Ellagic acid prevents dementia through modulation of PI3-kinase-endothelial nitric oxide synthase signalling in streptozotocin-treated rats
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.
KeywordsEllagic acid PI3-kinase-endothelial nitric oxide synthase (eNOS) Memory Wortmannin Streptozotocin Acetylcholinesterase
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.
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.
This research was assisted by a grant from AICTE, New Delhi (India), under Research Promotion Scheme.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Claiborne A (1985) Catalase activity. In: Greenwald RA (ed) CRC handbook of methods for oxygen radical research, 3rd edn. CRC, Boca Raton, pp 283–284Google Scholar
- Kiasalari Z, Heydarifard R, Khalili M, Afshin-Majd S, Baluchnejadmojarad T, Zahedi E, Sanaierad A, Roghani M (2017) Ellagic acid ameliorates learning and memory deficits in a rat model of Alzheimer’s disease: an exploration of underlying mechanisms. Psychopharmacology 234:1841–1852. https://doi.org/10.1007/s00213-017-4589-6 CrossRefPubMedGoogle Scholar
- Lee HJ, Ryu JM, Jung YH, Lee SJ, Kim JY, Lee SH, Hwang IK, Seong JK, Han HJ (2016) High glucose upregulates BACE1-mediated Aβ production through ROS-dependent HIF-1α and LXRα/ABCA1-regulated lipid raft reorganization in SK-N-MC cells. Sci Rep 6:36746. https://doi.org/10.1038/srep36746 CrossRefPubMedPubMedCentralGoogle Scholar
- Li ST, Pan J, Hua XM, Liu H, Shen S, Liu JF, Li B, Tao BB, Ge XL, Wang XH, Shi JH, Wang XQ (2014) Endothelial nitric oxide synthase protects neurons against ischemic injury through regulation of brain-derived neurotrophic factor expression. CNS Neurosci Ther 20:154–164. https://doi.org/10.1111/cns.12182 CrossRefPubMedGoogle Scholar
- Ou HC, Lee WJ, Lee SD, Huang CY, Chiu TH, Tsai KL, Hsu WC, Sheu WH (2010) Ellagic acid protects endothelial cells from oxidized low-density lipoprotein-induced apoptosis by modulating the PI3K/Akt/eNOS pathway. Toxicol Appl Pharmacol 248:134–143. https://doi.org/10.1016/j.taap.2010.07.025 CrossRefPubMedGoogle Scholar
- Provias J, Jeynes B (2008) Neurofibrillary tangles and senile plaques in Alzheimer’s brains are associated with reduced capillary expression of vascular endothelial growth factor and endothelial nitric oxide synthase. Curr Neurovasc Res 5:199–205. https://doi.org/10.2174/156720208785425729 CrossRefPubMedGoogle Scholar
- Utkan T, Yazir Y, Karson A, Bayramgurler D (2015) Etanercept improves cognitive performance and increases eNOS and BDNF expression during experimental vascular dementia in streptozotocin-induced diabetes. Curr Neurovasc Res 12:135–146. https://doi.org/10.2174/1567202612666150311111340 CrossRefPubMedGoogle Scholar