Superoxide dismutase as a target of clioquinol-induced neurotoxicity |
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Authors: | Kazuyuki Kawamura Yukiko Kuroda Masako Sogo Miki Fujimoto Toshio Inui Takao Mitsui |
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Affiliation: | 1. Department of Neurology, Tokushima National Hospital, National Hospital Organization, 1354 Shikiji, Kamojima, Yoshinogawa, Tokushima 776-8585, Japan;2. Department of Clinical Research, Tokushima National Hospital, National Hospital Organization, 1354 Shikiji, Kamojima, Yoshinogawa, Tokushima 776-8585, Japan |
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Abstract: | Subacute myelo-optico-neuropathy (SMON) is a progressive neurological disorder affecting the spinal cord, peripheral nerves and optic nerves. Although it has been assumed that SMON was caused by intoxication of clioquinol, the mechanism underlying clioquinol-induced neurotoxicity is not fully understood. This study aimed to clarify the relevance of oxidative stress to clioquinol-induced neurotoxicity and the cause of the enhanced oxidative stress. Clioquinol induced cell death in human-derived neuroblastoma cell line, SH-SY5Y, in a dose-dependent manner. This process was accompanied by activation of caspase-3 and enhanced production of reactive oxygen species (ROS). We examined whether clioquinol inhibited the activity of superoxide dismutase-1 (SOD1), based on its metal chelating properties. Clioquinol inhibited activities of purified SOD1 in a dose-dependent manner. Cytosolic SOD activities were also inhibited in SH-SY5Y cells treated with clioquinol. Finally, addition of exogenous SOD1 to the culture significantly reduced enhanced ROS production and cell death induced by clioquinol in SH-SY5Y cells. These findings suggested that enhanced oxidative stress caused by inhibition of SOD1 undelay clioquinol-induced neurotoxicity and was relevant to the pathogenesis of SMON. |
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Keywords: | Subacute myelo-optico neuropathy (SMON) Clioquinol Superoxide dismutase (SOD) Reactive oxygen species (ROS) |
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