Designer Cathinones N -Ethylhexedrone and Buphedrone Show Different In Vitro Neurotoxicity and Mice Behaviour Impairment
- PDF / 6,999,018 Bytes
- 21 Pages / 595.276 x 790.866 pts Page_size
- 72 Downloads / 161 Views
ORIGINAL ARTICLE
Designer Cathinones N-Ethylhexedrone and Buphedrone Show Different In Vitro Neurotoxicity and Mice Behaviour Impairment Cristina de Mello-Sampayo 1,2 & Ana Rita Vaz 1,2 & Sara C. Henriques 1 & Adelaide Fernandes 1,2 & Fabiana Paradinha 1 & Pedro Florindo 1,2 & Paulo Faria 1 & Rui Moreira 1,2 & Dora Brites 1,2 & Alvaro Lopes 2,3 Received: 18 September 2019 / Revised: 18 May 2020 / Accepted: 19 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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 In addition, mice withdrawn NEH displayed behaviour suggestive of depression, not seen with Buph.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 neuromicroglia 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. Keywords Synthetic cathinones . Addiction potential . Microglia activation . Human cell culture models . Mice behavioural tests . Neurotoxicity
Introduction
Cristina de Mello-Sampayo and Ana Rita Vaz contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12640-020-00229-6) contains supplementary material, which is available to authorized users. * Alvaro Lopes [email protected] 1
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
2
Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal
3
Egas Moniz-Cooperativa de Ensino Superior, Campus Universitário, Caparica, Portugal
A considerable and increasing worldwide public
Data Loading...
