Department of Otorhinolaryngology Head & Neck Surgery, Shanghai Sixth People's Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
Department of Otorhinolaryngology Head & Neck Surgery, Shanghai Sixth People's Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Program in Neuroscience and Mental Health, SickKids Research Institute, Toronto, ON M5G 1X8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Neuron. 2023 May 17;111(10):1609-1625.e6. doi: 10.1016/j.neuron.2023.02.022. Epub 2023 Mar 14.
Stroke prognosis is negatively associated with an elevation of serum bilirubin, but how bilirubin worsens outcomes remains mysterious. We report that post-, but not pre-, stroke bilirubin levels among inpatients scale with infarct volume. In mouse models, bilirubin increases neuronal excitability and ischemic infarct, whereas ischemic insults induce the release of endogenous bilirubin, all of which are attenuated by knockout of the TRPM2 channel or its antagonist A23. Independent of canonical TRPM2 intracellular agonists, bilirubin and its metabolic derivatives gate the channel opening, whereas A23 antagonizes it by binding to the same cavity. Knocking in a loss of binding point mutation for bilirubin, TRPM2-D1066A, effectively antagonizes ischemic neurotoxicity in mice. These findings suggest a vicious cycle of stroke injury in which initial ischemic insults trigger the release of endogenous bilirubin from injured cells, which potentially acts as a volume neurotransmitter to activate TRPM2 channels, aggravating Ca-dependent brain injury.
脑卒中预后与血清胆红素升高呈负相关，但胆红素如何使预后恶化仍不清楚。我们报告称，住院患者中风后而非中风前的胆红素水平与梗死体积呈正相关。在小鼠模型中，胆红素增加神经元兴奋性和缺血性梗死，而缺血性损伤诱导内源性胆红素释放，这些均被 TRPM2 通道或其拮抗剂 A23 的敲除所减弱。独立于经典的 TRPM2 细胞内激动剂，胆红素及其代谢衍生物可打开通道，而 A23 通过与同一腔结合来拮抗它。将胆红素结合点突变（TRPM2-D1066A）敲入，可有效拮抗小鼠的缺血性神经毒性。这些发现提示脑卒中损伤的恶性循环，其中最初的缺血性损伤触发受损细胞释放内源性胆红素，其可能作为一种容积神经递质激活 TRPM2 通道，加重钙依赖性脑损伤。
