Roles of sirtuins in the nervous system diseases

     As is reported in some studies, SIRT1 is expressed in the adult brain, with high levels in the cortex, hippocampus, cerebellum, and hypothalamus. In brain, SIRT2 is a cytoplasmic protein and plays an important role in the formation of myelin sheath and in the myelin-axon interaction. Other members of sirtuins is also found to exist in brain in various forms. Recent research indicates that a neuroprotective role of sirtuins, especially SIRT1 has been observed[1]. In fact, the effects of sirtuins on common neurological disorders has been described previously.
     Ischemic stroke is a common neurological disease, and the neuroprotective effect of SIRT1 was found to reduces ischemic neuronal injuries. One possible mechanism is downregulation of the mitochondrial uncoupling protein 2[2]. In addition, NAD+ pretreatment has been reported to markedly reduce neuronal death induced by oxygen-glucose deprivation. While The protective effect is SIRT1-dependent, since SIRT1 knockout blocks the protection[3].
Alzheimer's disease (AD) is considered as a terminal neurodegenerative disease, leading to neuronal death. previous studies have demonstrated that SIRT1 activation can reduce the neuronal death caused by AD[4]. The possible mechanisms are studied and the results indicate that SIRT1 deacetylates the acetylated tau and inhibit the accumulation of both tau and Aβ, two pathological hallmarks of AD. Moreover, SIRT1 can also reduce the NF-kappaB pathway in microglia to decrease Aβ level and consequently reduce its level[5].
In summary, SIRT1 shows a neuroprotective effect both on acute neurologica diseases and neurodegenerative diseases. Since SIRT1 activity is enhanced by small molecule compounds such as SRT1720, development of small-molecule activators could contribute to novel therapies against neurological diseases.

[1]. J. Cereb. Blood Flow Metab. 2011; 31: 1003–1019.
[2]. Neuroscience 2009; 159:993–1002.
[3]. Ann. Neurol. 2011; 69:360–374.
[4]. Neuron 2010; 67:953–966.
[5]. J. Biol. Chem. 2005; 280,:40364–40374.

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S1129 SRT1720 HCl SRT1720 HCl is a selective SIRT1 activator with EC50 of 0.16 μM in a cell-free assay, but is >230-fold less potent for SIRT2 and SIRT3. SRT1720 induces autophagy.

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