Histone deacetylase inhibitor attenuates neurotoxicity of clioquinol in PC12 cells. (4th May 2015)

• Record Type: Journal Article
• Authors: Fukui, Takao; Asakura, Kunihiko; Hikichi, Chika; Ishikawa, Tomomasa; Murai, Rie; Hirota, Seiko; Murate, Ken-ichiro; Kizawa, Madoko; Ueda, Akihiro; Ito, Shinji; Mutoh, Tatsuro
• Is Part Of: Toxicology. Volume 331(2015)
• Page Start: 112
• Page End: 118
• Publication Date: 2015-05-04
• Subjects: Clioquinol -- Deacetylation of histones -- Histone deacetylase inhibitor -- Subacute myeloopticoneuropathy; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2015.01.013
• Languages: English
• ISSNs: 0300-483X

Abstract

Highlights: Clioquinol reduced acetylated histones in PC12 cells. Histone deacetylase (HDAC) inhibitor upregulated acetylated histones. HDAC inhibitor treatment decreased neurite retraction by clioquinol. HDAC inhibitor decreased neuronal cell death by clioquinol. HDAC inhibitor restored the inhibition of Trk autophosphorylation by clioquinol. Abstract: Clioquinol is considered to be a causative agent of subacute myelo-optico neuropathy (SMON), although the pathogenesis of SMON is yet to be elucidated. We have previously shown that clioquinol inhibits nerve growth factor (NGF)-induced Trk autophosphorylation in PC12 cells transformed with human Trk cDNA. To explore the further mechanism of neuronal damage by clioquinol, we evaluated the acetylation status of histones in PC12 cells. Clioquinol reduced the level of histone acetylation, and the histone deacetylase (HDAC) inhibitor Trichostatin A upregulated acetylated histones and prevented the neuronal cell damage caused by clioquinol. In addition, treatment with HDAC inhibitor decreased neurite retraction and restored the inhibition of NGF-induced Trk autophosphorylation by clioquinol. Thus, clioquinol induced neuronal cell death via deacetylation of histones, and HDAC inhibitor alleviates the neurotoxicity of clioquinol. Clioquinol is now used as a potential medicine for malignancies and neurodegenerative diseases. Therefore, HDAC inhibitors can be used as a candidate medicine for the prevention of its side effects on neuronal cells.