Aprepitant attenuates NLRC4-dependent neuronal pyroptosis via NK1R/PKCδ pathway in a mouse model of intracerebral hemorrhage

Background Pyroptosis is a programmed cell death mediated by inflammasomes. Previous studies have reported that inhibition of neurokinin receptor 1 (NK1R) exerted neuroprotection in several neurological diseases. Herein, we have investigated the role of NK1R receptor inhibition using Aprepitant to attenuate NLRC4-dependent neuronal pyroptosis after intracerebral hemorrhage (ICH), as well as the underlying mechanism. Methods A total of 182 CD-1 mice were used. ICH was induced by injection of autologous blood into the right basal ganglia. Aprepitant, a selective antagonist of NK1R, was injected intraperitoneally at 1 h after ICH. To explore the underlying mechanism, NK1R agonist, GR73632, and protein kinase C delta (PKC delta) agonist, phorbol 12-myristate 13-acetate (PMA), were injected intracerebroventricularly at 1 h after ICH induction, and small interfering ribonucleic acid (siRNA) for NLRC4 was administered via intracerebroventricular injection at 48 h before ICH induction, respectively. Neurobehavioral tests, western blot, and immunofluorescence staining were performed. Results The expression of endogenous NK1R and NLRC 4 were gradually increased after ICH. NK1R was expressed on neurons. Aprepitant significantly improved the short- and long-term neurobehavioral deficits after ICH, which was accompanied with decreased neuronal pyroptosis, as well as decreased expression of NLRC4, Cleaved-caspase-1, GSDMD (gasdermin D), IL-1 beta, and IL-18. Activation of NK1R or PKC delta abolished these neuroprotective effects of Aprepitant after ICH. Similarly, knocking down NLRC4 using siRNA produced similar neuroprotective effects. Conclusion Aprepitant suppressed NLRC4-dependent neuronal pyroptosis and improved neurological function, possibly mediated by inhibition of NK1R/PKC delta signaling pathways after ICH. The NK1R may be a promising therapeutic target for the treatment of ICH.

Automated summary

This study found that inhibition of NK1R receptor using Aprepitant can attenuate neuronal pyroptosis and improve neurological function after intracerebral hemorrhage (ICH). The neuroprotective effects of Aprepitant may be mediated by inhibition of NK1R/PKC delta signaling pathways.