Cytotoxic Effects of 3,4-Catechol-PV (One Major MDPV Metabolite) on Human Dopaminergic SH-SY5Y Cells

Abstract

3,4-Methylenedioxypyrovalerone (MDPV), one of the most commonly abused synthetic cathinones, has caused several intoxications and deaths despite its short presence on the market. Apart from its effects on the monoamine systems in the brain, recent in vitro investigations have revealed cytotoxicity. In this study, the effects of increasing concentrations (10-1000 μM) of 3,4-Catechol-PV, one of major MDPV metabolites, on cell viability, morphology, and apoptosis have been evaluated after acute exposure (24-48 h) in human neuroblastoma SH-SY5Y cells-undifferentiated and differentiated to a more mature neuronal-like phenotype. Results indicated the following: (i) Cell viability: concentration-dependent decrease (15-55%) in differentiated SH-SY5Y after 24 h, with no exacerbation after 48 h (LC values 1028 and 951 μM, respectively); marked concentration-dependent decrease after 48 h (20-63%) in undifferentiated SH-SY5Y (LC 553.9 μM) with mild effect (18-22% cell death) after 24 h at ≥ 500 μM only; the lowest toxic concentrations were 500 and 100 μM after 24 h, for undifferentiated and differentiated SH-SY5Y, respectively, and 10 μM after 48 h. (ii) Concentration- and time-dependent alterations of cell morphology in both SH-SY5Y types characterized by several intracellular cytoplasmic vesicles (undifferentiated more susceptible (effect at ≥ 50 μM) than differentiated cells (effect at ≥ 100 μM)), loss of the typical cell shape, neurite retraction, and cell density decrease. (iii) Activation of caspase-3 enzyme in differentiated and undifferentiated cells after 48 h. These findings suggest the potential involvement of 3,4-Catechol-PV in MDPV-induced neurotoxicity and support the use of this human cellular model as a species-specific in vitro tool to clarify the neurotoxicity mechanisms of synthetic cathinones and metabolites.

Four Synthetic Cathinones: 3-Chloromethcathinone, 4-Chloromethcathinone, 4-Fluoro-α-Pyrrolidinopentiophenone, and 4-Methoxy-α-Pyrrolidinopentiophenone Produce Changes in the Spontaneous Locomotor Activity and Motor Performance in Mice with Varied Profiles

“…10 days in urine, suggesting a rapid enzymatic breakdown (Adamowicz and Malczyk 2019). Importantly, a similar case, where one of the major metabolites was found to be more cytotoxic than the parent compound, was reported for 3,4-MDPV (Coccini et al 2019;Wojcieszak et al 2016). The delay of emergence of cytotoxic effects of both chloromethcathinones distinguishes them from previously reported properties of 4-MeO-PVP and 4-F-PVP (Wojcieszak et al 2018a).…”

Synthetic Cathinones Induce Cell Death in Dopaminergic SH-SY5Y Cells via Stimulating Mitochondrial Dysfunction

“…Interestingly, PM findings have shown that the tissue levels of the drug MDMA can be up to 30 times higher in the human brain [57], consistent with the notion that these drugs can traverse the blood-brain barrier (BBB) and accumulate in the brain. Precise prediction of the SC concentration in the brain is unclear and complicated due to the different administration routes and BBB permeabilities of these drugs (which may or may not be compromised in abusers), as well as possible PM SC redistribution [58] and/or metabolism [59]. Moreover, it is important to note that the immortalized dopaminergic neuronal cell line SH-SY5Y can be more resistant to the cytotoxicity of added drugs.…”

Effects of Cathinones (Bath Salts) On Cultured Primary Neurons/Astroglia Cells and Neurobehavioral Functions in Mice

“…Similar consistent results are seen in other studies. [40,45,46] Even though the locomotor activity is increased, coordination and balance as tested by the rotarod test did not show any difference from the controls. This is inconsistent with what is observed in amphetamine exposure but this can be attributed to differences in structure, specific molecular targets, and dosage requirements to produce similar effects.…”

“…Neurotoxic effects of bath salts have been previously reported in various studies which showed reduced cell viability, altered morphology, and apoptosis after acute exposure (24-48 h) mostly in undifferentiated and differentiated human neuroblastoma SH-SY5Y cells. [25,40,41] However, a limitation of these studies has been the use of cell lines instead of in vitro cultures or in vivo animal models which would translate better to human physiology. Cell lines have altered proliferation rates, trans-epithelial resistance, cell permeability, metabolic activities and transport properties compared to the normal parental tissue.…”