Melanocortin 1 receptor attenuates early brain injury following subarachnoid hemorrhage by controlling mitochondrial metabolism AMPK/SIRT1/PGC-1α pathway in rats
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. We utilized BMS-470539, MSG-606, selisistat, and PGC-1α 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. The results of western blotting suggested that the expression of SIRT1 and PGC-1α 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-1α, 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-1α siRNA. 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-1α signaling pathway.
Xu, Weilin; Yan, Jun; Ocak, Umut; Lenahan, Cameron; Shao, Anwen; Tang, Jiping; Zhang, Jianmin; and Zhang, John H., "Melanocortin 1 receptor attenuates early brain injury following subarachnoid hemorrhage by controlling mitochondrial metabolism AMPK/SIRT1/PGC-1α pathway in rats" (2021). LLU Faculty Publications. 297.