Abstract
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-α 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-α 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 μg/rat; ICV) treatments. Wortmannin (PI3-kinase inhibitor) and L-NAME groups manifested elevated brain oxidative stress, TNF-α 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.
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17 April 2024
An Editorial Expression of Concern to this paper has been published: https://doi.org/10.1007/s00210-024-03096-6
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Acknowledgements
The authors are thankful to the management of ASBASJSM College of Pharmacy, Bela, for providing the necessary research facilities and IKG Punjab Technical University, Kapurthala.
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This research was assisted by a grant from AICTE, New Delhi (India), under Research Promotion Scheme.
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Prof. (Dr.) Nitin Bansal designed this study. Manish Kumar (PhD research scholar) conducted the research and analysed and interpreted the data. Both authors wrote the initial and final draft of the article.
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Kumar, M., Bansal, N. Ellagic acid prevents dementia through modulation of PI3-kinase-endothelial nitric oxide synthase signalling in streptozotocin-treated rats. Naunyn-Schmiedeberg's Arch Pharmacol 391, 987–1001 (2018). https://doi.org/10.1007/s00210-018-1524-2
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DOI: https://doi.org/10.1007/s00210-018-1524-2