Sezer Yigit, Jannuzzi Ayse Tarbin, Huestis Marilyn A, Alpertunga Buket
Council of Forensic Medicine, Ministry of Justice, Istanbul 34197, Turkey.
Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Istanbul University, Istanbul 34126, Turkey.
Toxicol Res (Camb). 2020 Nov 4;9(6):734-740. doi: 10.1093/toxres/tfaa078. eCollection 2020 Dec.
JWH-018 was the first synthetic cannabinoid introduced as a legal high and the first of the new generation of novel psychoactive substances that flooded worldwide drug markets. JWH-018 was marketed as "spice," "herbal incense," or "herbal blend," as a popular and legal (at the time) alternative to cannabis (marijuana). JWH-018 is a potent synthetic cannabinoid with considerable toxicity associated with its use. JWH-018 has qualitatively similar but quantitatively greater pharmacological effects than cannabis, leading to intoxications and even deaths. The mechanisms of action of the drug's toxicity require research, and thus, the aim of the present study was to investigate the toxicological profile of JWH-018 in human SH-SY5Y neuronal cells.
SH-SY5Y neuronal cells were exposed to increasing concentrations from 5 to 150 μM JWH-018 over 24 h. Cytotoxicity, DNA damage, the apoptotic/necrotic rate, and oxidative stress were assessed following SH-SY5Y exposure.
JWH-018 did not produce a significant decrease in SH-SY5Y cell viability, did not alter apoptotic/necrotic rate, and did not cause genotoxicity in SH-SY5Y cells with 24-h exposure. Glutathione reductase and catalase activities were significantly reduced; however, there was no significant change in glutathione peroxidase activity. Also, JWH-018 treatment significantly decreased glutathione concentrations, significantly increased protein carbonylation, and significantly increased malondialdehyde (MDA) concentrations. For significance, all < 0.05.
DISCUSSION/CONCLUSION: JWH-018 produced oxidative stress in SH-SY5Y cells that could be an underlying mechanism of JWH-018 neurotoxicity. Additional animal and human-based studies are needed to confirm our findings.
JWH-018是第一种作为合法兴奋剂引入的合成大麻素，也是充斥全球毒品市场的新一代新型精神活性物质中的第一种。JWH-018以“香料”“草药香料”或“草药混合物”的形式销售，作为大麻（大麻）的一种流行且合法（当时）的替代品。JWH-018是一种强效合成大麻素，使用时具有相当大的毒性。JWH-018在药理学作用上与大麻定性相似但定量更强，会导致中毒甚至死亡。该药物毒性的作用机制需要研究，因此，本研究的目的是调查JWH-018在人SH-SY5Y神经细胞中的毒理学特征。
在24小时内，将SH-SY5Y神经细胞暴露于浓度从5到150μM逐渐增加的JWH-018中。在SH-SY5Y细胞暴露后，评估细胞毒性、DNA损伤、凋亡/坏死率和氧化应激。
JWH-018在24小时暴露后，未导致SH-SY5Y细胞活力显著下降，未改变凋亡/坏死率，也未在SH-SY5Y细胞中引起基因毒性。谷胱甘肽还原酶和过氧化氢酶活性显著降低；然而，谷胱甘肽过氧化物酶活性没有显著变化。此外，JWH-018处理显著降低了谷胱甘肽浓度，显著增加了蛋白质羰基化，并显著增加了丙二醛（MDA）浓度。具有统计学意义，所有P<0.05。
讨论/结论：JWH-018在SH-SY5Y细胞中产生氧化应激，这可能是JWH-018神经毒性的潜在机制。需要更多基于动物和人类的研究来证实我们的发现。
