Methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxypyrovalerone (MDPV) induce differential cytotoxic effects in bovine brain microvessel endothelial cells

Abstract

Designer drugs such as synthetic psychostimulants are indicative of a worldwide problem of drug abuse and addiction. In addition to methamphetamine (METH), these drugs include 3,4- methylenedioxy-methamphetamine (MDMA) and commercial preparations of synthetic cathinones including 3,4-methylenedioxypyrovalerone (MDPV), typically referred to as “bath salts.” These psychostimulants exert neurotoxic effects by altering monoamine systems in the brain. Additionally, METH and MDMA adversely affect the integrity of the blood-brain barrier (BBB): there are no current reports on the effects of MDPV on the BBB. The aim of this study was to compare the effects of METH, MDMA and MDPV on bovine brain microvessel endothelial cells (bBMVECs), an accepted in vitro model of the BBB. Confluent bBMVEC monolayers were treated with METH, MDMA and MDPV (0.5 mM - 2.5 mM) for 24 hours. METH and MDMA increased lactate dehydrogenase release only at the highest concentration (2.5 mM), whereas MDPV induced cytotoxicity at all concentrations. MDMA and METH decreased cellular proliferation only at 2.5 mM, with similar effects observed after MDPV exposures starting at 1 mM. Only MDPV increased reactive oxygen species production at all concentrations tested whereas all 3 drugs increased nitric oxide production. Morphological analysis revealed different patterns of compound-induced cell damage. METH induced vacuole formation at 1 mM and disruption of the monolayer at 2.5 mM. MDMA induced disruption of the endothelial monolayer from 1 mM without vacuolization. On the other hand, MDPV induced monolayer disruption at doses ≥ 0.5 mM without vacuole formation; at 2.5 mM, the few remaining cells lacked endothelial morphology. These data suggest that even though these synthetic psychostimulants alter monoaminergic systems, they each induce BBB toxicity by different mechanisms with MDPV being the most toxic.

Monoaminergic toxicity induced by cathinone phthalimide: An in vitro study

“…This exposure time is similar to those used for other in vitro studies involving bath salts [38, 39, 44]. In PC12 cells, CP induced a slight but significant increase in cell death at 10µM and 100µM and drastically increases cell death at 1000µM (Fig.…”

“…However, it is not likely that the preparation used in the present study generated any metabolites. Even though metabolites of CP have not been investigated to date, it is reasonable investigate their presence and impact on toxicity as MDMA metabolites are reported to induce toxicity at lower concentrations than MDMA alone [8, 16, 39]. Because of the structural similarity between CP and MDMA, potential effects of CP metabolites cannot be ruled out and also warrant further investigation.…”

“…Because the addition of new ketals compared with the parent cathinone, it is possible that CP would be less polar and might therefore exhibit greater permeability through the blood-brain barrier, thereby increasing its availability in the brain and its psychoactive potency [43]. Further studies are warranted to compare its ability to pass the blood-brain barrier and to determine its ability to impair blood-brain barrier function, especially given that the bath salt MDPV has been found to induce toxicity in the blood-brain barrier at doses lower than that of METH and MDMA [39]. …”

Rates and features of methamphetamine‐related presentations to emergency departments: An integrative literature review

“…The effects of methamphetamine can last up to 12 hr (depending on route of administration), with a half‐life of 10 hr (Rosas‐Hernandeza et al., ). Withdrawal symptoms can begin 6 hr after use and last up to 2 weeks, while the drug can still have an effect for up to 4 days postdose (Toles, Jiang, Goebert, & Lettich, ).…”

“…Globally, there are an estimated 50 million users of methamphetamines (Rosas‐Hernandeza et al., ). This is supported by an increase in seizures of methamphetamine which is estimated to have risen to 170 tonnes globally in 2014, up 21% from 2009 (United Nations Office on Drugs and Crime, ).…”