Histone deacetylase inhibitor attenuates neurotoxicity of clioquinol in PC12 cells

• DOI: 10.1016/j.tox.2015.01.013
• Publication Date: 2015-03-07T07:46:49Z
• Authors: Takao Fukui; Kunihiko Asakura; Chika Hikichi; Tomomasa Ishikawa; Rie Murai; Seiko Hirota; Ken-ichiro Murate; Madoko Kizawa; Akihiro Ueda; Shinji Ito; Tatsuro Mutoh
• Keywords: Neurons; 0303 health sciences; Time Factors; Cell Death; Acetylation; Clioquinol; Hydroxamic Acids; Transfection; PC12 Cells; Rats; 3. Good health; Histone Deacetylase Inhibitors; Histones; 03 medical and health sciences; Neuroprotective Agents; Cytoprotection; Animals; Humans; Phosphorylation; Receptor, trkA; Cell Shape; Signal Transduction

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.