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 Ca²⁺-dependent brain injury.

中风预后与血清胆红素升高呈负相关，但胆红素如何恶化结果仍然是个谜。我们报告住院患者中风后而非中风前的胆红素水平与梗塞体积成比例。在小鼠模型中，胆红素会增加神经元兴奋性和缺血性梗死，而缺血性损伤会诱导内源性胆红素的释放，所有这些都会因 TRPM2 通道或其拮抗剂 A23 的敲除而减弱。独立于经典的 TRPM2 细胞内激动剂，胆红素及其代谢衍生物控制通道开放，而 A23 通过结合到相同的空腔来拮抗它。敲入胆红素结合点缺失突变 TRPM2-D1066A，可有效拮抗小鼠的缺血性神经毒性。²⁺ -依赖性脑损伤。