TY - JOUR
T1 - Clioquinol inhibits NGF-induced Trk autophosphorylation and neurite outgrowth in PC12 cells
AU - Asakura, Kunihiko
AU - Ueda, Akihiro
AU - Kawamura, Naoki
AU - Ueda, Madoka
AU - Mihara, Takateru
AU - Mutoh, Tatsuro
N1 - Funding Information:
This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (K.A. and T.M.) and a grant from the Ministry of Health, Labor, and Welfare of Japan (T.M.). We thank Ms. M. Yokoyama for the technical assistance.
PY - 2009/11/16
Y1 - 2009/11/16
N2 - 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.
AB - 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.
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U2 - 10.1016/j.brainres.2009.09.011
DO - 10.1016/j.brainres.2009.09.011
M3 - Article
C2 - 19748492
AN - SCOPUS:71849099656
SN - 0006-8993
VL - 1301
SP - 110
EP - 115
JO - Brain Research
JF - Brain Research
ER -