Opposite effects of cannabinoid CB1 and CB2 receptors on antipsychotic clozapine-induced cardiotoxicity
Opposite effects of cannabinoid CB1 and CB2 receptors on antipsychotic clozapine-induced cardiotoxicity
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大麻素 CB1 和 CB2 受体对抗精神病药物氯氮平诱导的心脏毒性的相反作用。
DOI：
10.1111/bph.14591
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发表时间：
2019-04-01
影响因子：
7.3
通讯作者：
Jiang, Yan
中科院分区：
文献类型：
--
作者：
Li, Liliang;Dong, Xiaoru;Jiang, Yan
背景和目的氯氮平是一种非典型抗精神病药物，对治疗精神病非常有效，但严重心脏毒性的风险限制了其临床使用。本研究调查了氯氮平对心肌的有害影响，并评估了大麻素受体在其心脏毒性中的作用。实验方法单独使用氯氮平或与选择性大麻素受体拮抗剂或激动剂组合来治疗小鼠和心肌细胞。主要结果 腹腔注射后 7 天，氯氮平诱导心肌炎症和浸润。注射。氯氮平使小鼠存活率、心肌浸润和纤维化病变呈剂量依赖性恶化。氯氮平降低血清和培养的心肌细胞中主要内源性大麻素水平。大麻素 CB1 受体在氯氮平治疗的心脏中减少，并从细胞膜易位到细胞质和细胞核，而 CB2 受体在氯氮平治疗的心脏中增加，并从细胞核反向易位到细胞膜。 CB1受体的选择性拮抗剂利莫那班和AM281可改善氯氮平诱导的心肌炎症浸润和纤维化病变，但其选择性激动剂花生四烯酰-2'-氯乙酰胺则无作用。相比之下，CB2受体的选择性激动剂AM1241和JWH-133，而不是其选择性拮抗剂AM630，可以减弱氯氮平介导的小鼠心脏毒性。在培养的心肌细胞中，氯氮平增加促炎因子 IL-1β 和心肌损伤标志物（LDH 和天冬氨酸转氨酶）的浓度；这些效应可通过 CB1 拮抗剂或 CB2 激动剂逆转，并通过联合预处理进一步预防。结论和意义我们的数据提供的证据表明，大麻素 CB1 和 CB2 受体具有相反的作用，选择性 CB1 拮抗剂或 CB2 受体激动剂可能对心肌具有针对氯氮平的保护作用。
Background and Purpose Clozapine is an atypical antipsychotic drug that is very efficacious in treating psychosis, but the risk of severe cardiotoxicity limits its clinical use. The present study investigated the harmful effects of clozapine on myocardium and assessed the involvement of cannabinoid receptors in its cardiotoxicity. Experimental Approach Clozapine alone or in combination with selective cannabinoid receptor antagonists or agonists were used to treat mice and cardiomyocytes. Key Results Clozapine induced myocardial inflammation and infiltration 7 days after i.p. injection. Mice survival rate and myocardial infiltration, and fibrotic lesions were dose-dependently worsened by clozapine. Clozapine decreased major endocannabinoid levels in sera and cultured cardiomyocytes. Cannabinoid CB1 receptors decreased in clozapine-treated hearts and were translocated from cytomembranes to cytoplasm and nuclei, whereas CB2 receptors increased in clozapine-treated hearts and inversely translocated from nuclei to the cytomembrane. Selective antagonists of CB1 receptors, rimonabant and AM281, but not its selective agonist arachidonyl-2 '-chloroethylamide, ameliorated clozapine-induced myocardial inflammatory infiltration and fibrotic lesions. In contrast, selective agonists of CB2 receptors, AM1241 and JWH-133, but not its selective antagonist AM630, blunted clozapine-mediated cardiotoxicity in mice. In cultured cardiomyocytes, clozapine increased the pro-inflammatory factor IL-1 beta and the concentrations of myocardial injury markers (LDH and aspartate aminotransferase); these effects were reversed by either a CB1 antagonist or CB2 agonist and further prevented by combined pretreatments. Conclusions and Implications Our data provide evidence that cannabinoid CB1 and CB2 receptors have opposite effects and selective antagonists of CB1 or agonists of CB2 receptors might confer protective effects against clozapine in myocardium.