Abstract
Silent information regulator 1 (SIRT1), an NAD+-dependent deacetylase, is involved in the regulation of gene transcription, energy metabolism, and cellular aging and has become an important therapeutic target across a range of diseases. Recent research has demonstrated that SIRT1 possesses neuroprotective effects; however, it is unknown whether it protects neurons from NMDA-mediated neurotoxicity. In the present study, by activation of SIRT1 using resveratrol (RSV) in cultured cortical neurons or by overexpression of SIRT1 in SH-SY5Y cell, we aimed to evaluate the roles of SIRT1 in NMDA-induced excitotoxicity. Our results showed that RSV or overexpression of SIRT1 elicited inhibitory effects on NMDA-induced excitotoxicity including a decrease in cell viability, an increase in lactate dehydrogenase (LDH) release, and a decrease in the number of living cells as measured by CCK-8 assay, LDH test, and Calcein-AM and PI double staining. RSV or overexpression of SIRT1 significantly improved SIRT1 deacetylase activity in the excitotoxicity model. Further study suggests that overexpression of SIRT1 partly suppressed an NMDA-induced increase in p53 acetylation. These results indicate that SIRT1 activation by either RSV or overexpression of SIRT1 can exert neuroprotective effects partly by inhibiting p53 acetylation in NMDA-induced neurotoxicity.
Highlights
Silent information regulator 1 (SIRT1), an NAD+-dependent deacetylase, is known to deacetylate histone and nonhistone proteins such as transcription factors
Pretreatment with five dosages (10 μM, 25 μM, 50 μM, 75 μM, and 100 μM) of RSV, a potent SIRT1 activator, showed that cell viability was increased by 20.43% (P < 0 05), 31.92% (P < 0 05), 17.78% (P < 0 05), 11.85% (P < 0 05), Figure 2: Effects of RSV on NMDA-induced lactate dehydrogenase (LDH) release in primary neurons
Activation of SIRT1 or overexpression of SIRT1 protected against NMDA-mediated excitotoxicity; second, the neuroprotective effects of SIRT1 on NMDA-induced excitotoxicity were attributed to its deacetylase activity; and third, inhibition of p53 acetylation might be one of the mechanisms underlying SIRT1-mediated neuroprotection
Summary
Silent information regulator 1 (SIRT1), an NAD+-dependent deacetylase, is known to deacetylate histone and nonhistone proteins such as transcription factors. It participates in a variety of physiopathological processes such as health maintenance in development, gametogenesis, homeostasis, longevity, and several neurodegenerative diseases as well as age-related disorders [1,2,3,4,5]. SIRT1 deacetylates p53, PGC-1α, and NF-κB to prevent many pathogenic processes. It remains unknown whether SIRT1 protects neurons from NMDA-mediated neurotoxicity in different excitotoxic insult models
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