title: Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy.
abstract: Oxaliplatin, an organoplatinum compound, is used in the treatment of colorectal cancer, but its clinical use can be limited due to the development of peripheral neuropathy. Whilst mitochondrial dysfunction has been implicated as a major pathomechanism for oxaliplatin-induced neurotoxicity, the prevention of autophagy may also aggravate neuronal cell death. Melatonin, a well-known mitoprotectant and autophagy inducer, was used to examine its neuroprotective role in oxaliplatin-induced peripheral neuropathy (OIPN). Melatonin prevented the loss of mitochondrial membrane potential (Ψm) and promoted neuritogenesis in oxaliplatin-challenged neuro-2a cells. It did not interfere with the cytotoxic activity of oxaliplatin in human colon cancer cell line, HT-29. Melatonin treatment significantly alleviated oxaliplatin-induced pain behavior and neuropathic deficits in rats. It also ameliorated nitro-oxidative stress mediated by oxaliplatin, thus prevented nitrosylation of proteins and loss of antioxidant enzymes, and therefore, it improved mitochondrial electron transport chain function and maintained cellular bioenergetics by improving the ATP levels. The protective effects of melatonin were attributed to preventing oxaliplatin-induced neuronal apoptosis by increasing the autophagy pathway (via LC3A/3B) in peripheral nerves and dorsal root ganglion (DRG). Hence, it preserved the epidermal nerve fiber density in oxaliplatin-induced neuropathic rats. Taken together, we provide detailed molecular mechanisms for the neuroprotective effect of melatonin and suggest it has translational potential for oxaliplatin-induced neuropathy.
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India.
authors.forename: Aparna
authors.initials: A
authors.lastname: Areti
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India.|Division of Neurology & Medical Science and Medical Health Institute, Department of Medicine, , University of Alberta, Edmonton, AB, Canada.
authors.forename: Prashanth
authors.initials: P
authors.lastname: Komirishetty
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India.
authors.forename: Manasaveena
authors.initials: M
authors.lastname: Akuthota
authors.affiliation: Weill Cornell Medicine-Qatar, Doha, Qatar.|Institute of Cardiovascular Medicine, University of Manchester, Manchester, UK.
authors.forename: Rayaz A
authors.initials: RA
authors.lastname: Malik
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India.
authors.forename: Ashutosh
authors.identifier: http://orcid.org/0000-0001-6659-4751
authors.initials: A
authors.lastname: Kumar
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000009:adverse effects* / Q000494:pharmacology; D000077150:Oxaliplatin; D010525:Peripheral Nerves / Q000378:metabolism / Q000473:pathology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D013126:Spinal Nerve Roots / Q000378:metabolism / Q000473:pathology
chemical_list: C477012:MAP1LC3A protein, human; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D008550:Melatonin
keywords: autophagy; melatonin; mitochondrial dysfunction; oxaliplatin; oxidative/nitrosative stress; peripheral neuropathy