Cytoprotective effect of novel histone deacetylase inhibitors against polyglutamine toxicity.
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.
Kariya
Shingo
S
Department of Neurology, Nara Medical University, Kashihara, Japan.
Hirano
Makito
M
Uesato
Shinichi
S
Nagai
Yoshitaka
Y
Nagaoka
Yasuo
Y
Furiya
Yoshiko
Y
Asai
Hirohide
H
Fujikake
Nobuhiro
N
Toda
Tatsushi
T
Ueno
Satoshi
S
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
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