Caffeic acid phenethyl ester protects the brain against hexavalent chromium toxicity by enhancing endogenous antioxidants and modulating the JAK/STAT signaling pathway

Hexavalent chromium [Cr(VI)] is commonly used in industry, and is a proven toxin and carcinogen. However, the information regarding its neurotoxic mechanism is not completely understood. The present study was designed to scrutinize the possible protective effects of caffeic acid phenethyl ester (CAPE), a bioactive phenolic of propolis extract, on Cr(VI)-induced brain injury in rats, with an emphasis on the JAK/STAT signaling pathway. Rats received 2 mg/kg K2CrO4 and concurrently treated with 20 mg/kg CAPE for 30 days. Cr(VI)-induced rats showed a significant increase in cerebral lipid peroxidation, nitric oxide and pro-inflammatory cytokines, with concomitantly declined antioxidants and acetylcholinesterase. CAPE attenuated oxidative stress and inflammation and enhanced antioxidant defenses in the cerebrum of rats. Cr(VI) significantly up-regulated JAK2, STAT3 and SOCS3, an effect that was reversed by CAPE. In conclusion, CAPE protects the brain against Cr(VI) toxicity through abrogation of oxidative stress, inflammation and down-regulation of JAK2/STAT3 signaling in a SOCS3-independent mechanism.