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Post-stroke Impairment of the Blood–Brain Barrier and Perifocal Vasogenic Edema Is Alleviated by Endovascular Mesenchymal Stem Cell Administration: Modulation of the PKCδ/MMP9/AQP4-Mediated Pathway

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Abstract

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 × 105 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 × 105 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 × 105 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.

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Fig. 1

adapted from Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com/.). B Summary of the experimental design

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Data Availability

Available upon reasonable request from the corresponding author.

Code Availability

NA.

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Acknowledgements

The authors acknowledge the National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad administration for providing the facility and support for conducting this study. The authors would also like to acknowledge Ms. Monika Seervi, Dr. Shirish Bhatiya, Mr. Pramod Kumar Suthar, and Mr. Vishal Gupta for their support in the study.

Funding

This study was funded by the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India and the Indian Council of Medical Research (ICMR), New Delhi, for the senior research fellowship grant of Ms. Aishika Datta (45/13/2020-PHA/BMS) and the NanoBio project grant to Dr. Pallab Bhattacharya (34/5/2019-TF/Nano/BMS).

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India

    Aishika Datta, Deepaneeta Sarmah, Harpreet Kaur, Antra Chaudhary, Kamisetty Leela Mounica, Kiran Kalia & Pallab Bhattacharya

  2. Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India

    Anupom Borah

  3. Department of Neurology and Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, USA

    Dileep R. Yavagal

Authors
  1. Aishika Datta
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  2. Deepaneeta Sarmah
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  3. Harpreet Kaur
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  4. Antra Chaudhary
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  5. Kamisetty Leela Mounica
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  6. Kiran Kalia
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  8. Dileep R. Yavagal
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  9. Pallab Bhattacharya
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Contributions

Conception and design of the study: PB. Data acquisition: AD, DS, HK, AC, and KLM. Analysis and interpretation of data: AD, DS, HK, AC, KK, AB, DY, and PB. Drafting and revision of the manuscript: AD, DS, KK, AB, DY, and PB. All authors have approved the final manuscript.

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Correspondence to Pallab Bhattacharya.

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Datta, A., Sarmah, D., Kaur, H. et al. Post-stroke Impairment of the Blood–Brain Barrier and Perifocal Vasogenic Edema Is Alleviated by Endovascular Mesenchymal Stem Cell Administration: Modulation of the PKCδ/MMP9/AQP4-Mediated Pathway. Mol Neurobiol 59, 2758–2775 (2022). https://doi.org/10.1007/s12035-022-02761-2

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