title: SN56 basal forebrain cholinergic neuronal loss after acute and long-term chlorpyrifos exposure through oxidative stress generation; P75(NTR) and α7-nAChRs alterations mediated partially by AChE variants disruption.
abstract: 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(NTR) and the α7-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(NTR) and α7-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 24h and 14days CPF exposure in vitro. This study shows that CPF upregulated P75(NTR) and downregulated α7-nAChRs expression, which increased H2O2 and malondialdehyde content and reduced cell viability partially through AChE variants induction. Alpha7-nAChRs repression induced oxidative stress and cell death partially through this mechanism, but P75(NTR) 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.
authors.affiliation: Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain. Electronic address: jdelpino@pdi.ucm.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Del Pino
authors.affiliation: Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041 Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Moyano
authors.affiliation: Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041 Madrid, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Anadon
authors.affiliation: Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041 Madrid, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: García
authors.affiliation: Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Díaz
authors.affiliation: Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041 Madrid, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Gómez
authors.affiliation: Department of Pharmacology, Health Sciences School, Alfonso X University, 28691 Madrid, Spain.
authors.forename: Jimena
authors.initials: J
authors.lastname: García
authors.affiliation: Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Frejo
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D066187:Basal Forebrain / Q000187:drug effects* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004390:Chlorpyrifos / Q000633:toxicity*; D059329:Cholinergic Neurons / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006861:Hydrogen Peroxide / Q000378:metabolism; D007306:Insecticides / Q000633:toxicity*; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D020800:Receptor, Nerve Growth Factor / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics
chemical_list: D007306:Insecticides; D020800:Receptor, Nerve Growth Factor; D064569:alpha7 Nicotinic Acetylcholine Receptor; D008315:Malondialdehyde; D006861:Hydrogen Peroxide; D004390:Chlorpyrifos; D000109:Acetylcholine
keywords: Acetylcholine; Acetylcholine esterase; Basal forebrain neurons; Cell death; Chlorpyrifos; Oxidative stress; P75(NTR); α(7)-nAChRs