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[PMID]: | 27799295 |
[Au] Autor: | Miller SL; Aroniadou-Anderjaska V; Pidoplichko VI; Figueiredo TH; Apland JP; Krishnan JK; Braga MF |
[Ad] Endereço: | Departments of Anatomy, Physiology, and Genetics (S.L.M., V.A.-A., V.I.P., T.H.F., J.K.S.K., M.F.M.B.) and Psychiatry (V.A.-A., M.F.M.B.), and Program in Neuroscience (S.L.M., V.A.-A., M.F.M.B.), F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Mar |
[Ti] Título: | The M1 Muscarinic Receptor Antagonist VU0255035 Delays the Development of Status Epilepticus after Organophosphate Exposure and Prevents Hyperexcitability in the Basolateral Amygdala. |
[So] Source: | J Pharmacol Exp Ther;360(1):23-32, 2017 Jan. | [Is] ISSN: | 1521-0103 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | Exposure to organophosphorus toxins induces seizures that progress to status epilepticus (SE), which can cause brain damage or death. Seizures are generated by hyperstimulation of muscarinic receptors, subsequent to inhibition of acetylcholinesterase; this is followed by glutamatergic hyperactivity, which sustains and reinforces seizure activity. It has been unclear which muscarinic receptor subtypes are involved in seizure initiation and the development of SE in the early phases after exposure. Here, we show that pretreatment of rats with the selective M receptor antagonist, VU0255035 [N-(3-oxo-3-(4-(pyridine-4-yl)piperazin-1-yl)propyl)-benzo[c][1,2,5]thiadiazole-4 sulfonamide], significantly suppressed seizure severity and prevented the development of SE for about 40 minutes after exposure to paraoxon or soman, suggesting an important role of the M receptor in the early phases of seizure generation. In addition, in in vitro brain slices of the basolateral amygdala (a brain region that plays a key role in seizure initiation after nerve agent exposure), VU0255035 blocked the effects produced by bath application of paraoxon-namely, a brief barrage of spontaneous inhibitory postsynaptic currents, followed by a significant increase in the ratio of the total charge transferred by spontaneous excitatory postsynaptic currents over that of the inhibitory postsynaptic currents. Furthermore, paraoxon enhanced the hyperpolarization-activated cation current I in basolateral amygdala principal cells, which could be one of the mechanisms underlying the increased glutamatergic activity, an effect that was also blocked in the presence of VU0255035. Thus, selective M antagonists may be an efficacious pretreatment in contexts in which there is risk for exposure to organophosphates, as these antagonists will delay the development of SE long enough for medical assistance to arrive. |
[Mh] Termos MeSH primário: |
Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos Paraoxon/toxicidade Receptor Muscarínico M1/antagonistas & inibidores Soman/toxicidade Estado Epiléptico/induzido quimicamente Estado Epiléptico/prevenção & controle Sulfonamidas/farmacologia Tiadiazóis/farmacologia
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[Mh] Termos MeSH secundário: |
Animais Complexo Nuclear Basolateral da Amígdala/patologia Complexo Nuclear Basolateral da Amígdala/fisiopatologia Masculino Ratos Ratos Sprague-Dawley Estado Epiléptico/patologia Estado Epiléptico/fisiopatologia Sinapses/efeitos dos fármacos Sinapses/patologia
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (N-(3-oxo-3-(4-(pyridin-4-yl)piperazin-1-yl)propyl)benzo(c)(1,2,5)thiadiazole-4-sulfonamide); 0 (Receptor, Muscarinic M1); 0 (Sulfonamides); 0 (Thiadiazoles); 96-64-0 (Soman); Q9CX8P80JW (Paraoxon) |
[Em] Mês de entrada: | 1705 |
[Cu] Atualização por classe: | 170526 |
[Lr] Data última revisão:
| 170526 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 161102 |
[St] Status: | MEDLINE |
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