Fasudil hydrochloride ameliorates memory deficits in rat model of streptozotocin-induced Alzheimer’s disease: Involvement of PI3-kinase, eNOS and NFκB

• Published in: Behavioural brain research 2018-10, Vol.351, p.4-16
• Main Authors: Kumar, Manish, Bansal, Nitin
• Format: Article
• Language: English
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology; Acetylcholinesterase; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - psychology; Animals; Disease Models, Animal; Endothelial NOS; Enzyme Inhibitors - pharmacology; Fasudil; Memory; Memory Disorders - drug therapy; Memory Disorders - etiology; Memory Disorders - metabolism; Neuroprotective Agents - pharmacology; NF-kappa B - metabolism; NFκB; NG-Nitroarginine Methyl Ester - pharmacology; Nootropic Agents - pharmacology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; PI3-kinase; Rats, Wistar; Streptozocin; Wortmannin; Wortmannin - pharmacology
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2018.05.024

•Intracerebroventricular administration of streptozotocin (STZ-ICV) impaired the spatial and recognition memory in rats.•ICV administration of fasudil hydrochloride (fasudil) negated the STZ-ICV induced rise in oxidative stress, inflammation and acetylcholinesterase activity.•The elevation in whole brain endothelial NOS and reduction in NFκB content by fasudil improved the cognitive abilities in STZ treated rats.•Administration of l-NAME (competitive eNOS inhibitor) and wortmannin (PI3-kinase inhibitor) impeded the memory revival functions of fasudil in STZ-ICV treated rats.•In the STZ-ICV model of AD, l-Arginine treatment potentiated the enhancement of memory by fasudil. 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 (300 μg/kg, ICV) averted the STZ-ICV (3 mg/kg) induced memory dysfunctions in rats. Wortmannin (5 μg/rat) or l-NAME (20 mg/kg) attenuated the memory restorative function of fasudil in STZ treated rats. However, l-Arginine (50 mg/kg) group exhibited marked improvement in memory functions. Markers of oxidative stress (TBARS, GSH, SOD, CAT), nitrite, AChE, TNF-α, eNOS and NFκB were measured in whole brain of rats. STZ-ICV group exhibited significant elevation in brain oxidative stress, AChE activity, TNF-α, NFκB 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 NFκB expression, whereas, decrease in same was observed in wortmannin group. l-Arginine lowered the brain oxidative stress, inflammation, AChE activity, eNOS expression (not activity), NFκB 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 NFκB activity.