Evaluation of the protective effect of diphenhydramine on doxorubicin-induced nephrotoxicity

Doxorubicin (Dox) is an anthracycline antitumor antibiotic used in the treatment of various tumors. Nephrotoxicity is one of the most common side effects of DOX use and therefore its use is limited. Different compounds are used to minimize the cytotoxic effects of Dox. It has been suggested that diphenhydramine (DPH), an antihistamine drug, may exhibit antioxidant, anti-inflammatory and anti-apoptotic effects in response to DOX damage, but its mechanism of action is not yet known. The aim of this study was to determine the protective effect of DPH against DOX-induced nephrotoxicity using biochemical, immunohistochemical and histopathological approaches. Forty male Wistar rats were randomly divided into four groups: control group, Dox group (20 mg/kg, i.p.), DPH group (20 mg/kg i.m.), and Dox + DPH group (20 mg/kg i.p. and 20 mg/kg i.m.). After 10 days, serum and kidney tissues of the rats were collected and biochemical kidney function tests, oxidative stress markers, antioxidant enzyme status, and histopathological changes were examined. Serum blood ürea nitrogen (BUN), creatinine (CR), catalase CAT, glutatyon (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), total antioxidant capacity TAS, total oxidant capacity TOS, oxidant stress indexing (OSI) concentrations were determined by ELISA technique. To determine the inflammatory status, IL-1β, IL-6, TNF-α and CRP levels were evaluated by ımmunohistochemistry. DOX caused some histopathological changes in the kidneys, such as glomerular vacuolization and degeneration, expansion of Bowman's capsule, tubular and glomerular capillary degeneration and irregularity and fibrosis. In addition, serum IL-1, IL-6, TNF-α and CRP immunoreactivities were observed to increase in the DOX group. DOX administration increased serum BUN and creatinine concentrations. With DOX administration, MDA and ISO concentrations increased, while GSH, SOD, CAT, TAS concentrations decreased. DPH inhibited DOX-induced histopathological changes in kidney tissue. DPH administration reduced serum creatinine, BUN, and MDA levels and reversed doxorubicin-induced changes in serum antioxidant parameters, enzymatic activity, and expression of inflammatory proteins. DPH alleviated Dox-induced nephrotoxicity by improving the antioxidant mechanism, reducing inflammation, and protecting the histological structure of the kidney. Collectively, these findings demonstrate the protective effects of DPH against DOX-induced nephrotoxicity in rats. Thus, DPH showed efficacy as a promising new preventive drug against DOX-induced renal toxicity.