Involvement of NOX-4/JAK/STAT pathway in the protective effect of aprepitant against diclofenac-induced renal toxicity

Abstract

AimsAprepitant, a neurokinin-1 (NK1) receptor antagonist, is a clinically approved anti-emetic drug. Recently, inhibition of the NK1 receptor has been reported as a potential nephroprotective strategy. We aimed to assess the pharmacological mechanisms of aprepitant against diclofenac (DIC)-induced renal toxicity. Main methodsAn in vivo study was conducted using twenty-four male Wistar rats, divided into 4 groups. Aprepitant was administered for 5 days (5 mg/kg/day) with or without DIC which was given on the 4th and 5th days (50 mg/kg, i.p.). At the end of the study, renal function biomarkers, renal oxidative parameters, prostaglandin E (PGE-2), and NADPH oxidase (NOX-4) were measured. Histopathological changes as well as expression of renal inflammatory and apoptotic markers (tumor necrosis factor alpha (TNF-α) and caspase-3) were investigated. Key findingsDIC caused significant renal damage, as evidenced by deterioration of renal functions, oxidative stress, inflammatory and apoptotic markers, and confirmed by histopathological findings. Pretreatment with aprepitant successfully ameliorated and improved all biochemical and molecular parameters induced by DIC. Moreover, aprepitant restored the decrease in renal PGE-2 concentration and inhibited DIC-activated Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling in renal tissues. SignificanceThe protective effect of aprepitant is possibly attributed to its anti-oxidant and anti-inflammatory roles via the NOX-4/JAK/STAT pathway.