387 - 7-Nitroindazole, Postoperatively Attenuates the 6-OHDA Induced S-Nitrosylation in Rat Model of Parkinson's Disease (PD)

Abstract

Progressive death of dopaminergic neurons due to the overproduction of highly reactive free reactive oxygen and nitrogen species (ROS/RNS) results in the molecular pathology of PD. Under physiological conditions, reactive free radicals are present at low levels, mediating several neurotrophic and neuroprotective signaling pathways. In contrast, under pathological conditions, there is a pronounced increase in free radical generation, impairing the normal neurological function by undesired S-nitrosylation of many important signaling proteins. S-nitrosylation has been implicated in the pathology of many neurodegenerative diseases including PD. In the present work bilateral 6-OHDA induced rat model had been used to mimic the human pathology and 7-Nitroindazole (7-NI), which has been reported to have neuroprotective effect, was administered postoperatively to evaluate the factual pharmacological effect of 7-NI on 6-OHDA induced S-nitrosylation. The current work demonstrates the differential level of S-nitrosylation of the many physiologically important proteins and the attenuation in the level of S-nitrosylation by 7-NI. Furthermore, our findings have revealed some novel proteins that have not been previously implicated in PD. Maldi-toff analysis identifies following proteins that are differentially S-nitrosylated: GAPDH, Actin, ATP synthase, calreticulin, cyclic nucleotide phosphodiesterase, 14-3-3 gamma, creatine kinase type-B, heat shock cognate 71 kDa protein, 78 kDa glucose regulated protein precursor, and Neurofilament light polypeptide. Among all these proteins GAPDH has been shown to be the mediator of neuronal cell death via translocation of N-cor to the nucleus. The present report suggests that 7-NI acts as efficient neuroprotective agent in 6-OHDA induced rat model by reducing the levels of S-nitrosylation.