Nobiletin prevents cadmium-induced neuronal apoptosis by inhibiting reactive oxygen species and modulating JNK/ERK1/2 and Akt/mTOR networks in rats

Objectives: Cadmium (Cd), an extremely noxious environmental pollutant is known to induce oxidative stress leading to neurodegenerative diseases. Nobiletin, a citrus flavonoid is reported to possess various pharmacological properties. This study investigates the effects of nobiletin over Cd-induced neuronal apoptosis in rodent experimental model. Methods: To separate group of male Sprague Dawley rats, Cd (2 mL/kg/day) was subcutaneously injected for one month which results in a dose level of 1 mg/kg Cd. Couple of days prior to Cd injection, the treatment group rats regularly received nobiletin (50, 100, or 200 mg/kg b.wt) orally through the study period. Results: Cd-induced ROS levels and malondialdehyde (MDA) content were inhibited by nobiletin and improved glutathione levels. Nobiletin reduced neuronal apoptosis induced by Cd and raised cleaved caspase-3 levels. Intriguingly, nobiletin blocked JNK and Erk1/2 phosphorylation and down-regulated the pathways. Raised expression of kinases -MKK and ASK1 were reduced by nobiletin. Discussion: The suppressed expression of phosphatases -PP2A and PP5 were up-regulated on nobiletin treatment. Nobiletin significantly blocked the activation of Akt/mTOR signaling. Enhanced phosphorylation of S6K1, Akt, and 4E-BP1 induced by Cd was significantly inhibited by nobiletin. The raised levels of raptor and rictor proteins were remarkably down-regulated on nobiletin treatment. Collectively, the observations of this study indicate protective effects of nobiletin against Cd-induced neurotoxicity.