The Neuroprotective Effects of SIRT1 on NMDA‐Induced Excitotoxicity

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.

Sirtuin 1 Regulates Mitochondrial Biogenesis and Provides an Endogenous Neuroprotective Mechanism Against Seizure-Induced Neuronal Cell Death in the Hippocampus Following Status Epilepticus

“…SIRT1 is distributed in various adult brain areas, with higher expression in the neuronal cells of the cortex, hippocampus, cerebellum, and hypothalamus, and lower expression in white matter [31]. Evidence has revealed that an enhanced SIRT1 and PGC-1α signaling pathway may counteract reactive oxidative species (ROS), promote mitochondrial biogenesis, and enhance mitochondrial functions in the neuronal cells, decrease neuronal and glial cell inflammation, and involve the pathway of neuron cell death and survival [29,30,32,33,34]. SIRT1 has been described as cleavage at the nuclear full-length SIRT1 (110 kDa) to generate a stable but enzymatically inactive 75 kDa fragment of SIRT1 under high levels of ROS or proinflammatory cytokines during injury and promote chondrocyte survival [35,36].…”

Resveratrol Promotes Mitochondrial Biogenesis and Protects against Seizure-Induced Neuronal Cell Damage in the Hippocampus Following Status Epilepticus by Activation of the PGC-1α Signaling Pathway

“…Whereas resveratrol exerts a wide range of beneficial effects on many diseases, its mechanisms have not yet been clearly elucidated. A number of literatures have revealed that resveratrol is provided with anti-inflammatory, antioxidative and metal-chelating properties [ 14 , 17 , 20 ]. Besides its antioxidant and anti-inflammatory properties, growing evidence showed that resveratrol can activate sirtuin 1 (SIRT1), a class III lysine-deacetylase, which plays an important role in the protective mechanism of resveratrol [ 20 ].…”

Effect of Resveratrol on Sirtuins, OPA1, and Fis1 Expression in Adult Zebrafish Retina

“…Previous studies also have shown that resveratrol or overexpression of SIRT1 elicited inhibitory effects on NMDA-induced excitotoxicty and regulated mitochondrial fission/fusion and biogenesis in neurotoxicity. 65,66 Additionally, prior studies revealed that resveratrol suppressed glutamatergic neurotransmission via the NMDA receptor in vivo and inhibited calcium channels. 67,68 Hence, mitochondrial sirtuins, OPA1 mRNA, and mitCN showed suppressed upregulation in the treatment group receiving NMDA with resveratrol, possibly through the inhibition of glutamatergic neurotransmission and/or calcium channels via NMDA receptors.…”