Sulforaphane, an Nrf-2 Agonist, Modulates Oxidative Stress and Inflammation in a Rat Model of Cuprizone-Induced Cardiotoxicity and Hepatotoxicity

Abstract

Cuprizone (CPZ) is a neurotoxic agent that is used to induce demyelination and neurotoxicity in rats. This study aimed to investigate the protective potential of sulforaphane (SF), nuclear factor E2 related factor (Nrf-2) activator, against CPZ-induced cardiotoxicity and hepatotoxicity. Male adult Wistar rats (n = 18) were fed with a regular diet or a CPZ-contained diet (0.2%) for four weeks. The rats were divided into three groups (n = 6): negative control rats, CPZ-exposed rats, and CPZ + SF treated rats. SF was intraperitoneally administrated (2 mg/kg/day) for two weeks. The anti-inflammatory and anti-oxidative functions of SF were investigated biochemically, histologically, and immunohistochemically. CPZ increased serum levels of cardiac troponin 1 (CTn1), aspartate amino transaminase (AST), alanine amino transaminase (ALT), and alkaline phosphatase (ALP). In addition, serum levels of inflammatory interferon-gamma (IFN-γ), and pro-inflammatory interleukin 1β (IL-1β) were significantly elevated. Moreover, CPZ administration provoked oxidative stress as manifested by declined serum levels of total antioxidant capacity (TAC), as well as, stimulated lipid peroxidation and decreased catalase activities in both cardiac and hepatic tissues. SF treatment reversed all these biochemical alterations through exerting anti-oxidative and anti-inflammatory activities, and this was supported by histopathological investigations in both cardiac and hepatic tissues. This SF-triggered modulation of oxidative stress and inflammation is strongly associated with Nrf-2 activation, as evidenced by activated immunoexpression in both cardiac and hepatic tissues. This highlights the cardioprotective and hepatoprotective activities of SF via Nrf-2 activation and enhancing catalase function.

Anti-Inflammatory Therapeutic Mechanisms of Isothiocyanates: Insights from Sulforaphane

“…Other rat models of inflammation in the liver where sulforaphane has shown positive results include non-alcoholic fatty liver disease [ 38 ] and sodium valproate-induced acute liver injury [ 39 ]. In a rat heart inflammation model, sulforaphane ameliorated doxorubicin-induced chronic heart failure [ 40 ] and reduced fibrosis and the scores of post-myocardial infarction associated with an increased HO-1 level [ 41 ], as well as the positive anti-inflammatory score in acrolein-induced cardiomyopathy [ 42 ], the cardiac ischaemia/reperfusion model [ 43 ], and cuprizone-induced cardiotoxicity [ 44 ]. Ischaemia/reperfusion injuries in rats have been further used to demonstrate the anti-inflammatory activity of sulforaphane in various organs, including the lungs [ 45 ] and retina [ 46 , 47 ].…”