Neurotoxicity of Anhydroecgonine Methyl Ester, a Crack Cocaine Pyrolysis Product

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Tamborelli Garcia, Raphael Caio ; Munhoz Dati, Livia Mendona ; Fukuda, Suelen ; Lobo Torres, Larissa Helena ; Moura, Sidnei ^[1] ; de Carvalho, Nathalia Delazeri ^[2] ; Carrettiero, Daniel Carneiro ^[3] ; Camarini, Rosana ^[4] ; Levada-Pires, Adriana Cristina ^[5] ; Yonamine, Mauricio ; Negrini-Neto, Osvaldo ^[6] ; Francis Abdalla, Fernando Maurcio ^[2] ; Lopes Sandoval, Maria Regina ^[2] ; Afeche, Solange Castro ^[2] ; Marcourakis, Tania ^[7]

Afiliação do(s) autor(es)

^[1] Univ Caxias do Sul, Ctr Technol, Inst Biotechnol, BR-95070560 Caxias Do Sul, RS - Brazil

^[2] Butantan Inst, Pharmacol Lab, BR-05503000 Sao Paulo - Brazil

^[3] Fed Univ ABC, Nat & Human Sci Ctr, BR-09090400 Santo Andre, SP - Brazil

^[4] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, BR-05508900 Sao Paulo - Brazil

^[5] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol, BR-05508900 Sao Paulo - Brazil

^[6] Criminalist Inst Sao Paulo, BR-05507060 Sao Paulo - Brazil

^[7] Univ Sao Paulo, Fac Ciencias Farmaceut, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, BR-05508900 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: TOXICOLOGICAL SCIENCES; v. 128, n. 1, p. 223-234, JUL 2012.
• Citações Web of Science: 21

Resumo

Smoking crack cocaine involves the inhalation of cocaine and its pyrolysis product, anhydroecgonine methyl ester (AEME). Although there is evidence that cocaine is neurotoxic, the neurotoxicity of AEME has never been evaluated. AEME seems to have cholinergic agonist properties in the cardiovascular system; however, there are no reports on its effects in the central nervous system. The aim of this study was to investigate the neurotoxicity of AEME and its possible cholinergic effects in rat primary hippocampal cell cultures that were exposed to different concentrations of AEME, cocaine, and a cocaineAEME combination. We also evaluated the involvement of muscarinic cholinergic receptors in the neuronal death induced by these treatments using concomitant incubation of the cells with atropine. Neuronal injury was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. The results of the viability assays showed that AEME is a neurotoxic agent that has greater neurotoxic potential than cocaine after 24 and 48 h of exposure. We also showed that incubation for 48 h with a combination of both compounds in equipotent concentrations had an additive neurotoxic effect. Although both substances decreased cell viability in the MTT assay, only cocaine increased LDH release. Caspase-3 activity was increased after 3 and 6 h of incubation with 1mM cocaine and after 6 h of 0.1 and 1.0mM AEME exposure. Atropine prevented the AEME-induced neurotoxicity, which suggests that muscarinic cholinergic receptors are involved in AEME's effects. In addition, binding experiments confirmed that AEME has an affinity for muscarinic cholinergic receptors. Nevertheless, atropine was not able to prevent the neurotoxicity produced by cocaine and the cocaineAEME combination, suggesting that these treatments activated other neuronal death pathways. Our results suggest a higher risk for neurotoxicity after smoking crack cocaine than after cocaine use alone. (AU)

• Processo FAPESP: 11/02734-6 - Caracterização das vias de morte neuronal induzida pela metilecgonidina, produto da pirólise da cocaína, e seu envolvimento na farmacodependência
• Beneficiário: Tania Marcourakis
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 06/58631-2 - Efeitos neurodegenerativos da metilecgonidina e da cocaina em cultura celular primaria de hipocampo.
• Beneficiário: Raphael Caio Tamborelli Garcia
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 09/11149-0 - Caracterização das vias de morte celular induzida pela metilecgonidina, produto da pirólise da cocaína.
• Beneficiário: Lívia Mendonça Munhoz Dati
• Modalidade de apoio: Bolsas no Brasil - Mestrado