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

Weilin Xu, Jun Mo, Umut Ocak, Zachary D. Travis, Budbazar Enkhjargal, Tongyu Zhang, Pei Wu, Jianhua Peng, Tao Li, Yuchun Zuo, Anwen Shao, Jiping Tang, Jianmin Zhang, John H. Zhang

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)294-308
Number of pages15
JournalNeurotherapeutics
Volume17
Issue number1
DOIs
StatePublished - Jan 1 2020

ASJC Scopus Subject Areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

Keywords

  • Early brain injury
  • Melanocortin 1 Receptor
  • Neuroinflammation
  • Subarachnoid hemorrhage
  • TBK1
  • Receptor, Melanocortin, Type 1/administration & dosage
  • Microglia/metabolism
  • Male
  • Rats, Sprague-Dawley
  • Signal Transduction/drug effects
  • Brain Injuries/complications
  • AMP-Activated Protein Kinase Kinases
  • Subarachnoid Hemorrhage/complications
  • Animals
  • Protein Kinases/metabolism
  • Protein Serine-Threonine Kinases/metabolism
  • NF-kappa B/metabolism
  • Encephalitis/complications
  • Brain/metabolism

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