title: Doxorubicin-induced neurotoxicity is attenuated by a 43-kD protein from the leaves of Cajanus indicus L. via NF-κB and mitochondria dependent pathways.
abstract: 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.
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, India.
authors.forename: Sankhadeep
authors.initials: S
authors.lastname: Pal
authors.forename: Manisha
authors.initials: M
authors.lastname: Ahir
authors.forename: Parames C
authors.initials: PC
authors.lastname: Sil
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D036561:Cajanus / Q000737:chemistry*; D004317:Doxorubicin / Q000633:toxicity*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology; D018515:Plant Leaves / Q000737:chemistry; D010940:Plant Proteins / Q000494:pharmacology*; D011897:Random Allocation; D017382:Reactive Oxygen Species; D015398:Signal Transduction
chemical_list: D000903:Antibiotics, Antineoplastic; D016328:NF-kappa B; D010936:Plant Extracts; D010940:Plant Proteins; D017382:Reactive Oxygen Species; D004317:Doxorubicin