Journal
MOLECULAR NEUROBIOLOGY
Volume 55, Issue 4, Pages 3067-3078Publisher
HUMANA PRESS INC
DOI: 10.1007/s12035-017-0520-8
Keywords
Ethanol; Estradiol; ROS; Brain; Neuroinflammation; SIRT1
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Funding
- Brain Research Program through the National Research Foundation of Korea - Ministry of Science, ICT & Future Planning [2016M3C7A1904391]
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Growing evidences reveal that 17 beta-estradiol has a wide variety of neuroprotective potential. Recently, it has been shown that 17 beta-estradiol can limit ethanol-induced neurotoxicity in neonatal rats. Whether it can stimulate SIRT1 signaling against ethanol intoxicity in developing brain remain elusive. Here, we report for the first time that 17 beta-estradiol activated SIRT1 to deacetylate p53 proteins against acute ethanol-induced oxidative stress, neuroinflammation, and neurodegeneration. A single subcutaneous injection of ethanol-induced oxidative stress triggered phospho c-jun N terminal kinase (p-JNK) and phospho mammalian target of rapamycin (p-mTOR) accompanied by neuroinflammation and widespread neurodegeneration. In contrast, 17 beta-estradiol cotreatment positively regulated SIRT1, inhibited p53 acetylation, reactive oxygen species (ROS) production, p-JNK, and p-mTOR activation and reduced neuroinflammation and neuronal cell death in the postnatal rat brain. Interestingly, SIRT1 inhibition with its inhibitor, i.e., EX527 further enhanced ethanol intoxication and also abolished the beneficial effects of 17 beta-estradiol against ethanol in the young rat's brain. Indeed, 17 beta-estradiol treatment increased the cell viability (HT22 cells), inhibited ROS production via the SIRT1/Acetyl-p53 pathway, and reduced the nuclear translocation of phospho-nuclear factor kappa B (p-NF-kB) in the BV2 microglia cells. Taken together, these results show that 17 beta-estradiol can be used as a potential neuroprotective agent against acute ethanol intoxication.
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