Clioquinol inhibits NGF-induced Trk autophosphorylation and neurite outgrowth in PC12 cells.
Clioquinol is considered to be a causative agent of subacute myelo-optico neuropathy (SMON), although the pathogenesis of SMON is yet to be elucidated. To investigate the mechanism of neurotoxicity of clioquinol, we used PC12 cell line and focused on nerve growth factor (NGF) signaling through Trk receptor, which is essential for survival and differentiation of neuronal cells. Clioquinol inhibited NGF-induced Trk autophosphorylation in a dose-dependent manner. This inhibitory activity was further confirmed by the data of the inhibition of NGF-induced mitogen-activated protein kinase (MAPK) phosphorylation, which is located in the down stream of NGF-Trk intracellular signaling pathway. Clioquinol also caused neurite retraction induced by NGF and cell death. NGF-stimulated (differentiated) cells were more vulnerable than naïve cells. These results strongly suggest that clioquinol may cause the perturbation of the intracellular survival pathway by inhibiting Trk-initiated signaling pathway.
Asakura
Kunihiko
K
Department of Neurology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan. kasakura@fujita-hu.ac.jp
Ueda
Akihiro
A
Kawamura
Naoki
N
Ueda
Madoka
M
Mihara
Takateru
T
Mutoh
Tatsuro
T
D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D048430:Cell Shape; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D007464:Clioquinol / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009498:Neurotoxins / Q000008:administration & dosage; D016716:PC12 Cells / Q000166:cytology; D010766:Phosphorylation / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D016900:Neurofilament Proteins; D009498:Neurotoxins; D007464:Clioquinol; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D020928:Mitogen-Activated Protein Kinases