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

Mehtab Khan1, Rahat Ullah1, Shafiq Ur Rehman1

  • 1Division of Life sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea.

Cells
|August 22, 2019
PubMed

Insights

17β-estradiol protects against d-galactose-induced cognitive decline by reducing oxidative stress and neuroinflammation. This effect is mediated through the estrogen receptor α (ERα)/silent mating type information regulation 2 homolog 1 (SIRT1) pathway, improving memory and preventing neuronal damage.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Oxidative stress, reactive oxygen species (ROS), and neuroinflammation are key factors in neurodegenerative diseases like Alzheimer's and Parkinson's.
  • Chronic d-galactose (d-gal) administration induces oxidative damage, neuroinflammation, and cognitive impairment, mimicking aging processes.
  • Estrogen receptor α (ERα) and SIRT1 are implicated in cellular protection and aging.

Purpose of the Study:

  • To investigate the antioxidant and neuroprotective effects of 17β-estradiol in a d-gal-induced mouse model of cognitive dysfunction.
  • To elucidate the role of the ERα/SIRT1 pathway in mediating these protective effects.

Main Methods:

  • Male mice were treated with d-galactose for 10 weeks to induce oxidative stress and cognitive impairment.
  • 17β-estradiol was administered to assess its protective effects.
  • SIRT1 inhibition was achieved using Ex527 to evaluate its impact on 17β-estradiol's efficacy.
  • Molecular docking studies were performed to analyze interactions between 17β-estradiol and SIRT1.

Main Results:

  • 17β-estradiol significantly ameliorated d-gal-induced cognitive deficits, AD-like pathology, and synaptic dysfunction.
  • Treatment with 17β-estradiol reduced oxidative stress, neuroinflammation (JNK/NF-κB pathways), and neuronal apoptosis.
  • SIRT1 inhibition abolished the beneficial effects of 17β-estradiol, confirming its critical role.
  • Molecular docking revealed that 17β-estradiol allosterically enhances SIRT1 expression and counteracts d-galactose's inhibitory effects.

Conclusions:

  • 17β-estradiol exerts significant neuroprotective effects against d-galactose-induced cognitive impairment via an ERα/SIRT1-dependent mechanism.
  • The ERα/SIRT1 pathway is crucial for mitigating oxidative stress, neuroinflammation, and neurodegeneration.
  • 17β-estradiol represents a potential therapeutic agent for age-related cognitive decline and neurodegenerative diseases.
Keywords:
17β-EstradiolROSSIRT1d-galactoseneuroinflammation neurodegeneration

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