3-(1-azepanylsulfonyl)-n-(3-bromphenyl)benzamide and Parkinson-Disease

Proper and efficient differentiation of dopaminergic (DA) neurons is essential for the cell-based dopamine replacement strategies that have become an attractive therapeutical option in Parkinson's disease, a disorder typically known for the degeneration of the nigral DA neurons. Here, we established that the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 2 (SIRT2) interacts with protein kinase B, and, via the glycogen synthase kinase 3β/β-catenin pathway, modulates the differentiation of DA neurons. Deletion of SIRT2 resulted in a decreased number of DA neurons in the substantia nigra and lower striatal fiber density in SIRT2 knock-out mice. Similarly, we found a decreased ratio of DA neurons in primary midbrain cultures treated with the SIRT2 inhibitor AK-7. Using protein kinase B and glycogen synthase kinase 3β inhibitors, we found that those molecules act downstream of SIRT2. Thus, SIRT2 acts as a novel regulator of the differentiation process of DA neurons, further supporting its potential as a therapeutic target in Parkinson's disease.

Topics: Animals; Benzamides; beta Catenin; Cell Differentiation; Cells, Cultured; Dopaminergic Neurons; Glycogen Synthase Kinase 3 beta; Mesencephalon; Mice, Knockout; Parkinson Disease; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Wistar; Signal Transduction; Sirtuin 2; Substantia Nigra; Sulfonamides

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.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; alpha-Synuclein; Amyotrophic Lateral Sclerosis; Animals; Benzamides; Brain Ischemia; Cell Line; Disease Models, Animal; Humans; Male; Mice; Neuroprotective Agents; Parkinson Disease; Sirtuin 2; Small Molecule Libraries; Sulfonamides