Designer Cathinones N-Ethylhexedrone and Buphedrone Show Different In Vitro Neurotoxicity and Mice Behaviour Impairment

Neurotoxicity Research - Tập 39 - Trang 392-412 - 2020
Cristina de Mello-Sampayo1,2, Ana Rita Vaz1,2, Sara C. Henriques1, Adelaide Fernandes1,2, Fabiana Paradinha1, Pedro Florindo1,2, Paulo Faria1, Rui Moreira1,2, Dora Brites1,2, Alvaro Lopes2,3
1Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
2Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
3Egas Moniz-Cooperativa de Ensino Superior, Campus Universitário, Caparica, Portugal

Tóm tắt

N-Ethylhexedrone (NEH) and buphedrone (Buph) are emerging synthetic cathinones (SC) with limited information about their detrimental effects within central nervous system. Objectives: To distinguish mice behavioural changes by NEH and Buph and validate their differential harmful impact on human neurons and microglia. In vivo safety data showed the typical induced behaviour of excitation and stereotypies with 4–64 mg/kg, described for other SC. Buph additionally produced jumping and aggressiveness signs, while NEH caused retropulsion and circling. Transient reduction in body-weight gain was obtained with NEH at 16 mg/kg and induced anxiolytic-like behaviour mainly with Buph. Both drugs generated place preference shift in mice at 4 and 16 mg/kg, suggestive of abuse potential. In addition, mice withdrawn NEH displayed behaviour suggestive of depression, not seen with Buph. When tested at 50–400 μM in human nerve cell lines, NEH and Buph caused neuronal viability loss at 100 μM, but only NEH produced similar results in microglia, indicating different cell susceptibilities. NEH mainly induced microglial late apoptosis/necrosis, while Buph caused early apoptosis. NEH was unique in triggering microglia shorter/thicker branches indicative of cell activation, and more effective in increasing microglial lysosomal biogenesis (100 μM vs. 400 μM Buph), though both produced the same effect on neurons at 400 μM. These findings indicate that NEH and Buph exert neuro-microglia toxicities by distinct mechanisms and highlight NEH as a specific inducer of microglia activation. Buph and NEH showed in vivo/in vitro neurotoxicities but enhanced specific NEH-induced behavioural and neuro-microglia dysfunctionalities pose safety concerns over that of Buph.

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Neurotoxicity Research

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