Chen Junhui, Shi Zhonghua, Chen Yuhua, Xiong Kun, Wang Yuhai, Zhang Hongqi
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, China International Neuroscience Institute, National Center for Neurological Disorders, Beijing, China; Department of Neurosurgery, 904th Hospital of Joint Logistic Support Force of PLA, Wuxi Clinical College of Anhui Medical University, Wuxi, 214044, China.
Department of Neurosurgery, 904th Hospital of Joint Logistic Support Force of PLA, Wuxi Clinical College of Anhui Medical University, Wuxi, 214044, China.
Redox Biol. 2025 Jul;84:103684. doi: 10.1016/j.redox.2025.103684. Epub 2025 May 16.
Subarachnoid hemorrhage (SAH) represents a stroke subtype that can lead to prolonged cognitive deficits as well as death or disability. Prior investigation has suggested that CoQ10 analogs can mitigate oxidative stress and inflammation and promote mitochondrial biogenesis in the context of brain injury and neurodegenerative disorders. However, the precise mechanisms underlying early brain injury (EBI) following SAH remain incompletely understood, and the detailed molecular processes have yet to be completely clarified. This investigation examined the neuroprotective properties of a CoQ10 analog concerning EBI post-SAH and identified potential mechanistic pathways. Our findings indicate that SAH led to alterations in innate and learned behaviors in aged C57BL/6J mice while also triggering ferroptosis and neuroinflammation within hippocampal neurons. Additionally, SAH was associated with reduced ferroptosis-related proteins, exacerbation of iron accumulation, elevation of lipid ROS, and decreased FSP1, HO-1, and NQO1 levels. The CoQ10 analog idebenone (IDB) demonstrated a capacity to alleviate EBI, as evidenced by improvements in both innate and learned behaviors, alongside a reduction in ferroptosis-related gene/protein expression. Silencing of FSP1 exacerbated EBI, ferroptosis, and neuroinflammation, and partially counteracted the neuroprotective effects of the CoQ10 analog. These results suggest that IDB may enhance the recovery from SAH-induced EBI in aged mice by modulating FSP1 protein stability via NMT-mediated N-myristoylation, thereby inhibiting both ferroptosis and neuroinflammation. The potential therapeutic application of IDB as a clinical intervention for EBI following SAH is also highlighted.
蛛网膜下腔出血（SAH）是一种中风亚型，可导致长期认知缺陷以及死亡或残疾。先前的研究表明，辅酶Q10类似物在脑损伤和神经退行性疾病的背景下可减轻氧化应激和炎症，并促进线粒体生物发生。然而，SAH后早期脑损伤（EBI）的精确机制仍未完全了解，详细的分子过程也尚未完全阐明。本研究考察了一种辅酶Q10类似物对SAH后EBI的神经保护特性，并确定了潜在的作用机制途径。我们的研究结果表明，SAH导致老年C57BL/6J小鼠的先天和习得行为发生改变，同时还引发海马神经元内的铁死亡和神经炎症。此外，SAH与铁死亡相关蛋白减少、铁积累加剧、脂质活性氧升高以及FSP1、HO-1和NQO1水平降低有关。辅酶Q10类似物艾地苯醌（IDB）表现出减轻EBI的能力，这表现为先天和习得行为均得到改善，同时铁死亡相关基因/蛋白表达减少。FSP1基因沉默会加剧EBI、铁死亡和神经炎症，并部分抵消辅酶Q10类似物的神经保护作用。这些结果表明，IDB可能通过NMT介导的N-肉豆蔻酰化调节FSP1蛋白稳定性，从而抑制铁死亡和神经炎症，进而促进老年小鼠从SAH诱导的EBI中恢复。本研究还强调了IDB作为SAH后EBI临床干预措施的潜在治疗应用。
