Ma Liqiu, Yao Lan, Zhang Zhaowei, Hao Bing
Department of Neurosurgery, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, China.
Department of Neurology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, China.
Hum Cell. 2025 Jan 20;38(2):46. doi: 10.1007/s13577-025-01174-2.
Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke, and the neuroprotective effects of nimodipine following SAH have been well-documented. Sirtuin 3 (SIRT3), a mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, plays a significant role in mitigating oxidative stress in various neurodegenerative conditions. However, the role of SIRT3 in the neuroprotective mechanisms of nimodipine after SAH remains unclear. In this study, the in vitro cytotoxicity of neurons exposed to 2% ethanol (to stimulate oxidative stress) was assessed. An in vivo experimental SAH model was established in adult mice through internal carotid perforation. A series of in vitro and in vivo experiments were conducted to investigate the function of SIRT3 and its potential mechanisms in nimodipine-treated SAH. Nimodipine, at a concentration of 10 μM within 48 h of incubation, exerted significant neuroprotective effects, enhancing SIRT3 protein expression under oxidative stress. Functional in vitro studies revealed that elevated SIRT3 expression improved mitochondrial function and promoted neuronal autophagy. Additional studies unveiled that SIRT3 knockdown or inhibition of autophagosome formation using inhibitor 3-methyladenine suppressed nimodipine-induced autophagy. The absence of autophagy increased neuronal cytotoxicity and mitochondrial dysfunction, decreased the release of anti-inflammatory cytokines, and increased the release of proinflammatory cytokines. Furthermore, blocking autophagy exacerbated neuronal apoptosis worsened neurological outcomes, and nullified the neuroprotective effects of nimodipine in the SAH mouse model. These findings highlight a mechanism where SIRT3 mediates nimodipine's neuroprotective effects by regulating mitochondrial function and autophagy. This suggests that SIRT3 serves as a promising therapeutic target for SAH.
蛛网膜下腔出血（SAH）是一种出血性中风，尼莫地平在SAH后的神经保护作用已有充分记录。沉默调节蛋白3（SIRT3）是一种线粒体烟酰胺腺嘌呤二核苷酸（NAD）依赖性脱乙酰酶，在减轻各种神经退行性疾病中的氧化应激方面发挥着重要作用。然而，SIRT3在SAH后尼莫地平神经保护机制中的作用仍不清楚。在本研究中，评估了暴露于2%乙醇（以刺激氧化应激）的神经元的体外细胞毒性。通过颈内动脉穿孔在成年小鼠中建立体内实验性SAH模型。进行了一系列体外和体内实验，以研究SIRT3的功能及其在尼莫地平治疗的SAH中的潜在机制。在孵育48小时内，浓度为10μM的尼莫地平发挥了显著的神经保护作用，在氧化应激下增强了SIRT3蛋白表达。体外功能研究表明，SIRT3表达升高改善了线粒体功能并促进了神经元自噬。进一步的研究发现，使用抑制剂3-甲基腺嘌呤敲低SIRT3或抑制自噬体形成可抑制尼莫地平诱导的自噬。自噬缺失增加了神经元细胞毒性和线粒体功能障碍，减少了抗炎细胞因子的释放，并增加了促炎细胞因子的释放。此外，阻断自噬加剧了神经元凋亡，恶化了神经功能结局，并消除了尼莫地平在SAH小鼠模型中的神经保护作用。这些发现突出了一种机制，即SIRT3通过调节线粒体功能和自噬来介导尼莫地平的神经保护作用。这表明SIRT3有望成为SAH的治疗靶点。
