Datta Aishika, Sarmah Deepaneeta, Kaur Harpreet, Chaudhary Antra, Mounica Kamisetty Leela, Kalia Kiran, Borah Anupom, Yavagal Dileep R, Bhattacharya Pallab
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India.
Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India.
Mol Neurobiol. 2022 May;59(5):2758-2775. doi: 10.1007/s12035-022-02761-2. Epub 2022 Feb 21.
Post-stroke edema and upregulation of aquaporin 4 (AQP4) water transport channels play a significant role in the progression of stroke pathology and deteriorating stroke outcomes. Prior studies from our lab have demonstrated the safety and efficacy of intra-arterial (IA) 1 × 10 mesenchymal stem cells (MSCs) administration post-stroke towards functional restoration and neuroprotection. Protein kinases have been reported to be involved in the signaling cascade of edema, with evidence supporting both its upregulation and downregulation at 24 h post-stroke. Among different protein kinase C (PKC) isoforms, the δ isoform is widely reported to play a pivotal role in the progression of ischemic reperfusion injury. Our present study aims to decipher the molecular mechanism of post-stroke IA MSCs mediated alleviation of perifocal vasogenic edema by PKCδ-mediated AQP4 regulation. Ovariectomized female SD rats were infused with 1 × 10 IA MSCs at 6 h post middle cerebral artery occlusion (MCAo). Animals were evaluated for behavioral and functional outcomes. Brains were harvested for evaluating infarct size and brain edema. Further, brain tissues were used for biochemical and molecular studies to decipher the possible molecular mechanism related to the regulation of PKCδ-mediated AQP4 expression. 1 × 10 IA MSCs at 6 h post-stroke confers neuroprotection as evident by the reduction in infarct size, edema, and improvement of functional outcome. An increase in GSH and catalase and a reduction in nitrite and MDA were observed along with a decrease in AQP4 and PKCδ expressions within the cortical brain regions of IA MSC-infused animals. The study gives preliminary evidence that IA MSCs administration post-stroke modulates PKCδ to regulate AQP4 expression which alleviates vasogenic edema towards neuroprotection. The study is novel and clinically relevant as no previous studies have looked into this aspect following IA delivery of stem cells in an animal model of ischemic stroke.
中风后水肿以及水通道蛋白4（AQP4）水转运通道的上调在中风病理进展和中风预后恶化中起重要作用。我们实验室先前的研究已经证明，中风后经动脉内（IA）给予1×10间充质干细胞（MSCs）对功能恢复和神经保护具有安全性和有效性。据报道，蛋白激酶参与水肿的信号级联反应，有证据支持其在中风后24小时上调和下调。在不同的蛋白激酶C（PKC）亚型中，δ亚型被广泛报道在缺血再灌注损伤进展中起关键作用。我们目前的研究旨在阐明中风后IA MSCs介导减轻灶周血管源性水肿的分子机制，即通过PKCδ介导的AQP4调节。对去卵巢雌性SD大鼠在大脑中动脉闭塞（MCAo）后6小时经动脉内注入1×10 MSCs。对动物的行为和功能结果进行评估。取脑以评估梗死面积和脑水肿。此外，使用脑组织进行生化和分子研究，以阐明与PKCδ介导的AQP4表达调节相关的可能分子机制。中风后6小时经动脉内给予1×10 MSCs具有神经保护作用，梗死面积减小、水肿减轻以及功能结果改善即可证明。在注入IA MSCs的动物的大脑皮质区域内，观察到谷胱甘肽（GSH）和过氧化氢酶增加，亚硝酸盐和丙二醛（MDA）减少，同时AQP4和PKCδ表达降低。该研究提供了初步证据，表明中风后经动脉内给予MSCs可调节PKCδ以调节AQP4表达，从而减轻血管源性水肿并实现神经保护。该研究具有创新性且与临床相关，因为之前没有研究在缺血性中风动物模型中经动脉内递送干细胞后研究过这一方面。
