The Sirtuin-2 Inhibitor AK7 Is Neuroprotective in Models of Parkinson’s Disease but Not Amyotrophic Lateral Sclerosis and Cerebral Ischemia

Abstract

Sirtuin deacetylases regulate diverse cellular pathways and influence disease processes. Our previous studies identified the brain-enriched sirtuin-2 (SIRT2) deacetylase as a potential drug target to counteract neurodegeneration. In the present study, we characterize SIRT2 inhibition activity of the brain-permeable compound AK7 and examine the efficacy of this small molecule in models of Parkinson’s disease, amyotrophic lateral sclerosis and cerebral ischemia. Our results demonstrate that AK7 is neuroprotective in models of Parkinson’s disease; it ameliorates alpha-synuclein toxicity in vitro and prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion and dopaminergic neuron loss in vivo. The compound does not show beneficial effects in mouse models of amyotrophic lateral sclerosis and cerebral ischemia. These findings underscore the specificity of protective effects observed here in models of Parkinson’s disease, and previously in Huntington’s disease, and support the development of SIRT2 inhibitors as potential therapeutics for the two neurodegenerative diseases.

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

“…A very recent study using the Sirt2 inhibitor AK7 did not detect a significant difference of the neurological deficit scores according to Bederson, but a tendency toward a better neurological outcome in the AK7-treated animals when compared with vehicle-treated animals at 24 hours after 1 hour MCAO. 32 These results are consistent with our own findings, as we did not see a significant difference between the groups using the Bederson Score at 24 hours after 45 minutes MCAO. However, after 48 hours both mNSS and Bederson Scores revealed significantly reduced neurological deficits in Sirt2 − / − mice when compared with wild-type mice.…”

“…Thus the difference of the neurological deficit in both groups is not evident by the use of a rather rough test such as the Bederson Score at 24 hours of reperfusion. Moreover, it is possible that AK7 inhibits Sirt1 to some degree as well, 32 which would cloud the result of the Sirt2 inhibition, as Sirt1 and Sirt2 are currently suspected to have opposite effects on the outcome of cerebral ischemia. 3,5 The absence of significant changes regarding the immune response in Sirt2-deficient mice after stroke, measured by FACS analysis, argues against a prominent role of Sirt2 concerning the initiation of an inflammatory response.…”

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

“…In vitro studies have identified tubulin deacetylation and alterations in cholesterol biosynthesis as possible effectors of Sirt2 however conflicting results have been obtained in vivo (Luthi-Carter et al, 2010; Bobrowska et al, 2012). 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).…”

“…In contrast, Sirt2 plays an opposing role in activating cell death mechanisms and inhibitors of this isoform have potential as a therapy for neurodegenerative diseases. Indeed, Sirt2 inhibition has been demonstrated to provide benefit against neurodegeneration in cellular and in vivo models of Huntington’s and Parkinson’s disease, but not amyotrophic lateral sclerosis or ischemic stroke (Outeiro et al, 2007; Chopra et al, 2012; Donmez, 2013; Donmez and Outeiro, 2013; Chen et al, 2015). In vitro studies have identified tubulin deacetylation and alterations in cholesterol biosynthesis as possible effectors of Sirt2 however conflicting results have been obtained in vivo (Luthi-Carter et al, 2010; Bobrowska et al, 2012).…”

SIRT2 regulates nuclear envelope reassembly through ANKLE2 deacetylation

“…Interestingly, SIRT2 has already been implicated in neurodegenerative diseases as a negative regulator of neuronal motility (Harting and Knöll, 2010; Pandithage et al, 2008). SIRT2 inhibition has been shown to have a neuroprotective effect in various Parkinson's disease models (Chen et al, 2015; Godena et al, 2014; Outeiro et al, 2007), which was linked to the axonal transport rescue through an increase in tubulin acetylation (Godena et al, 2014). Our finding that modulating the SIRT2 levels causes changes in the nuclear envelope morphology that are also observed in Parkinson's disease provides an additional insight into the mechanism of SIRT2-mediated neurodegeneration.…”