The H4R antagonist, JNJ-7777120 treatments ameliorate mild traumatic brain injury by reducing oxidative damage, inflammatory and apoptotic responses through blockage of the ERK1/2/NF-κB pathway in a rat model

Abstract

Growing evidence reveals that microglia activation and neuroinflammatory responses trigger cell loss in the brain. Histamine is a critical neurotransmitter and promotes inflammatory responses; thus, the histaminergic system is a potential target for treating neurodegenerative processes. JNJ-7777120, a histamine H4 receptor (H₄R) antagonist, has been shown to alleviate inflammation, brain damage, and behavioral deficits effectively, but there is no report on its role in brain trauma. Herein, we investigated the neuroprotective effects of JNJ-7777120 (shortly JNJ) in a mild traumatic brain injury (mTBI). mTBI setup was performed using a weight-drop model in adult male Sprague-Dawley rats. JNJ (1 mg/kg, twice/day for 7 days) was intraperitoneally administered following mTBI. Modified neurological severity score and beam-walking test used to assess motor, sensory, reflex, and balance functions (post-TBI days-1/3/7) showed that JNJ had significantly improved these functions. HE-staining revealed reduced neurodegenerative cells after JNJ-treatments compared to vehicle (2.85 % DMSO) treated group. JNJ also decreased the injury-induced apoptosis (Bax/Bcl-2, cleaved-Cas-3, cleaved-PARP1), oxidative (4HNE, MDA), and inflammatory (IBA1, TNF-α, IL-1β, IL-6, and IL-10) responses. Furthermore, blocking the activation of the ERK1/2/NF-κB pathway was determined to be involved in its therapeutic mechanism. The network pharmacology analyses for JNJ-7777120 and TBI confirmed the importance of targeting neurotransmitter receptor activity, signaling receptor activity, and kinase activation. Our results provide the first proof of the efficacy of an H₄R antagonist in a mild TBI rat model and suggest that H₄R targeting by JNJ-treatment might be a promising therapeutic approach to clinically halt the progression of brain injury.