Anhydroecgonine methyl ester, a cocaine pyrolysis product, contributes to cocaine-induced rat primary hippocampal neuronal death in a synergistic and time-dependent manner

Author(s)

Udo, Mariana Sayuri Berto ^[1] ; da Silva, Mariana Aguilera Alencar ^[1] ; de Souza Prates, Sara ^[1] ; Dal'Jovem, Leandro Ferreira ^[1] ; de Oliveira Duro, Stephanie ^[1] ; Faiao-Flores, Fernanda ^[1] ; Garcia, Raphael Caio Tamborelli ^[2] ; Maria-Engler, Silvya Stuchi ^[1] ; Marcourakis, Tania ^[1]

Affiliation

^[1] Univ Sao Paulo, Dept Clin & Toxicol Anal, Sch Pharmaceut Sci, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Dept Pharmaceut Sci, Inst Environm Chem & Pharmaceut Sci, Diadema, SP - Brazil

• Document type: Journal article
• Source: ARCHIVES OF TOXICOLOGY; v. 95, n. 5 MAR 2021.
• Web of Science Citations: 0

Abstract

Crack cocaine users are simultaneously exposed to volatilized cocaine and to its main pyrolysis product, anhydroecgonine methyl ester (AEME). Although the neurotoxic effects of cocaine have been extensively studied, little is known about AEME or its combination. We investigated cell death processes using rat primary hippocampal cells exposed to cocaine (2 mM), AEME (1 mM) and their combination (C + A), after 1, 3, 6 and 12 h. Cocaine increased LC3 I after 6 h and LC3 II after 12 h, but reduced the percentage of cells with acid vesicles, suggesting failure in the autophagic flux, which activated the extrinsic apoptotic pathway after 12 h. AEME neurotoxicity did not involve the autophagic process; rather, it activated caspase-9 after 6 h and caspase-8 after 12 h leading to a high percentage of cells in early apoptosis. C + A progressively reduced the percentage of undamaged cells, starting after 3 h; it activated both apoptotic pathways after 6 h, and was more neurotoxic than cocaine and AEME alone. Also, C + A increased the phosphorylation of p62 after 12 h, but there was little difference in LC3 I or II, and a small percentage of cells with acid vesicles at all time points investigated. In summary, the present study provides new evidence for the neurotoxic mechanism and timing response of each substance alone and in combination, indicating that AEME is more than just a biological marker for crack cocaine consumption, as it may intensify and hasten cocaine neurotoxicity. (AU)

• FAPESP's process: 14/08881-9 - Neurotoxicity induced by environmental tobacco smoke and anhydroecgonine methyl ester, a cocaine pyrolysis product
• Grantee: Tania Marcourakis
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/20952-6 - Neurotoxicity of anhydroecgonine methyl ester in vitro: apoptosis death pathway caracterization and the autophagic process involvent
• Grantee: Mariana Sayuri Berto Udo
• Support Opportunities: Scholarships in Brazil - Doctorate