Prakash Ravi, Waseem Arshi, Siddiqui Abu Junaid, Naime Mohammad, Khan Mohsin Ali, Robertson Avril Ab, Boltze Johannes, Raza Syed Shadab
Laboratory for Stem Cell & Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College and Hospital, Era University, Sarfarazganj, Lucknow 226003, India.
Central Research Institute of Unani Medicine (Under Central Council for Research in Unani Medicine, Ministry of Ayush, Govt of India), Lucknow-226026, Uttar Pradesh, India.
Biomed Pharmacother. 2025 Feb;183:117861. doi: 10.1016/j.biopha.2025.117861. Epub 2025 Jan 27.
Sustained activation of the SIRT3-NLRP3 inflammasome has been associated with worse outcomes after ischemic stroke. The objective of this study was to examine the potential mechanism by which the SIRT3-NLRP3 inflammasome affects neural stem and progenitor cells (NSPCs) after transient middle cerebral artery occlusion (tMCAO) in rats. Following tMCAO, significantly elevated levels of NLRP3, ASC, cleaved caspase 1, IL-1β, and IL-18 were observed in the ischemic subventricular zone. Moreover, tMCAO increased NLRP3 expression while decreasing SIRT3 levels, suggesting a connection between these two processes. Furthermore, we discovered that inflammation induced by the NLRP3 inflammasome impaired post-stroke hippocampal and subventricular neurogenesis, while nestin (a marker for NSPCs) and Sox2 (a marker for stem cell pluripotency) were downregulated after tMCAO. However, systemic administration of MCC950 reduced inflammatory signaling and effectively restored neurogenesis. Overall, our results suggest that protecting NSPCs and neurogenesis in the ischemically damaged brain by mitigating the impact of the SIRT3-NLRP3 inflammasome may be a feasible treatment strategy for ischemic stroke.
SIRT3-NLRP3炎性小体的持续激活与缺血性中风后更差的预后相关。本研究的目的是探讨SIRT3-NLRP3炎性小体在大鼠短暂性大脑中动脉闭塞（tMCAO）后影响神经干细胞和祖细胞（NSPCs）的潜在机制。tMCAO后，在缺血的脑室下区观察到NLRP3、ASC、裂解的半胱天冬酶1、IL-1β和IL-18水平显著升高。此外，tMCAO增加了NLRP3的表达，同时降低了SIRT3水平，表明这两个过程之间存在联系。此外，我们发现NLRP3炎性小体诱导的炎症损害了中风后海马和脑室下区的神经发生，而巢蛋白（NSPCs的标志物）和Sox2（干细胞多能性的标志物）在tMCAO后下调。然而，全身给予MCC950可减少炎症信号并有效恢复神经发生。总体而言，我们的结果表明，通过减轻SIRT3-NLRP3炎性小体的影响来保护缺血性损伤大脑中的NSPCs和神经发生可能是缺血性中风的一种可行治疗策略。
