Abstract
Increasing reports of neurological and psychiatric complications due to psychostimulant synthetic cathinones (SCs) have recently raised public concern. However, the precise mechanism of SC toxicity is unclear. This paucity of understanding highlights the need to investigate the in-vitro toxicity and mechanistic pathways of three SCs: butylone, pentylone, and 3,4-Methylenedioxypyrovalerone (MDPV). Human neuronal cells of SH-SY5Y were cultured in supplemented DMEM/F12 media and differentiated to a neuronal phenotype using retinoic acid (10 μM) and 12-O-tetradecanoylphorbol-13-acetate (81 nM). Trypan blue and lactate dehydrogenase assays were utilized to assess the neurotoxicity potential and potency of these three SCs. To investigate the underlying neurotoxicity mechanisms, measurements included markers of oxidative stress, mitochondrial bioenergetics, and intracellular calcium (Ca2+), and cell death pathways were evaluated at two doses (EC15 and EC40), for each drug tested. Following 24 h of treatment, all three SCs exhibited a dose-dependent neurotoxicity, characterized by a significant (p < 0.0001 vs. control) production of reactive oxygen species, decreased mitochondrial bioenergetics, and increased intracellular Ca2+ concentrations. The activation of caspases 3 and 7 implicated the orchestration of mitochondrial-mediated neurotoxicity mechanisms for these SCs. Identifying novel therapeutic agents to enhance an altered mitochondrial function may help in the treatment of acute-neurological complications arising from the illicit use of these SCs.
Highlights
Synthetic cathinones (SCs) have emerged as popular supplements to “traditional” drugs of abuse, such as cocaine, 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy or “Molly”), and methamphetamine, due to their psychostimulant and entactogenic effects [1]
The present study aimed to evaluate the neurotoxicity potential and potency of butylone and pentylone in relation to MDPV using the well-established SH-SY5Y cell line that can be differentiated into a dopaminergic neuronal phenotype [41]
Our study demonstrates that SCs exert significant neurotoxic effects on cultured dopaminergic neuronal SH-SY5Y cells
Summary
Synthetic cathinones (SCs) have emerged as popular supplements to “traditional” drugs of abuse, such as cocaine, 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy or “Molly”), and methamphetamine (meth), due to their psychostimulant and entactogenic effects [1]. These illicit psychostimulants, often labeled as “not for human consumption”, are marketed as “legal highs”,. “bath salts”, “plant food”, and “research chemicals” to evade scrutiny and detection by law enforcement agencies Their relatively low cost, ease of internet purchases, and the lack of control over clandestine drug manufacturers have greatly contributed to the explosion of these drugs in the recreational drug scene [2].
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