Functional and biochemical evidence indicating beneficial effect of Melatonin and Nicotinamide alone and in combination in experimental diabetic neuropathy

Oxidative stress resulting in excessive generation of ROS is a compelling initiator of DNA damage along with damage to various cellular proteins and other macromolecules. Poly(ADP-ribose) polymerase (PARP) activation in response to DNA damage, stirs an energy-consuming cellular metabolic cycle; culminating into cell death. The present study was designed to determine the effect of combining an antioxidant, Melatonin and a PARP inhibitor, Nicotinamide on the hallmark deficits developing in diabetic neuropathy (DN). Streptozotocin (STZ, 55 mg/kg, i.p.) was administered to induce diabetes. Six weeks post diabetes induction, two week treatment with Melatonin (3 and 10 mg/kg) and Nicotinamide (100 and 300 mg/kg) either alone or in combination was given. Effect of these interventions on the functional, behavioral and biochemical changes caused by hyperglycemia were studied in treated animals. Melatonin and Nicotinamide alone as well as in combination ameliorated the functional deficits along with improvement in pain parameters. The combination also demonstrated an essential reversal of biochemical alterations. Nitrotyrosine and Poly ADP Ribose (PAR) immunopositivity was significantly decreased in sciatic nerve micro-sections of treatment group. The results of this study advocate that simultaneous inhibition of oxidative stress-PARP activation cascade may prove useful for the pharmacotherapy of DN. (C) 2009 Elsevier Ltd. All rights reserved.