Activation of Melanocortin 1 Receptor Attenuates Early Brain Injury in a Rat Model of Subarachnoid Hemorrhage viathe Suppression of Neuroinflammation through AMPK/TBK1/NF-κB Pathway in Rats

Abstract

Neuroinflammation plays a vital role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). The hypothesis of this study was that activation of melanocortin 1 receptor (MC1R) with BMS-470539 attenuates EBI by suppression of neuroinflammation after SAH. We utilized BMS-470539, MSG-606, and MRT-68601 to verify the neuroprotective effects of MC1R. We evaluated brain water content, short-term and long-term neurobehavior after SAH. Western blotting and immunofluorescence staining were utilized to assess the changes of protein levels. The results of western blotting suggested that the expressions of MC1R, phosphorylated-adenosine monophosphate-activated protein kinase (p-AMPK), and phosphorylated-TANK binding kinase 1 (p-TBK1) were increased and reached their peak points at 24 h following SAH. Moreover, BMS-470539 treatment notably attenuated neurological deficits caused by SAH, and also notably improved long-term spatial learning and memory abilities after SAH. The underlying mechanisms of the neuroprotection of BMS-470539 involved the suppression of microglia activation, promotion of CD206+ microglia transformation and reduction of neutrophil infiltration by increasing the levels of p-AMPK and p-TBK1 while decreasing the levels of NF-κB, IL-1β, and TNFα. The neuroprotective effects of BMS-470539 were significantly abolished by MSG-606 and MRT-68601. The activation of MC1R with BMS-470539 notably attenuates EBI after SAH by suppression of microglial activation and neutrophil infiltration via the AMPK/TBK1/NF-κB signaling pathway.

Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage

“…Based on the evidence above, we further investigated the role of AMPK in C-176-mediated anti-inflammatory effects after SAH. Consistent with the previous study [28], an increased ratio of p-AMPK/AMPK after SAH was noted in this study. And we found that C-176 further promoted the phosphorylation of AMPK, which can be explained by the elimination of the negative impact of TBK1 on AMPK as reported [32].…”

“…The frozen brain slides used for Nissl staining and hematoxylin and eosin (HE) staining were prepared in the same way as those used to immunofluorescence staining. Nissl staining was conducted to demonstrate the number of normal neuron in cortex and hippocampus as previously reported [28]. The frozen brain slides were immersed with 0.5% cresyl violet (Sigma-Aldrich, St. Louis, MO, USA) solution and dehydrated with 100% alcohol.…”

Bakuchiol Attenuates Oxidative Stress and Neuron Damage by Regulating Trx1/TXNIP and the Phosphorylation of AMPK After Subarachnoid Hemorrhage in Mice

“…In the present study, an increase in AMPK phosphorylation was observed after Bak administration. Besides, the upregulation of AMPK phosphorylation occurs after SAH in the present study, which has also been reported previously (Osuka et al, 2009;Xu et al, 2019;Xu et al, 2020). In our opinion, this phenomenon may be caused by the compensation mechanism during which the self-protecting signal pathways have been activated to tolerate the stress.…”

Nrf2 mitigates prolonged PM2.5 exposure-triggered liver inflammation by positively regulating SIKE activity: Protection by Juglanin

“…TBK1/NF-κB signaling pathway contributed to inflammatory response [ 32 , 43 , 44 ]. To further explore the underlying molecular mechanism, the gain- and loss-of-function studies were conducted in L02 cells through infection with either Ad-shSIKE to suppress SIKE expression or Ad-SIKE to over-express SIKE ( Fig.…”