title: Cytoprotective effect of novel histone deacetylase inhibitors against polyglutamine toxicity.
abstract: Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurological disorder caused by a CAG repeat expansion in the DRPLA gene encoding polyglutamine (polyQ). Although previous experimental studies have demonstrated that histone deacetylase (HDAC) inhibitors are therapeutically active, known HDAC inhibitors have considerable adverse effects clinically. To identify new HDAC inhibitors for the treatment of DRPLA, we evaluated a new series of HDAC inhibitors, N-hydroxycarboxamides, with our drug screening system, which uses neuronal PC12 cells stably transfected with a part of the DRPLA gene. We found that two of four N-hydroxycarboxamides significantly reduced polyQ-induced cell death. The essential structure of these compounds is a hydroxamic acid residue, which is shared with trichostatin A, a known HDAC inhibitor. Although our study showed mild neuroprotective effects, further structural modification of compounds that retain this residue may decrease cytotoxicity and increase protective activity against polyQ toxicity.
authors.affiliation: Department of Neurology, Nara Medical University, Kashihara, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kariya
authors.forename: Makito
authors.initials: M
authors.lastname: Hirano
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uesato
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Nagai
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Nagaoka
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Furiya
authors.forename: Hirohide
authors.initials: H
authors.lastname: Asai
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Fujikake
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Toda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueno
mesh_terms: D000818:Animals; D002193:Cantharidin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry; D009419:Nerve Tissue Proteins / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D010455:Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051381:Rats; D014162:Transfection / Q000379:methods
chemical_list: D056572:Histone Deacetylase Inhibitors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010455:Peptides; C095278:atrophin-1; C097188:polyglutamine; C031018:N-hydroxycantharidinimide; D006655:Histone Deacetylases; D002193:Cantharidin