Cerebral reperfusion injury in stroke, stemming from interconnected thrombotic and inflammatory signatures, often involves platelet activation, aggregation and its interaction with various immune cells, contributing to microvascular dysfunction. However, the regulatory mechanisms behind this platelet activation and the resulting inflammation are not well understood, complicating the development of effective stroke therapies. Utilizing animal models and platelets from hemorrhagic stroke patients, our research demonstrates that human cerebral dopamine neurotrophic factor (CDNF) acts as an endogenous antagonist, mitigating platelet aggregation and associated neuroinflammation. CDNF moderates mitochondrial membrane potential, reactive oxygen species production, and intracellular calcium in activated platelets by interfering with GTP binding to Rap1b, thereby reducing Rap1b activation and downregulating the Rap1b-MAPK-PLA2 signaling pathway, which decreases release of the pro-inflammatory mediator thromboxane A2. In addition, CDNF reduces the inflammatory response in BV2 microglial cells co-cultured with activated platelets. Consistent with ex vivo findings, subcutaneous administration of CDNF in a rat model of ischemic stroke significantly reduces platelet activation, aggregation, lipid mediator production, infarct volume, and neurological deficits. In summary, our study highlights CDNF as a promising therapeutic target for mitigating platelet-induced inflammation and enhancing recovery in stroke. Harnessing the CDNF pathway may offer a novel therapeutic strategy for stroke intervention.

中文翻译：

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用 CDNF 靶向 Rap1b 信号级联反应：减轻中风中的血小板活化、血浆脂氧化物和再灌注损伤


中风中的脑再灌注损伤，源于相互关联的血栓形成和炎症特征，通常涉及血小板活化、聚集及其与各种免疫细胞的相互作用，导致微血管功能障碍。然而，这种血小板活化和由此产生的炎症背后的调节机制尚不清楚，这使得有效中风疗法的开发复杂化。利用出血性中风患者的动物模型和血小板，我们的研究表明，人脑多巴胺神经营养因子 （CDNF） 是一种内源性拮抗剂，可减轻血小板聚集和相关的神经炎症。CDNF 通过干扰 GTP 与 Rap1b 的结合来调节活化血小板中的线粒体膜电位、活性氧产生和细胞内钙，从而减少 Rap1b 激活并下调 Rap1b-MAPK-PLA2 信号通路，从而减少促炎介质血栓素 A2 的释放。此外，CDNF 可降低与活化血小板共培养的 BV2 小胶质细胞的炎症反应。与离 体研究结果一致，在缺血性中风大鼠模型中皮下施用 CDNF 可显着减少血小板活化、聚集、脂质介质产生、梗死体积和神经功能缺损。总之，我们的研究强调 CDNF 是减轻血小板诱导的炎症和促进中风恢复的有前途的治疗靶点。利用 CDNF 通路可能为卒中干预提供一种新的治疗策略。