Department of Neurology, Lanzhou University Second Hospital, No.82, Cuiyingmen, Lanzhou, 730030, Gansu, China.
Institute of Genetics, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, Gansu, China.
Mol Neurobiol. 2023 Aug;60(8):4261-4272. doi: 10.1007/s12035-023-03336-5. Epub 2023 Apr 15.
Irisin is a muscle-derived hormone that promotes the survival of motor neurons and enhances muscle size following injury. In this study, we investigated the beneficial effects and mechanism(s) of action of irisin in response to cerebral ischemia-reperfusion injury (CIRI). Right-middle cerebral artery occlusion (MCAO) and hypoxia/reoxygenation (H/R) models were generated in C57BL/6 J mice. Mouse neuronal cell lines (NSC-34) were used to confirm the molecular mechanisms of the protection afforded by irisin in response to CIRI. We found that irisin (250 μg/kg) improved cerebral function and reduced the cerebral infarct volume following CIRI. Irisin also protected neuronal cells against ischemia-reperfusion (I/R) induced apoptosis, assessed via TUNEL, and cleaved Caspase-3 staining. Western blotting of neuronal tissue from irisin treated I/R mice showed lower expression of pro-apoptotic Bax and caspase-9 (P < 0.001 and P < 0.01) and increased levels of the pro-survival protein Bcl-2 (P < 0.01 & P < 0.001 vs. I/R). Irisin also reduced the levels of reactive oxygen species (ROS) characterized through malondialdehyde (MDA) assays. Irisin was found to maintain mitochondrial homeostasis through the suppression of mitochondrial fission-linked dynamin-related protein 1 in CIRI mice (P < 0.01 and P < 0.05 v. I/R cohort). Moreover, mitochondrial fusion-related protein (Mfn2) and Opa1 expression were rescued following irisin treatment (P < 0.001 and P < 0.01 v. I/R cohort). Cell-based assays showed that irisin activates PI3K/AKT/mTOR signaling in the neurons of CIRI mice. Furthermore, the beneficial effects of irisin on NSC-34 cell-survival, mitochondrial function, and ROS generation were reversed by VS-5584, a highly specific PI3K/AKT/mTOR inhibitor. Collectively, these data highlight the ability of irisin to alleviate CIRI in vivo and in vitro. The mechanisms of action of irisin include the attenuation of apoptosis through the prevention of mitochondrial fission and increased mitochondrial fusion and the alleviation of oxidative stress through activation of the PI3K/AKT/mTOR axis. We therefore identify irisin as a much-needed therapeutic for CIRI.
鸢尾素是一种肌肉来源的激素，可促进运动神经元的存活，并增强损伤后的肌肉大小。在这项研究中，我们研究了鸢尾素对脑缺血再灌注损伤（CIRI）的有益作用及其作用机制。在 C57BL/6J 小鼠中生成右大脑中动脉闭塞（MCAO）和缺氧/复氧（H/R）模型。使用小鼠神经元细胞系（NSC-34）来确认鸢尾素在应对 CIRI 时提供的保护的分子机制。我们发现，鸢尾素（250μg/kg）可改善 CIRI 后的脑功能并减少脑梗死体积。鸢尾素还通过 TUNEL 和 cleaved Caspase-3 染色保护神经元细胞免受缺血再灌注（I/R）诱导的细胞凋亡。用鸢尾素处理的 I/R 小鼠的神经元组织的 Western blot 显示，促凋亡 Bax 和 caspase-9 的表达降低（P < 0.001 和 P < 0.01），而促生存蛋白 Bcl-2 的水平升高（P < 0.01 和 P < 0.001 与 I/R 相比）。鸢尾素还通过丙二醛（MDA）测定降低活性氧（ROS）水平。在 CIRI 小鼠中，发现鸢尾素通过抑制线粒体分裂相关 dynamin 相关蛋白 1 来维持线粒体稳态（P < 0.01 和 P < 0.05 与 I/R 队列相比）。此外，在用鸢尾素处理后，线粒体融合相关蛋白（Mfn2）和 Opa1 的表达得到恢复（P < 0.001 和 P < 0.01 与 I/R 队列相比）。细胞基础测定表明，鸢尾素在 CIRI 小鼠的神经元中激活 PI3K/AKT/mTOR 信号通路。此外，用高度特异性的 PI3K/AKT/mTOR 抑制剂 VS-5584 逆转了鸢尾素对 NSC-34 细胞存活、线粒体功能和 ROS 生成的有益作用。总之，这些数据强调了鸢尾素在体内和体外减轻 CIRI 的能力。鸢尾素的作用机制包括通过防止线粒体分裂和增加线粒体融合来减轻细胞凋亡，以及通过激活 PI3K/AKT/mTOR 轴来减轻氧化应激。因此，我们将鸢尾素鉴定为 CIRI 急需的治疗方法。
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