Protective effects of BAY 73-6691, a selective inhibitor of phosphodiesterase 9, on amyloid-beta peptides-induced oxidative stress in in-vivo and in-vitro models of Alzheimer's disease

摘要

Alzheimer's disease (AD) is accompanied by enhanced oxidative stress and excess free radicals. Phosphodiesterase 9 inhibitors (PDE-91s) showed memory improving effects in many pharmacological deficit models. However, whether BAY 73-6691 (a selective PDE-9I) may attenuate the oxidative stress during the development of AD is still unclear. For this purpose, primary cultures of SH-SY5Y cells were incubated with 20 mu M beta-amyloid(25-35) (A beta(25-35)), followed by exposure to different concentrations (50, 100, 150 and 200 mu g/ml) of BAY 73-6691. Furthermore, the antioxidant effect of BAY 73-6691 was evaluated in mice subjected to intracerebroventricular injection of A beta(25-35) (day 0) and treatment with BAY 73-6691 by intraperitoneal injection once daily (days 1-10). Our results elucidated that treatment with BAY 736691 attenuated the A beta(25-35)-induced cytotoxicity and oxidative stress in SH-SY5Y cells. In vivo, BAY 736691 protected A beta(25-35)-induced oxidative damage in hippocampus, associated with the attenuation of impairments in hippocampal neurons. Administration of BAY 73-6691 improved learning and memory in the Morris water maze test, and restored several hippocampal memory-associated proteins. Our study identified a neuroprotective role for BAY 73-6691 against A beta(25-35)-induced oxidative stress in vivo and in vitro, harboring therapeutic potential for the treatment of AD by alleviating the impairments in spatial memory and hippocampal neurons. (C) 2016 Elsevier B.V. All rights reserved.