição a inseticidas seja um fator no aumento da incidência da doença de Alzheimer (Zaganas, et al., 2013), mas pode estar contribuindo para muitos outros problemas, envolvendo inflamação, edema e degeneração. Outra fonte importante de envenenamento por organofosforados é o ar utilizado para pressurizar os aviões, que pode estar contaminado com vapores de organofosforados provenientes do motor usado para comprimi-lo.

Possivelmente, o componente mais tóxico do nosso ambiente é a forma como a sociedade foi projetada, para eliminar escolhas significativas para a maioria das pessoas. Na experiência de Freund, et al., alguns ratos tornaram-se mais exploradores devido às escolhas que fizeram, enquanto a vida de outros se tornou mais rotineira e limitada. A nossa cultura reforça a vida rotineira. Na ausência de oportunidades para variar a forma como se trabalha e vive de acordo com os novos conhecimentos adquiridos, os fatores nutricionais, hormonais e físicos têm especial importância.

Está provado que os suplementos de tireoide e de progesterona geralmente protegem contra as ameaças colinérgicas, mas existem muitos outros fatores que podem ser ajustados de acordo com as necessidades específicas. A niacinamida, tal como a progesterona, inibe a produção de óxido nítrico e, tal como a progesterona, melhora a recuperação de lesões cerebrais (Hoane, et al., 2008). Em ratos geneticamente modificados com uma característica de Alzheimer, a niacinamida corrige o defeito (Green, et al., 2008). Medicamentos como a atropina e os anti-histamínicos podem ser utilizados em situações de crise. A luz brilhante, sem excesso de ultravioleta, deve estar disponível todos os dias.

O sistema colinérgico é muito mais do que uma parte do sistema nervoso e está envolvido no metabolismo celular e na renovação dos tecidos. A maioria das pessoas pode se beneficiar da redução da ingestão de fosfato, ferro e gorduras poli-insaturadas (que podem inibir a colinesterase; Willis, et al., 2009) e da escolha de alimentos que reduzem a produção e a absorção de endotoxinas. E, obviamente, devem ser evitados os medicamentos que têm como objetivo aumentar os efeitos do óxido nítrico (Asparagina, Sildenafila/Viagra, Minoxidil/Rogaine) e da acetilcolina (Betanecol, Benzpyrinium, etc.).

Texto original traduzido por Elias Heinzen

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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. ZlatkoviÄ‡ J, FilipoviÄ‡ D.

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.

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.

[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."

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.

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.

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.

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.