Knockout of Silent Information Regulator 2 (SIRT2) Preserves Neurological Function after Experimental Stroke in Mice

Abstract

Sirtuin-2 (Sirt2) is a member of the NAD(+)-dependent protein deacetylase family. Various members of the sirtuin class have been found to be involved in processes related to longevity, regulation of inflammation, and neuroprotection. Induction of Sirt2 mRNA was found in the whole hemisphere after experimental stroke in a recent screening approach. Moreover, Sirt2 protein is highly expressed in myelin-rich brain regions after stroke. To examine the effects of Sirt2 on ischemic stroke, we induced transient focal cerebral ischemia in adult male Sirt2-knockout and wild-type mice. Two stroke models with different occlusion times were applied: a severe ischemia (45 minutes of middle cerebral artery occlusion (MCAO)) and a mild one (15 minutes of MCAO), which was used to focus on subcortical infarcts. Neurological deficit was determined at 48 hours after 45 minutes of MCAO, and up to 7 days after induction of 15 minutes of cerebral ischemia. In contrast to recent data on Sirt1, Sirt2(-/-) mice showed less neurological deficits in both models of experimental stroke, with the strongest manifestation after 48 hours of reperfusion. However, we did not observe a significant difference of stroke volumes or inflammatory cell count between Sirt2-deficient and wild-type mice. Thus we postulate that Sirt2 mediates myelin-dependent neuronal dysfunction during the early phase after ischemic stroke.

SIRT2 Plays Significant Roles in Lipopolysaccharides-Induced Neuroinflammation and Brain Injury in Mice

“…It has been reported that SIRT2 inhibition can decrease the injury in cellular and animal models of PD, HD [8] and ischemia stroke [9]. Since inflammation plays critical pathological roles in these diseases [13][14][15] and SIRT2 is necessary for bacteria infection [6], we hypothesized that SIRT2 may be important for neuroinflammation.…”

“…SIRT2 inhibition or deficiency has been shown to produce neuroprotective effects in models of both neurodegenerative diseases [8] and ischemia stroke [9]: SIRT2 inhibition led to a decrease in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal damage [10]; SIRT2 deletion was shown to decrease α-synuclein-induced neurotoxicity in models of Parkinson's disease [11]; SIRT2 inhibitor AK-7 was shown to produce beneficial effects in a mouse model of HD [12]; and SIRT2 deficiency mice also showed decreased neurological deficits after ischemia stroke [9]. However, it is warranted to investigate the mechanisms underlying the neuroprotective effects of SIRT2 inhibition.…”

Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders

“…Results in cerebral ischemia are less clear [186, 190]. However, SIRT2 has also been shown to contribute to the pathology of the vascular system and to the effects of oxidative stress in the endothelium, which have immediate impact on brain oxygen supply [191, 192].…”

Sirtuin-2 mediates male specific neuronal injury following experimental cardiac arrest through activation of TRPM2 ion channels

“…The lack of neuroprotection in a model of ischemic stroke with pharmacological or genetic inhibition of Sirt2 is in direct contrast to our observations with the protection observed with AGK2 in our mouse CA/CPR model (Chen et al, 2015). Interestingly, while Sirt2 knockout mice did not display histological benefit following ischemic stroke, they had improved functional outcome compared to wild-type mice (Krey et al, 2015). Oxidative stress is a common injury mechanisms in many neurodegenerative disease, particularly those resulting from cerebral ischemia and TRPM2 is a well-established mediator of oxidative cell death (Belrose et al, 2012).…”

“…Sirt2 is a cytosolic protein that is expressed in many cell types and tissues throughout the body including the central nervous system. Expression of Sirt2 is observed in neurons as well as oligodendrocytes, microglia and astrocytes (Krey et al, 2015). Sirt2 has been demonstrated to contribute to neurodegeneration in models of Parkinson’s and Huntington’s disease (Donmez, 2013).…”