2. Academic Validation
  3. 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

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

  • Neurotherapeutics. 2020 Jan;17(1):294-308. doi: 10.1007/s13311-019-00772-x.
Weilin Xu  # 1 2,  Jun Mo  # 1 3,  Umut Ocak 2,  Zachary D Travis 4,  Budbazar Enkhjargal 2,  Tongyu Zhang 2,  Pei Wu 2,  Jianhua Peng 2,  Tao Li 2,  Yuchun Zuo 2,  Anwen Shao 1,  Jiping Tang 2,  Jianmin Zhang 5 6,  John H Zhang 7 8 9 10
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Rd, Hangzhou, 310009, Zhejiang, China.
  • 2 Department of Physiology & Pharmacology, Loma Linda University, Loma Linda, CA, 92350, USA.
  • 3 Department of Neurosurgery, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Rd, Hangzhou, 310009, Zhejiang, China.
  • 4 Department of Earth and Biological Sciences, Loma Linda University, Loma Linda, CA, 92350, USA.
  • 5 Department of Neurosurgery, The second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Rd, Hangzhou, 310009, Zhejiang, China. zjm135@zju.edu.cn.
  • 6 Brain Research Institute, Zhejiang University, Hangzhou, 310009, Zhejiang, China. zjm135@zju.edu.cn.
  • 7 Department of Physiology & Pharmacology, Loma Linda University, Loma Linda, CA, 92350, USA. johnzhang3910@yahoo.com.
  • 8 Department of Neurosurgery, Loma Linda University, Loma Linda, CA, 92350, USA. johnzhang3910@yahoo.com.
  • 9 Department of Anesthesiology, Loma Linda University, Loma Linda, CA, 92350, USA. johnzhang3910@yahoo.com.
  • 10 Department of Physiology and Pharmacology, Loma Linda University, Risley Hall, Room 219, 11041 Campus St, Loma Linda, CA, 92354, USA. johnzhang3910@yahoo.com.
  • # Contributed equally.
PMID: 31486022 DOI: 10.1007/s13311-019-00772-x
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.

Keywords

Early brain injury; Melanocortin 1 Receptor; Neuroinflammation; Subarachnoid hemorrhage; TBK1.

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