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.

BMS-470539 Attenuates Oxidative Stress and Neuronal Apoptosis via MC1R/cAMP/PKA/Nurr1 Signaling Pathway in a Neonatal Hypoxic-Ischemic Rat Model

“…As a promising route of administration for CNS targeting, intranasal drug administration has several advantages, including bypassing the blood-brain barrier, targeting the brain directly, shorter time to onset of effect, and higher bioavailability due to avoidance of hepatic first-pass metabolism [ 39 , 40 ]. Previous studies and our data showed that BMS-470539 administration 1 h after SAH or HI via the intranasal pathway exerts neuroprotective effects in the SAH and HIE rat models [ 20 , 24 , 26 ]. Based on the above studies, BMS-470539 was also administered intranasally at 1 h after HI induction in the present study.…”

“…MC1R activation also exerted anti-inflammatory, antiapoptotic, and neuroprotective effects in a mice model of experimental traumatic brain injury [ 22 ]. As a synthesized small-molecule and specific selective agonist of MC1R, 1-[1-(3-methyl-L-histidyl-O-methyl-D-tyrosyl)-4-phenyl-4-piperidinyl]-1-butanone (BMS-470539) has been shown to attenuate early brain injury (EBI) following subarachnoid hemorrhage (SAH) by inhibiting oxidative stress, neuronal apoptosis, and mitochondrial fission via MC1R signaling [ 23 , 24 ]. By binding with MC1R, BMS-470539 suppressed lipopolysaccharide- (LPS-) induced inflammatory responses and delayed neutrophil apoptosis [ 25 ].…”

An Update on Antioxidative Stress Therapy Research for Early Brain Injury After Subarachnoid Hemorrhage

“…After SAH, exhibiting aberrant redox hemostasis, the production of oxidants mainly comes from the disruption of mitochondria ( Yan et al, 2015 ; Fan et al, 2021 ; Xu W. et al, 2021 ), extravascular hemolyzed blood ( Vecchione et al, 2009 ; Deng et al, 2018 ), and enzymatic sources of free radicals ( Sies et al, 2017 ; Yang et al, 2017 ; Sies and Jones, 2020 ). Intrinsic antioxidant activity can be exhausted by excessive free radicals, resulting in lipid peroxidation, protein breakdown, and DNA damage.…”

“…The mechanisms for ROS generated by mitochondria are under the consensus that the production of ROS is maximal when the ingredients of the electron transport chains (ETCs) are superlatively impaired ( Murphy et al, 1999 ; Moro et al, 2005 ). Particularly interacting with autophagy and apoptosis, activation of autophagic pathways attenuates EBI after SAH in rats ( Jing et al, 2012 ; Shi et al, 2020 ; Xu W. et al, 2021 ). Among the mounts of antioxidant agents, docosahexaenoic acid (DHA), the so-called omega-3 fatty acid, reduces OS through enhancing mitochondrial dynamics in EBI ( Zhang T. et al, 2018 ).…”

“…Interestingly, derived from seaweeds, fucoxanthin (Fx) mitigates SAH-induced oxidative damage via the SIRT1-dependent pathway ( Zhang X. S. et al, 2020 ). The activation of melanocortin 1 receptor with BMS-470539 immensely reduced EBI after SAH by restraining OS, apoptosis, and mitochondrial fission via the AMPK/SIRT1/PGC-1α signaling pathway ( Xu W. et al, 2021 ). Modulated by SIRT1 activation, salvianolic acid B protects against SAH-triggered oxidative damage by upregulating the Nrf2 antioxidant signaling pathway ( Zhang X. et al, 2018 ).…”