Xiong Shuai, Xiao Hui, Sun Meng, Liu Yunjie, Gao Ling, Xu Ke, Liang Haiying, Jiang Nan, Lin Yuhui, Chang Lei, Wu Haiyin, Zhu Dongya, Luo Chunxia
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
Acta Pharm Sin B. 2023 Jul;13(7):3008-3026. doi: 10.1016/j.apsb.2023.05.012. Epub 2023 May 15.
Many efforts have been made to understand excitotoxicity and develop neuroprotectants for the therapy of ischemic stroke. The narrow treatment time window is still to be solved. Given that the ischemic core expanded over days, treatment with an extended time window is anticipated. Bestrophin 1 (BEST1) belongs to a bestrophin family of calcium-activated chloride channels. We revealed an increase in neuronal BEST1 expression and function within the peri-infarct from 8 to 48 h after ischemic stroke in mice. Interfering the protein expression or inhibiting the channel function of BEST1 by genetic manipulation displayed neuroprotective effects and improved motor functional deficits. Using electrophysiological recordings, we demonstrated that extrasynaptic glutamate release through BEST1 channel resulted in delayed excitotoxicity. Finally, we confirmed the therapeutic efficacy of pharmacological inhibition of BEST1 during 6-72 h post-ischemia in rodents. This delayed treatment prevented the expansion of infarct volume and the exacerbation of neurological functions. Our study identifies the glutamate-releasing BEST1 channel as a potential therapeutic target against ischemic stroke with a wide time window.
为了理解兴奋性毒性并开发用于治疗缺血性中风的神经保护剂，人们已经做出了许多努力。狭窄的治疗时间窗仍有待解决。鉴于缺血核心在数天内会扩大，人们期待能有更长治疗时间窗的治疗方法。最佳rophin 1（BEST1）属于钙激活氯离子通道的最佳rophin家族。我们发现，在小鼠缺血性中风后8至48小时内，梗死周边区神经元的BEST1表达和功能会增加。通过基因操作干扰BEST1的蛋白表达或抑制其通道功能，显示出神经保护作用，并改善了运动功能缺陷。通过电生理记录，我们证明通过BEST1通道释放的突触外谷氨酸会导致延迟性兴奋性毒性。最后，我们证实了在啮齿动物缺血后6至72小时内对BEST1进行药物抑制的治疗效果。这种延迟治疗可防止梗死体积扩大和神经功能恶化。我们的研究确定了释放谷氨酸的BEST1通道是一个具有宽时间窗的抗缺血性中风潜在治疗靶点。
