Abstract：
The use of synthetic cannabinoid receptor agonists (SCRAs) represents a public health concern. Besides abuse liability and cognitive impairments, SCRAs consumption is associated with serious medical consequences in humans, including cardiotoxicity. The precise mechanisms underlying cardiac or other toxicities induced by SCRAs are not well understood. Here, we used in silico, in vivo, and ex vivo approaches to investigate the toxicological consequences induced by exposure to the SCRA JWH-018. Along with in silico predictive toxicological screening of 36 SCRAs by MC4PC software, adult male Sprague-Dawley rats were repeatedly exposed to JWH-018 (0.25 mg/kg ip) for 14 consecutive days, with body temperature and cardiovascular parameters measured over the course of treatment. At 1 and 7 days after JWH-018 discontinuation, multiorgan tissue pathologies and heart mitochondria bioenergetics were assessed. The in silico findings predicted risk of cardiac adverse effects specifically for JWH-018 and other aminoalkylindole SCRAs (i.e., electrocardiogram abnormality and QT prolongation). The results from rats revealed that repeated, but not single, JWH-018 exposure induced hypothermia and cardiovascular stimulation (e.g., increased blood pressure and heart rate) which persisted throughout treatment. Post-mortem findings demonstrated cardiac lesions (i.e., vacuolization, waving, edema) 1 day after JWH-018 discontinuation, which may contribute to lung, kidney, and liver tissue degeneration observed 7 days later. Importantly, repeated JWH-018 exposure induced mitochondrial dysfunction in cardiomyocytes, i.e., defective lipid OXPHOS, which may represent one mechanism of JWH-018-induced toxicity. Our results demonstrate that repeated administration of even a relatively low dose of JWH-018 is sufficient to affect cardiovascular function and induce enduring toxicological consequences, pointing to risks associated with SCRA consumption.
摘要：
合成大麻素受体激动剂(SCRAs)的使用代表了公共卫生问题。除了滥用责任和认知障碍，SCRA消耗与人类严重的医疗后果有关，包括心脏毒性.SCRAs诱导的心脏或其他毒性的确切机制尚不清楚。这里,我们用的是硅片,在体内，和离体方法来研究暴露于SCRAJWH-018引起的毒理学后果。随着MC4PC软件对36个SCRAs进行硅预测毒理学筛选，成年雄性Sprague-Dawley大鼠连续14天反复暴露于JWH-018（0.25mg/kgip），在治疗过程中测量体温和心血管参数。在JWH-018停药后1天和7天，评估了多器官组织病理学和心脏线粒体生物能学。计算机研究结果预测了JWH-018和其他氨基烷基吲哚SCRA的心脏不良反应的风险（即，心电图异常和QT延长）。老鼠的结果显示，重复，但不是单身,JWH-018暴露诱导体温过低和心血管刺激(例如，血压和心率升高）在整个治疗过程中持续存在。验尸结果显示心脏病变(即，真空化,挥手,水肿）JWH-018停药后1天，这可能有助于肺，肾脏，7天后观察到肝组织变性。重要的是,重复JWH-018暴露诱导心肌细胞线粒体功能障碍，即，脂质缺陷OXPHOS，这可能代表了JWH-018诱导毒性的一种机制。我们的结果表明，即使是相对低剂量的JWH-018的重复给药也足以影响心血管功能并引起持久的毒理学后果。指出与SCRA消费相关的风险。
