Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat 382007, India.
Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar 788011, Assam, India.
ACS Chem Neurosci. 2021 Oct 6;12(19):3745-3759. doi: 10.1021/acschemneuro.1c00506. Epub 2021 Sep 23.
Ischemic stroke is devastating, with serious long-term disabilities affecting millions of people worldwide. Growing evidence has shown that mesenchymal stem cells (MSCs) administration after stroke provides neuroprotection and enhances the quality of life in stroke patients. Previous studies from our lab have shown that 1 × 10 MSCs administered intra-arterially (IA) at 6 h post stroke provide neuroprotection through the modulation of inflammasome and calcineurin signaling. Ischemic stroke induces endoplasmic reticulum (ER) stress, which exacerbates the pathology. The current study intends to understand the involvement of brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) signaling in preventing apoptosis induced by ER stress post stroke following IA MSCs administration. Ischemic stroke was induced in ovariectomized female Sprague Dawley rats. The MSCs were administered IA, and animals were sacrificed at 24 h post stroke. Infarct area, neurological deficit score, motor coordination, and biochemical parameters were evaluated. The expression of various genes and proteins was assessed. An inhibition study was also carried out to confirm the involvement of BDNF/TrkB signaling in ER stress-induced apoptosis. IA-administered MSCs improved functional outcomes, reduced infarct area, increased neuronal survival, and normalized biochemical parameters. mRNA and protein expression of ER stress markers were reduced, while those of BDNF and TrkB were increased. Reduction in ER stress-mediated apoptosis was also observed. The present study shows that IA MSCs administration post stroke provides neuroprotection and can modulate ER stress-mediated apoptosis via the BDNF/TrkB signaling pathway.
缺血性中风具有破坏性，严重的长期残疾影响着全世界数百万人。越来越多的证据表明，中风后给予间充质干细胞（MSCs）治疗可提供神经保护并提高中风患者的生活质量。我们实验室之前的研究表明，中风后 6 小时内经动脉内（IA）给予 1×10 MSCs 可通过调节炎症小体和钙调神经磷酸酶信号来提供神经保护。缺血性中风会引起内质网（ER）应激，从而加重病变。本研究旨在了解脑源性神经营养因子/原肌球蛋白受体激酶 B（BDNF/TrkB）信号在中风后经 IA 给予 MSCs 治疗以防止 ER 应激诱导的细胞凋亡中的作用。在去卵巢雌性 Sprague Dawley 大鼠中诱导缺血性中风。经 IA 给予 MSCs，中风后 24 小时处死动物。评估梗死面积、神经功能缺损评分、运动协调和生化参数。评估各种基因和蛋白的表达。还进行了抑制研究以确认 BDNF/TrkB 信号在 ER 应激诱导的细胞凋亡中的作用。IA 给予 MSCs 可改善功能结果，减少梗死面积，增加神经元存活，并使生化参数正常化。ER 应激标志物的 mRNA 和蛋白表达减少，而 BDNF 和 TrkB 的表达增加。还观察到 ER 应激介导的细胞凋亡减少。本研究表明，中风后 IA 给予 MSCs 治疗可提供神经保护，并可通过 BDNF/TrkB 信号通路调节 ER 应激介导的细胞凋亡。
