The Role of NMDA Receptor Partial Antagonist, Carbamathione, as a Therapeutic Agent for Transient Global Ischemia
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Published:2023-07-03
Issue:7
Volume:11
Page:1885
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ISSN:2227-9059
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Container-title:Biomedicines
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language:en
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Short-container-title:Biomedicines
Author:
Modi Jigar Pravinchandra12, Shen Wen13, Menzie-Suderam Janet13, Xu Hongyuan1, Lin Chun-Hua4ORCID, Tao Rui13, Prentice Howard M.123, Schloss John5, Wu Jang-Yen123
Affiliation:
1. Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA 2. Center of Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA 3. Program in Integrative Biology, Florida Atlantic University, Boca Raton, FL 33431, USA 4. Department of Nursing, Kang-Ning University, Taipei 11485, Taiwan 5. Department of Pharmaceutical Science, American University of Health Sciences, Signal Hill, CA 90755, USA
Abstract
Carbamathione (Carb), an NMDA glutamate receptor partial antagonist, has potent neuroprotective functions against hypoxia- or ischemia-induced neuronal injury in cell- or animal-based stroke models. We used PC-12 cell cultures as a cell-based model and bilateral carotid artery occlusion (BCAO) for stroke. Whole-cell patch clamp recording in the mouse retinal ganglion cells was performed. Key proteins involved in apoptosis, endoplasmic reticulum (ER) stress, and heat shock proteins were analyzed using immunoblotting. Carb is effective in protecting PC12 cells against glutamate- or hypoxia-induced cell injury. Electrophysiological results show that Carb attenuates NMDA-mediated glutamate currents in the retinal ganglion cells, which results in activation of the AKT signaling pathway and increased expression of pro-cell survival biomarkers, e.g., Hsp 27, P-AKT, and Bcl2 and decreased expression of pro-cell death markers, e.g., Beclin 1, Bax, and Cleaved caspase 3, and ER stress markers, e.g., CHOP, IRE1, XBP1, ATF 4, and eIF2α. Using the BCAO animal stroke model, we found that Carb reduced the brain infarct volume and decreased levels of ER stress markers, GRP 78, CHOP, and at the behavioral level, e.g., a decrease in asymmetric turns and an increase in locomotor activity. These findings for Carb provide promising and rational strategies for stroke therapy.
Funder
Florida Department of Health, James and Esther King Biomedical Research Program of Florida Ed and Ethel Moore Alzheimer’s Disease Research Program
Subject
General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)
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