Kumar_2018_Naunyn.Schmiedebergs.Arch.Pharmacol_391_987

Ellagic acid (EGA)-enriched dietary supplements are widely acclaimed, owing to its versatile bioactivities. Previously, we reported that chronic administration of EGA prevented the impairment of cognitive abilities in rats using the intracerebroventricular-administered streptozotocin (STZ-ICV) model of Alzheimer's disease. Impairment of phosphoinositide 3 (PI3)-kinase-regulated endothelial nitric oxide synthase (eNOS) activity by central administration of STZ in rodents instigates dementia. The aim of the present study was to delineate the role of PI3-kinase-eNOS activity in the prevention of STZ-ICV-induced memory dysfunctions by EGA. The Morris water maze and elevated plus maze tests were conducted, and brain oxidative stress markers (TBARS, GSH, SOD, CAT), nitrite, acetylcholinesterase (AChE), LDH, TNF-alpha and eNOS were quantified. Administration of EGA (35 mg/k, p.o.) for 4 weeks daily attenuated the STZ-ICV (3 mg/kg)-triggered increase of brain oxidative stress, nitrite and TNF-alpha levels; AChE and LDH activity; and decline of brain eNOS activity. The memory restoration by EGA in STZ-ICV-treated rats was conspicuously impaired by N((G))-nitro-L-arginine methyl ester (L-NAME) (20 mg/kg, 28 days) and wortmannin (5 mug/rat; ICV) treatments. Wortmannin (PI3-kinase inhibitor) and L-NAME groups manifested elevated brain oxidative stress, TNF-alpha content and AChE and LDH activity and diminished nitrite content. L-NAME (arginine-based competitive eNOS inhibitor) enhanced the eNOS expression (not activity) whereas wortmannin reduced the brain eNOS levels in EGA- and STZ-ICV-treated rats. However, the L-NAME group exhibited superior cognitive abilities in comparison to the wortmannin group. It can be concluded that EGA averted the memory deficits by precluding the STZ-ICV-induced loss of PI3-kinase-eNOS signalling in the brain of rats.