TY - JOUR
T1 - Neurokinin Receptor 1 (NK1R) Antagonist Aprepitant Enhances Hematoma Clearance by Regulating Microglial Polarization via PKC/p38MAPK/NFκB Pathway After Experimental Intracerebral Hemorrhage in Mice
AU - Jin, Peng
AU - Deng, Shuixiang
AU - Sherchan, Prativa
AU - Cui, Yuhui
AU - Huang, Lei
AU - Li, Gaigai
AU - Lian, Lifei
AU - Xie, Shucai
AU - Lenahan, Cameron
AU - Travis, Zachary D.
AU - Zhang, John H.
AU - Gong, Ye
AU - Tang, Jiping
N1 - Publisher Copyright:
© 2021, The American Society for Experimental NeuroTherapeutics, Inc.
PY - 2021/7
Y1 - 2021/7
N2 - Hematoma clearance is an important therapeutic target to improve outcome following intracerebral hemorrhage (ICH). Recent studies showed that Neurokinin receptor-1 (NK1R) inhibition exerts protective effects in various neurological disease models, but its role in ICH has not been explored. The objective of this study was to investigate the role of NK1R and its relation to hematoma clearance after ICH using an autologous blood injection mouse model. A total of 332 adult male CD1 mice were used. We found that the expression levels of NK1R and its endogenous ligand, substance P (SP), were significantly upregulated after ICH. Intraperitoneal administration of the NK1R selective antagonist, Aprepitant, significantly improved neurobehavior, reduced hematoma volume and hemoglobin levels after ICH, and promoted microglia polarization towards M2 phenotype. Aprepitant decreased phosphorylated PKC, p38MAPK, and NFκB p65, and downregulated M1 markers while upregulating M2 markers after ICH. Intracerebroventricular administration of the NK1R agonist, GR73632 or PKC agonist, phorbol 12-myristate 13-acetate (PMA) reversed the effects of Aprepitant. To demonstrate the upstream mediator of NK1R activation, we performed thrombin injection and found that it increased SP. Inhibiting thrombin suppressed SP and decreased M1 markers while increasing M2 microglia polarization. Thus, NK1R inhibition promoted hematoma clearance after ICH by increasing M2 microglial polarization via downregulating PKC/p38MAPK/NFκB signaling pathway, and thrombin may be a key upstream mediator of NK1R activation. Therapeutic interventions inhibiting NK1R signaling may be a new target for the treatment of ICH.
AB - Hematoma clearance is an important therapeutic target to improve outcome following intracerebral hemorrhage (ICH). Recent studies showed that Neurokinin receptor-1 (NK1R) inhibition exerts protective effects in various neurological disease models, but its role in ICH has not been explored. The objective of this study was to investigate the role of NK1R and its relation to hematoma clearance after ICH using an autologous blood injection mouse model. A total of 332 adult male CD1 mice were used. We found that the expression levels of NK1R and its endogenous ligand, substance P (SP), were significantly upregulated after ICH. Intraperitoneal administration of the NK1R selective antagonist, Aprepitant, significantly improved neurobehavior, reduced hematoma volume and hemoglobin levels after ICH, and promoted microglia polarization towards M2 phenotype. Aprepitant decreased phosphorylated PKC, p38MAPK, and NFκB p65, and downregulated M1 markers while upregulating M2 markers after ICH. Intracerebroventricular administration of the NK1R agonist, GR73632 or PKC agonist, phorbol 12-myristate 13-acetate (PMA) reversed the effects of Aprepitant. To demonstrate the upstream mediator of NK1R activation, we performed thrombin injection and found that it increased SP. Inhibiting thrombin suppressed SP and decreased M1 markers while increasing M2 microglia polarization. Thus, NK1R inhibition promoted hematoma clearance after ICH by increasing M2 microglial polarization via downregulating PKC/p38MAPK/NFκB signaling pathway, and thrombin may be a key upstream mediator of NK1R activation. Therapeutic interventions inhibiting NK1R signaling may be a new target for the treatment of ICH.
KW - Hematoma clearance
KW - Intracerebral hemorrhage
KW - Microglia polarization
KW - Neurokinin receptor-1
KW - Thrombin
KW - Microglia/drug effects
KW - Male
KW - Neurokinin-1 Receptor Antagonists/pharmacology
KW - Cell Polarity/drug effects
KW - Hematoma/drug therapy
KW - Protein Kinase C/antagonists & inhibitors
KW - Aprepitant/pharmacology
KW - Animals
KW - p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
KW - Cerebral Hemorrhage/drug therapy
KW - Mice
KW - NF-kappa B/antagonists & inhibitors
KW - Receptors, Neurokinin-1/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85109900254&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85109900254&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/1029a8e6-cfb9-30fb-ad9e-93871b7802fc/
U2 - 10.1007/s13311-021-01077-8
DO - 10.1007/s13311-021-01077-8
M3 - Article
C2 - 34244927
SN - 1933-7213
VL - 18
SP - 1922
EP - 1938
JO - Neurotherapeutics
JF - Neurotherapeutics
IS - 3
ER -