17β-Estradiol Modulates SIRT1 and Halts Oxidative Stress-Mediated Cognitive Impairment in a Male Aging Mouse Model

Mehtab Khan, Rahat Ullah, Shafiq Ur Rehman, Shahid Ali Shah, Kamran Saeed, Tahir Muhammad, Hyun Young Park, Myeung Hoon Jo, Kyonghwan Choe, Bart P. P. Rutten, Myeong Ok Kim*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

42 Citations (Web of Science)

Abstract

Oxidative stress has been considered the main mediator in neurodegenerative disease and in normal aging processes. Several studies have reported that the accumulation of reactive oxygen species (ROS), elevated oxidative stress, and neuroinflammation result in cellular malfunction. These conditions lead to neuronal cell death in aging-related neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease. Chronic administration of d-galactose (d-gal) for a period of 10 weeks causes ROS generation and neuroinflammation, ultimately leading to cognitive impairment. In this study, we evaluated the estrogen receptor alpha (ER alpha)/silent mating type information regulation 2 homolog 1 (SIRT1)-dependent antioxidant efficacy of 17 beta-estradiol against d-gal-induced oxidative damage-mediated cognitive dysfunction in a male mouse model. The results indicate that 17 beta-estradiol, by stimulating ER alpha/SIRT1, halts d-gal-induced oxidative stress-mediated JNK/NF-?B overexpression, neuroinflammation and neuronal apoptosis. Moreover, 17 beta-estradiol ameliorated d-gal-induced AD-like pathophysiology, synaptic dysfunction and memory impairment in adult mouse brains. Interestingly, inhibition of SIRT1 with Ex527 (a potent and selective SIRT1 inhibitor) further enhanced d-gal-induced toxicity and abolished the beneficial effect of 17 beta-estradiol. Most importantly, for the first time, our molecular docking study reveals that 17 beta-estradiol allosterically increases the expression of SIRT1 and abolishes the inhibitory potential of d-ga. In summary, we can conclude that 17 beta-estradiol, in an ER alpha/SIRT1-dependent manner, abrogates d-gal-induced oxidative stress-mediated memory impairment, neuroinflammation, and neurodegeneration in adult mice.

Original languageEnglish
Article number928
Number of pages20
JournalCells
Volume8
Issue number8
DOIs
Publication statusPublished - Aug 2019

Keywords

  • d-galactose
  • 17 beta-Estradiol
  • SIRT1
  • ROS
  • neuroinflammation neurodegeneration
  • NF-KAPPA-B
  • D-GALACTOSE
  • BETA
  • BRAIN
  • INHIBITION
  • SIRTUINS
  • RECEPTOR
  • PATHWAY
  • ALPHA
  • MICE

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