Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China.
J Neuroinflammation. 2024 Aug 3;21(1):195. doi: 10.1186/s12974-024-03187-4.
Chronic cerebral hypoperfusion (CCH), a disease afflicting numerous individuals worldwide, is a primary cause of cognitive deficits, the pathogenesis of which remains poorly understood. Bruton's tyrosine kinase inhibition (BTKi) is considered a promising strategy to regulate inflammatory responses within the brain, a crucial process that is assumed to drive ischemic demyelination progression. However, the potential role of BTKi in CCH has not been investigated so far. In the present study, we elucidated potential therapeutic roles of BTK in both in vitro hypoxia and in vivo ischemic demyelination model. We found that cerebral hypoperfusion induced white matter injury, cognitive impairments, microglial BTK activation, along with a series of microglia responses associated with inflammation, oxidative stress, mitochondrial dysfunction, and ferroptosis. Tolebrutinib treatment suppressed both the activation of microglia and microglial BTK expression. Meanwhile, microglia-related inflammation and ferroptosis processes were attenuated evidently, contributing to lower levels of disease severity. Taken together, BTKi ameliorated white matter injury and cognitive impairments induced by CCH, possibly via skewing microglia polarization towards anti-inflammatory and homeostatic phenotypes, as well as decreasing microglial oxidative stress damage and ferroptosis, which exhibits promising therapeutic potential in chronic cerebral hypoperfusion-induced demyelination.
慢性脑灌注不足（CCH）是一种影响全球众多人群的疾病，是认知功能障碍的主要原因，但其发病机制仍不清楚。布鲁顿酪氨酸激酶抑制（BTKi）被认为是调节大脑内炎症反应的一种有前途的策略，这是一个关键的过程，被认为是推动缺血性脱髓鞘进展的因素。然而，BTKi 在 CCH 中的潜在作用尚未得到研究。在本研究中，我们阐明了 BTK 在体外缺氧和体内缺血性脱髓鞘模型中的潜在治疗作用。我们发现，脑灌注不足引起的白质损伤、认知障碍、小胶质细胞 BTK 激活以及与炎症、氧化应激、线粒体功能障碍和铁死亡相关的一系列小胶质细胞反应。托利布替尼治疗抑制了小胶质细胞的激活和 BTK 的表达。同时，小胶质细胞相关的炎症和铁死亡过程明显减弱，导致疾病严重程度降低。综上所述，BTKi 通过使小胶质细胞向抗炎和稳态表型倾斜，并减少小胶质细胞氧化应激损伤和铁死亡，改善了 CCH 引起的白质损伤和认知障碍，这在慢性脑灌注不足引起的脱髓鞘中显示出有希望的治疗潜力。
