Evaluation of Neuroprotective Effects of Avanafil Against Streptozotocin Induced Alzheimer's Disease Model in Rats

Abstract

Background: Alzheimer’s disease (AD) is an old age disorder characterized by amnesia and dementia. Pathogenesis for AD are mainly β-Amyloid senile plagues and Tau protein hyperphosphorylation leading to neurofibrillary tangles, reduced Acetylcholine levels, free radicals generation due to oxidative stress. Till now no cure exists for this disorder and current approved treatment includes Acetylcholinesterase inhibitors and NMDA antagonists. Aim and objective: The aim of the study is to investigate the neuroprotective effects of a novel PDE5 inhibitor; Avanafiland its mechanism of action against Streptozotocin induced Alzheimer’s disease model in rats. Materials and methods: The Wistar rats were divided into the seven groups each consisting of 6 animals: NC- Normal Control, DC- Disease Control (AD induced by ICV-STZ), AV0.25- Disease treated with Avanafil 0.25mg/kg/day for 28 days, AV0.4- Disease treated with Avanafil 0.4mg/kg/day for 28 days, AV0.55- Disease treated with Avanafil 0.55mg/kg/day for 28 days, DNP0.2- Disease treated with Donepezil 0.2mg/kg/day for 28 days, SC: Sham Control. Neurobehavioral parameters like Morris Water Maze test, Novel Object Recognition test, YMaze test and Conditioned avoidance test were performed. Biochemical estimations were performed including antioxidant parameters, Amyloid-β (1-40), Amyloid-β (1-42), total Tau, Phospho Tau, Neprilysin, β- Nerve Growth Factor estimations, Haematoxylin and Eosin (H.E.) staining for histopathological examination and Glial Fibrillary Acidic Protein (GFAP) Immunohistochemistry was done to confirm the neuroprotective mechanism. Results: In neurobehavioural parameters, decrease in latency to platform was observed in the animals treated with Avanafil. Escape latency to avoid foot shocks also decreased in the animals treated with Avanafil. Discrimination index between novel and familiar object increased as compared to disease control. The exploratory behaviour in Y-maze test was also observed in an elevated manner. The biochemical estimations revealed that SOD and Glutathione levels were elevated and MDA and catalase levels were reduced in the treatment arms. Neuroprotective markers such as Neprilysin and β- Nerve Growth Factor were found to be elevated in treatment arms. Amyloid-β (1-40) was elevated while Amyloid-β (1-42), Total Tau and PhosphoTau were found to be reduced. Histopathological analysis indicated the reduction in neurofibrillary tangles to a greater extent in the treatment arm. Conclusion: Collective data of neurobehavioral parameters, biochemical estimations and histopathological analysis indicated a significant improvement in cognitive functions, elevated neuroprotective markers and reduction in Tau tangles in the treatment groups with Avanafil (AV0.4 being the best in result) and provides the primary data for further research and development.