期刊
THERANOSTICS
卷 11, 期 2, 页码 522-539出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.49426
关键词
melanocortin 1 receptor; mitochondrial fission; oxidative stress; peroxisome proliferator-activated receptor gamma coactivator 1-alpha; subarachnoid hemorrhage
资金
- National Institutes of Health [NS084921, NS082184, NS43338]
- National Natural Science Foundation of China [82001231, 82060225]
- Guangxi Natural Science Foundation [2018JJA140243]
Activation of MC1R using BMS-470539 significantly attenuated early brain injury following SAH by suppressing oxidative stress, apoptosis, and mitochondrial fission through the AMPK/SIRT1/PGC-1 alpha signaling pathway, improving neurological deficits and memory impairments.
Mitochondria-mediated oxidative stress and apoptosis contribute greatly to early brain injury (EBI) following subarachnoid hemorrhage (SAH). This study hypothesized that activation of melanocortin 1 receptor (MC1R), using BMS-470539, attenuates EBI by controlling mitochondrial metabolism after SAH. Methods: We utilized BMS-470539, MSG-606, selisistat, and PGC-1 alpha to verify the neuroprotective effects of MC1R. We evaluated short- and long-term neurobehavior after SAH. Western blotting, immunofluorescence, and Golgi staining techniques were performed to assess changes in protein levels. Results: The results of western blotting suggested that the expression of SIRT1 and PGC-1 alpha were increased, reaching their peaks at 24 h following SAH. Moreover, BMS-470539 treatment notably attenuated neurological deficits, and also reduced long-term spatial learning and memory impairments caused by SAH. The underlying neuroprotective mechanisms of the BMS-470539/MC1R system were mediated through the suppression of oxidative stress, apoptosis, and mitochondrial fission by increasing the levels of SIRT1, PGC-1 alpha, UCP2, SOD, GPx, Bcl-2, cyto-Drp1, and ATP, while decreasing the levels of cleaved caspase-3, Bax, mito-Drp1, ROS, GSH/GSSG, and NADPH/NADP+ ratios. The neuroprotective effects of the BMS-470539/MC1R system were significantly abolished by MSG-606, selisistat, and PGC-1 alpha siRNA. Conclusions: The activation of MC1R with BMS-470539 significantly attenuated EBI after SAH by suppressing the oxidative stress, apoptosis, and mitochondrial fission through the AMPK/SIRT1/PGC-1 alpha signaling pathway.
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