TY - JOUR
T1 - 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
AU - Xu, Weilin
AU - Mo, Jun
AU - Ocak, Umut
AU - Travis, Zachary D.
AU - Enkhjargal, Budbazar
AU - Zhang, Tongyu
AU - Wu, Pei
AU - Peng, Jianhua
AU - Li, Tao
AU - Zuo, Yuchun
AU - Shao, Anwen
AU - Tang, Jiping
AU - Zhang, Jianmin
AU - Zhang, John H.
N1 - Publisher Copyright:
© 2019, The American Society for Experimental NeuroTherapeutics, Inc.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
KW - Early brain injury
KW - Melanocortin 1 Receptor
KW - Neuroinflammation
KW - Subarachnoid hemorrhage
KW - TBK1
KW - Receptor, Melanocortin, Type 1/administration & dosage
KW - Microglia/metabolism
KW - Male
KW - Rats, Sprague-Dawley
KW - Signal Transduction/drug effects
KW - Brain Injuries/complications
KW - AMP-Activated Protein Kinase Kinases
KW - Subarachnoid Hemorrhage/complications
KW - Animals
KW - Protein Kinases/metabolism
KW - Protein Serine-Threonine Kinases/metabolism
KW - NF-kappa B/metabolism
KW - Encephalitis/complications
KW - Brain/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85073795817&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85073795817&partnerID=8YFLogxK
U2 - 10.1007/s13311-019-00772-x
DO - 10.1007/s13311-019-00772-x
M3 - Article
C2 - 31486022
SN - 1933-7213
VL - 17
SP - 294
EP - 308
JO - Neurotherapeutics
JF - Neurotherapeutics
IS - 1
ER -