Doxorubicin-induced neurotoxicity is attenuated by a 43-kD protein from the leaves of Cajanus indicus L. via NF-κB and mitochondria dependent pathways.

Doxorubicin (Dox) is an effective anthracycline antitumour drug although its clinical efficacy is restricted because of several acute and chronic side effects. It has been suggested that Dox-induced anticancer effect and neurotoxicity do not follow identical mechanism. The present study has been carried out to investigate the neuroprotecive role of a 43-kD protein (Cajanus indicus (CI) protein) against Dox-induced oxidative impairment and brain tissue damage. Administration of Dox (25 mg/kg body weight) increased reactive oxygen species (ROS) production, altered neuro antioxidant status, activities of brain specific coenzymes (like acetyl coenzyme, monoamine oxidase, etc.), ATPases (like Na(+)/K(+), Ca(2+), etc.) and brain biogenic amines levels. Signal transduction studies showed that Dox markedly decreased mitochondrial membrane potential, disturbed Bcl-2 family protein balance, enhanced cytochrome c release in the cytosol, increased levels of Apaf1, caspase-9/3, cleaved PARP protein and ultimately led to apoptotic cell death. In addition, Dox markedly increased nuclear factor kappa B (NF-κB) nuclear translocation in association with IKKα/β phosphorylation and IκBα degradation. Post-treatment with CI protein (3 mg/kg body weight, once daily for next 4 days), however, reduced Dox-induced oxidative stress, attenuated the nuclear translocation of NF-κB and protected the brain tissue from Dox-induced apoptotic death. Histological studies also support these experimental findings. Results suggest that CI protein might act as a beneficial agent against Dox-induced neuronal dysfunctions.