Amelioration of diabetes-induced neurobehavioral and neurochemical changes by melatonin and nicotinamide: implication of oxidative stress-PARP pathway

Abstract

Diabetes associated hyperglycemia results in generation of reactive oxygen species which induces oxidative stress and initiate massive DNA damage leading to overactivation of poly (ADP-ribose) polymerase (PARP). In this study, we have elucidated the involvement of oxidative stress-PARP pathway using pharmacological interventions (melatonin, as an anti-oxidant and nicotinamide, as a PARP inhibitor) in diabetes-induced neurobehavioral and neurochemical alterations. Sprague-Dawley rats were rendered diabetic by a single intraperitoneal injection of streptozotocin. Behavioral and cognitive deficits were assessed after 8weeks of diabetes induction using a functional observation battery, passive avoidance and rotarod test. Acetylcholinesterase activity was significantly decreased in hippocampus of diabetic rats as compared to control rats. Diabetic animals showed significant increase in malondialdehyde levels and reduction in NAD levels in hippocampus. Glutamate and GABA levels were also altered in hippocampus of the diabetic animals. Two week treatment with melatonin (3 and 10mg/kg) and nicotinamide (300 and 1000mg/kg) alone and in combination significantly improved the neurobehavioral parameters which were altered in diabetes. Neurotransmitter (glutamate and GABA) levels were improved by these interventions. Our results emphasize that simultaneous inhibition of oxidative stress-PARP overactivation cascade can be beneficial in treatment of diabetes associated CNS changes.

Keywords: AChE; AIF; B AP-1; Behavioral changes; Diabetes; FOB; Functional Observational Battery; IGF; MAPK; MDA; Melatonin; NF-κB; Nicotinamide; OPA; Oxidative stress; PARP; STZ; acetylcholinesterase; activator protein-1; apoptosis inducing factor; insulin growth factor; malondialdehyde; mitogen-activated protein kinase; nuclear factor-kappa; o-phthalaldehyde; poly (ADP-ribose) polymerase; streptozotocin.