The Sirtuin-2 Inhibitor AK7 Is Neuroprotective in Models of Parkinson's Disease but Not Amyotrophic Lateral Sclerosis and Cerebral Ischemia
2015
Sirtuindeacetylases 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
SIRT2inhibition activity of the brain-permeable compound AK7 and examine the efficacy of this small molecule in models of
Parkinson’s disease,
amyotrophic lateral sclerosisand cerebral ischemia. Our results demonstrate that AK7 is neuroprotective in models of
Parkinson’s disease; it ameliorates
alpha-synucleintoxicity 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 sclerosisand 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
SIRT2inhibitors as potential therapeutics for the two neurodegenerative diseases.
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