The Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, China.
Shenzhen Key Laboratory of Neuroimmunomodulation for Neurological Diseases, Shenzhen, China.
Mol Neurobiol. 2024 Oct;61(10):7384-7402. doi: 10.1007/s12035-024-04052-4. Epub 2024 Feb 22.
Ischemic stroke is a major cause of death and disability in adults. Hypothermic treatment is successful in treating neonatal cerebral ischemia, but its application is restricted in adult patients due to complex management strategies and severe adverse effects. Two homologous RNA-binding proteins, RBM3 and CIRP, are the only known cold-inducible proteins in vertebrates, and their expression levels are robustly elevated by mild to moderate hypothermia. In previous studies, we and others have demonstrated that both RBM3 and CIRP mediate the neuroprotective and neurogenic effects of hypothermia in cell and animal models. However, CIRP can also be detrimental to neurons by triggering neuroinflammatory responses, complicating its post-stroke functions. In this study, we compared the properties of the two cold-inducible RNA-binding proteins after ischemic stroke. Our results indicated that RBM3 expression was stimulated in the ischemic brain of stroke patients, while CIRP expression was not. In an experimental model, RBM3 can ameliorate ischemic-like insult by promoting neuronal survival and eliciting anti-inflammatory responses in activated microglia, while the impact of CIRP was intriguing. Collectively, our data supported the notion that RBM3 may be a more promising therapeutic target than CIRP for treating ischemic stroke. We further demonstrated that zr17-2, a small molecule initially identified to target CIRP, can specifically target RBM3 but not CIRP in microglia. zr17-2 demonstrated anti-inflammatory and neuroprotective effects after ischemic stroke both in vitro and in vivo, suggesting its potential therapeutic value.
缺血性中风是成年人死亡和残疾的主要原因。低温治疗在治疗新生儿脑缺血方面是成功的，但由于复杂的管理策略和严重的不良反应，其在成年患者中的应用受到限制。两种同源的 RNA 结合蛋白，RBM3 和 CIRP，是脊椎动物中唯一已知的冷诱导蛋白，它们的表达水平在轻度至中度低温下会显著升高。在以前的研究中，我们和其他人已经证明，RBM3 和 CIRP 都介导了低温对细胞和动物模型的神经保护和神经发生作用。然而，CIRP 也可以通过触发神经炎症反应对神经元造成损害，从而使它在中风后的作用变得复杂。在这项研究中，我们比较了两种冷诱导 RNA 结合蛋白在缺血性中风后的特性。我们的结果表明，RBM3 的表达在中风患者的缺血大脑中受到刺激，而 CIRP 的表达则没有。在一个实验模型中，RBM3 可以通过促进神经元存活和引发激活的小胶质细胞中的抗炎反应来改善类似缺血的损伤，而 CIRP 的影响则很有趣。总的来说，我们的数据支持这样一种观点，即 RBM3 可能比 CIRP 更有希望成为治疗缺血性中风的治疗靶点。我们进一步证明，最初被确定为针对 CIRP 的小分子 zr17-2 可以特异性地靶向小胶质细胞中的 RBM3 而不是 CIRP。Zr17-2 在体外和体内都显示出了抗炎和神经保护作用，表明了其潜在的治疗价值。
