基于内源性大麻素系统研究抗精神病药致心肌损害的分子毒理学机制

Sudden cardiac deaths are among the most common causes of death. Long-term use of psychiatric drugs, especially anti-psychotics may impair myocardium and even lead to cardiac deaths. Endocannabinoid system is a known cardio-protective system and its deregulation correlates with cardiovascular diseases, but whether it is directly involved in antipsychotics-induced myocardial injury remains to be elucidated. Our preliminary data showed that after medium dose of clozapine treatments for 14 days, mice exhibited impaired heart function; the plasma levels of endocannabinoids AEA and 2-AG were decreased and the expression of cannabinoid receptor 1 (CB1R) also decreased with its subcellular location changed remarkably. Based on the preliminary expression data, the current program is going to focus on CB1R and further (1) employ selective receptor agonist and antagonist to validate the functional roles of CB1R in antipsychotics-induced myocardial injury; (2) explore the upstream signaling that regulates CB1R and underlies its function in antipsychotics-induced myocardial injury. This program aims to uncover the endocannabinoid system-based molecular toxicological mechanisms of antipsychotics-induced myocardial injury. Our results would be valuable for clinical monitoring of antipsychotics use and for the juridical evaluation of drug-related sudden deaths in forensic science.

心源性猝死是司法鉴定中最常见的死亡原因之一。长期服用精神类药物，尤其是抗精神病药可致心肌损害，甚至诱发心源性猝死。近期已证实内源性大麻素系统具有心脏保护作用，其失衡与心血管疾病密切相关，但内源性大麻素系统是否直接参与抗精神病药致心肌损害有待进一步明确。我们前期发现给予中等剂量的氯氮平14天后，小鼠心功能显著减弱，血浆主要内源性大麻素逐渐下降，心肌I型大麻素受体（CB1R）表达亦显著下降且细胞亚定位发生改变。基于前期研究结果，本项目拟进一步以CB1R为切入点，（1）应用CB1R选择性激动剂和拮抗剂确定CB1R在抗精神病药致心肌损害中的生物学功能，（2）研究CB1R参与抗精神病药致心肌损害的上游信号机制，从而揭示内源性大麻素系统在抗精神病药致心肌损害中的功能及毒理机制，为临床监测抗精神病药心脏毒副作用提供参考，为药物性心肌损害相关司法鉴定提供辅助分子诊断依据。

心源性猝死是司法鉴定中最常见的死亡原因之一。长期服用精神类药物，尤其是抗精神病药可致心肌损害，甚至诱发心源性猝死。近期已证实内源性大麻素系统具有心脏保护作用，其失衡与心血管疾病密切相关，但内源性大麻素系统是否直接参与抗精神病药致心肌损害有待进一步明确。本项目首先通过解剖案例，分析了与心源性猝死密切相关的抗精神病药种类及其引起的心肌病理形态学特征，为抗精神病药心肌毒性仅有临床观测提供了直接的解剖学证据。我们发现氯氮平、氯丙嗪、奥氮平、喹硫平等药物最常见与心源性猝死相关，这类药物慢性心肌毒性具有时间和剂量依赖性，引起的毒性以心肌程序性细胞坏死为特征，而非传统的凋亡。进一步，我们发现以氯氮平为代表的抗精神病药影响了主要内源性大麻素的含量及其水解酶的表达，并导致2种大麻素受体的差异性表达。采用1型大麻素受体拮抗剂（而非激动剂）或2型大麻素受体激动剂（而非拮抗剂）可显著抑制氯氮平、喹硫平等心肌毒性及细胞坏死性凋亡。最后，基于磷酸激酶预测及验证，我们鉴定了1型大麻素受体的重要调节激酶GRK3，并验证了GRK3通过调控1型大麻素受体磷酸化而抑制抗精神病药心肌毒性。本项目的结果说明不同大麻素受体亚型在抗精神病药心肌毒性中具有反式效应，基于特定受体的高选择性药物才能治疗抗精神病药心肌毒性。本项目解析了抗精神病药心肌毒性机制，为司法鉴定及临床干预提供了理论依据。