Melanocortin 1 receptor attenuates early brain injury following subarachnoid hemorrhage by controlling mitochondrial metabolism via AMPK/SIRT1/PGC-1α pathway in rats.

Abstract

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-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. Results: 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. 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-1α signaling pathway.

• Authors: Weilin Xu, Jun Yan, Umut Ocak, Cameron Lenahan, Anwen Shao, Jiping Tang, Jianmin Zhang, John H Zhang
• Journal: Theranostics (Theranostics) Vol. 11 Issue 2 Pg. 522-539 ( 2021) ISSN: 1838-7640 [Electronic] Australia
• PMID: 33391490 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Neuroprotective Agents
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, rat
• Receptor, Melanocortin, Type 1
• AMP-Activated Protein Kinases
• Sirt1 protein, rat
• Sirtuin 1

Topics

• AMP-Activated Protein Kinases (genetics, metabolism)
• Animals
• Apoptosis
• Brain Injuries (etiology, metabolism, pathology, prevention & control)
• Male
• Mitochondria (metabolism)
• Neuroprotective Agents
• Oxidative Stress
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptor, Melanocortin, Type 1 (genetics, metabolism)
• Signal Transduction
• Sirtuin 1 (genetics, metabolism)
• Subarachnoid Hemorrhage (complications)