Neurokinin Receptor 1 (NK1R) Antagonist Aprepitant Enhances Hematoma Clearance by Regulating Microglial Polarization via PKC/p38MAPK/NFκB Pathway After Experimental Intracerebral Hemorrhage in Mice

Abstract

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.

Aprepitant Inhibits JNK and p38/MAPK to Attenuate Inflammation and Suppresses Inflammatory Pain

“…The activation of JNK and p38 can initiate the NF-κBp65 signaling ( An et al, 2019 ; Subedi et al, 2019 ; Wu et al, 2019 ). In mice with intracerebral hemorrhage, aprepitant can downregulate PKC/p38/NFκB signaling pathway ( Jin et al, 2021 ). In addition, the inhibition of NF-κBp65 can reverse the production and expression of pro-inflammatory mediators following carrageenan or LPS treatment ( Alam et al, 2019 ).…”

“…A previous study has reported that aprepitant can act as an anti-inflammatory agent and attenuate lipopolysaccharide (LPS)-induced inflammatory responses in macrophages ( Zhao et al, 2020 ). Aprepitant not only significantly suppresses HIV-1 infection of microglia ( Wang et al, 2008 ), but also downregulates microglia M1 markers, and upregulates microglia M2 markers following intracerebral hemorrhage ( Jin et al, 2021 ). However, there is currently no research on the role of aprepitant in inflammatory pain.…”

Activation of LRP6 with HLY78 Attenuates Oxidative Stress and Neuronal Apoptosis via GSK3β/Sirt1/PGC-1α Pathway after ICH

“…Three behavioral tests were applied at 24 and 72 h after ICH: modified Garcia test, corner turn test, and forelimb placement test, as previously described [ 27 ].…”

Application Effect of Whole-Process Seamless Nursing Model Based on Smart Healthcare Mode in Perioperative Period of Patients Undergoing Hematoma Removal

“…General data: after the patients were enrolled, the general data were collected, and the information files were established, including gender, age, height, weight, BMI, Glasgow Coma Scale (GCS) index [ 12 ], and hematoma volume.…”