Laboratory of Clinical and Experimental Toxicology, ICS Maugeri SpA - Benefit Corporation, IRCCS Pavia, Via Maugeri 10, 27100, Pavia, Italy.
Poison Control Centre and National Toxicology Information Centre, Toxicology Unit, ICS Maugeri SpA - Benefit Corporation, IRCCS Pavia, Pavia, Italy.
Neurotox Res. 2019 Jan;35(1):49-62. doi: 10.1007/s12640-018-9924-0. Epub 2018 Jun 22.
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.
3,4-亚甲二氧基吡咯戊酮（MDPV）是最常被滥用的合成卡西酮之一，尽管它在市场上的出现时间很短，但已经导致了几起中毒和死亡事件。除了对大脑单胺系统的影响外，最近的体外研究还揭示了其细胞毒性。在这项研究中，评估了 3,4-儿茶酚-PV（MDPV 的主要代谢物之一）在浓度增加（10-1000 μM）后的急性暴露（24-48 h）对人神经母细胞瘤 SH-SY5Y 细胞（未分化和分化为更成熟的神经元样表型）活力、形态和细胞凋亡的影响。结果表明：（i）细胞活力：24 h 后分化的 SH-SY5Y 细胞浓度依赖性降低（15-55%），48 h 后无恶化（LC 值分别为 1028 和 951 μM）；48 h 后未分化的 SH-SY5Y 细胞浓度依赖性显著降低（20-63%）（LC 553.9 μM），仅在≥500 μM 时才产生轻度作用（18-22%细胞死亡）；24 h 时最低毒性浓度分别为 500 和 100 μM，用于未分化和分化的 SH-SY5Y，48 h 时为 10 μM。（ii）两种 SH-SY5Y 类型的细胞形态均表现出浓度和时间依赖性改变，特征为多个细胞内细胞质囊泡（未分化的比分化的细胞更容易受到影响（≥50 μM 时出现影响）），典型细胞形状丧失，轴突回缩和细胞密度降低。（iii）48 h 后分化和未分化细胞中 caspase-3 酶的激活。这些发现表明 3,4-儿茶酚-PV 可能参与了 MDPV 诱导的神经毒性，并支持使用这种人类细胞模型作为物种特异性体外工具，以阐明合成卡西酮及其代谢物的神经毒性机制。
