Kumar_2018_Behav.Brain.Res_351_4

Restoration of PI3-kinase signaling portrays therapeutic potential in Alzheimer's disease (AD). Hyperactive Rho-kinase in AD negatively modulates PI3-kinase pathway, thereby cause cognitive decline. Fasudil is a Rho-kinase inhibitor that has shown therapeutic benefits in brain disorders. The present study is aimed to decipher the role of PI3-kinase pathway in neuroprotective activity of fasudil using STZ-ICV model of AD. MWM and NORT showed that fasudil (300mug/kg, ICV) averted the STZ-ICV (3mg/kg) induced memory dysfunctions in rats. Wortmannin (5mug/rat) or l-NAME (20mg/kg) attenuated the memory restorative function of fasudil in STZ treated rats. However, l-Arginine (50mg/kg) group exhibited marked improvement in memory functions. Markers of oxidative stress (TBARS, GSH, SOD, CAT), nitrite, AChE, TNF-alpha, eNOS and NFkappaB were measured in whole brain of rats. STZ-ICV group exhibited significant elevation in brain oxidative stress, AChE activity, TNF-alpha, NFkappaB expression and decrease in eNOS level. These effects of STZ were effectively ameliorated by administration of fasudil for 21 days. Wortmannin (PI3-kinase inhibitor) or l-NAME (NOS blocker) attenuated the antioxidative, anti-inflammatory and cholinergic activities of fasudil. Although brain nitrite content was decreased by l-NAME and wortmannin, the l-NAME group depicted rise in eNOS content (not activity) and NFkappaB expression, whereas, decrease in same was observed in wortmannin group. l-Arginine lowered the brain oxidative stress, inflammation, AChE activity, eNOS expression (not activity), NFkappaB levels and elevated nitrite content. In STZ-ICV rat model of AD, fasudil (Rho-kinase inhibitor) ameliorated the AD symptoms by reinstating PI3-kinase mediated upregulation of eNOS and control over brain NFkappaB activity.