title: A novel histone deacetylase 1 and 2 isoform-specific inhibitor alleviates experimental Parkinson's disease.
abstract: With increased histone deacetylase (HDAC) activity and histone hypoacetylation being implicated in neurodegeneration, HDAC inhibitors have been reported to have considerable therapeutic potential. Yet, existing inhibitors lack specificity and may show substantial adverse effect. In this study, we identified a novel HDAC1/2 isoform-specific inhibitor, K560, with protective effects against 1-methyl-4-phenylpyridinium (MPP(+))- and/or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neuronal death in both in vitro and in vivo Parkinson's disease model. K560 attenuated cell death induced by MPP(+) in differentiated SH-SY5Y cells through the sustained expression of an antiapoptotic protein, X-linked inhibitor of apoptosis (XIAP). Inhibition of XIAP expression by locked nucleic acid antisense oligonucleotides abolished the protective effect of K560. Inactivation of mitogen-activated protein kinase cascades, reduced p53 phosphorylation, and down-regulation of p53-upregulated modulator of apoptosis on K560 treatment were also observed. Furthermore, pre- and post-oral administration of K560 to mice prevented MPTP-induced loss of dopaminergic neurons in substantia nigra, suggesting that selective inhibition of HDAC1 and HDAC2 by K560 may pave the way to new strategies for Parkinson's disease treatment.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Chi-Jing
authors.initials: CJ
authors.lastname: Choong
authors.affiliation: Department of Neurology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Neurology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayakawa
authors.affiliation: Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Yasuda
authors.affiliation: Department of Neurology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Baba
authors.affiliation: Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Osaka, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Osaka, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uesato
authors.affiliation: Department of Neurology, Graduate School of Medicine, Osaka University, Osaka, Japan. Electronic address: hmochizuki@neurol.med.osaka-u.ac.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
mesh_terms: D000107:Acetylation; D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D054659:Diketopiperazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes; D051379:Mice; D058990:Molecular Targeted Therapy; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; D054659:Diketopiperazines; D004791:Enzyme Inhibitors; D006657:Histones; D007527:Isoenzymes; C000610970:K560 compound; D018696:Neuroprotective Agents; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2
keywords: Histone deacetylase; Histone deacetylase inhibitor; Isoform-specific; K560; MPTP; Neurodegeneration; Parkinson's disease