SN56 basal forebrain cholinergic neuronal loss after acute and long-term chlorpyrifos exposure through oxidative stress generation; P75<sup>NTRsup> and α<sub>7sub>-nAChRs alterations mediated partially by AChE variants disruption
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- 作者：Javier del Pino<sup>asup><sup> ; sup><sup>1sup><sup> ; sup><sup>jdelpino@pdi.ucm.es" class="auth_mail" title="E-mail the corresponding authorsup> ; Paula Moyano<sup>bsup><sup> ; sup><sup>1sup> ; Marí ; a José ; Anadon<sup>bsup> ; José ; Manuel Garcí ; a<sup>bsup> ; Marí ; a Jesú ; s Dí ; az<sup>asup> ; Gloria Gó ; mez<sup>bsup> ; Jimena Garcí ; a<sup>csup> ; Marí ; a Teresa Frejo<sup>asup>
- 关键词：Ach ; acetylcholine ; AChE ; acetylcholine esterase ; AD ; Alzheirmer&rsquo ; s disease ; α7-nAChRs ; 7-nicotinic acetylcholine receptors ; BSA ; bovine serum albumin ; CPF ; chlorpyrifos ; DMEM ; Dulbecco&rsquo ; s Modified Eagle&rsquo ; s Medium ; DMSO ; dimethylsulphoxide ; FBS ; fetal bovine serum ; MTT ; 3-[4 ; 5-dimethylthiazol-2-yl]-2 ; 5-diphenyl-tetrazolium bromide ; NAC ; N-acetylcysteine ; OP ; organophosphates ; P75NTR ; P75 nerve growth factor receptors ; PBS ; phosphate-buffered saline ; ROS ; reactive oxygen species
- 刊名：Toxicology
- 出版年：2016
- 出版时间：15 April 2016
- 年：2016
- 卷：353-354
- 期：Complete
- 页码：48-57
- 全文大小：2566 K
文摘
Chlorpyrifos (CPF) is an organophosphates insecticide reported to induce, both after acute and repeated exposure, cognitive disorders and basal forebrain cholinergic neuronal loss, involved on learning and memory regulation, which could be the cause of such cognitive disorders. This neuronal loss was mediated partially by AChE variants alteration, suggesting other mechanisms are involved. In this regard, CPF induces oxidative stress that is implicated in the induction of cognitive deficits, changes in AChE variants expression and neuronal loss. Otherwise, it has been shown that P75<sup>NTRsup> and the α<sub>7sub>-nAChRs expression is altered in basal forebrain of rats after CPF long-term exposure; this alteration has been related with oxidative stress induction, cholinergic cell loss, and disruption of learning and memory processes. According to these data, we hypothesized that CPF induces basal forebrain cholinergic neuronal loss through induction of oxidative stress produced by P75<sup>NTRsup> and α<sub>7sub>-nAChRs altered expression, which could mediate this action in part through AChE variants disruption. We evaluated this hypothesis in septal SN56 basal forebrain cholinergic neurons, after 24 h and 14 days CPF exposure in vitro. This study shows that CPF upregulated P75<sup>NTRsup> and downregulated α<sub>7sub>-nAChRs expression, which increased H<sub>2sub>O<sub>2sub> and malondialdehyde content and reduced cell viability partially through AChE variants induction. Alpha<sub>7sub>-nAChRs repression induced oxidative stress and cell death partially through this mechanism, but P75<sup>NTRsup> overexpression did not produce these effects, although it increased oxidative stress and cell death after CPF treatment, showing that its overexpression increases cell vulnerability. Our present results provide new understanding of the mechanisms contributing to the harmful effects of CPF.