The sirtuin-2 inhibitor AK7 is neuroprotective in models of Parkinson's disease but not amyotrophic lateral sclerosis and cerebral ischemia

• Published in: PloS one Vol. 10; no. 1; p. e0116919
• Main Authors: Chen, Xiqun, Wales, Pauline, Quinti, Luisa, Zuo, Fuxing, Moniot, Sébastien, Herisson, Fanny, Rauf, Nazifa Abdul, Wang, Hua, Silverman, Richard B, Ayata, Cenk, Maxwell, Michelle M, Steegborn, Clemens, Schwarzschild, Michael A, Outeiro, Tiago F, Kazantsev, Aleksey G
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.01.2015; Public Library of Science (PLoS)
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - adverse effects; alpha-Synuclein - metabolism; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - physiopathology; Analysis; Animal models; Animals; Benzamides - administration & dosage; Benzamides - pharmacology; Biochemistry; Biocompatibility; Brain; Brain Ischemia - physiopathology; Brain research; Cell Line; Cerebral ischemia; Disease; Disease Models, Animal; Dopamine; Dopamine receptors; Drug dosages; Hospitals; Humans; Ischemia; Male; Medical schools; Mice; Microscopy; MPTP; Neurodegeneration; Neurodegenerative diseases; Neurological diseases; Neurology; Neuroprotection; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - pharmacology; Parkinson Disease - metabolism; Parkinson Disease - prevention & control; Parkinson's disease; Parkinsons disease; Peptides; Physiology; Proteins; R&D; Research & development; Rodents; Sirtuin 2 - antagonists & inhibitors; Small Molecule Libraries - administration & dosage; Small Molecule Libraries - pharmacology; Sulfonamides - administration & dosage; Sulfonamides - pharmacology; Synuclein; Toxic diseases; Toxicity
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0116919

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.