title: Superoxide dismutase as a target of clioquinol-induced neurotoxicity.
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.
authors.affiliation: Department of Neurology, Tokushima National Hospital, National Hospital Organization, 1354 Shikiji, Kamojima, Yoshinogawa, Tokushima 776-8585, Japan. Electronic address: kawamura@tokusima.hosp.go.jp.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kawamura
authors.affiliation: Department of Clinical Research, Tokushima National Hospital, National Hospital Organization, 1354 Shikiji, Kamojima, Yoshinogawa, Tokushima 776-8585, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kuroda
authors.affiliation: Department of Clinical Research, Tokushima National Hospital, National Hospital Organization, 1354 Shikiji, Kamojima, Yoshinogawa, Tokushima 776-8585, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Sogo
authors.affiliation: Department of Clinical Research, Tokushima National Hospital, National Hospital Organization, 1354 Shikiji, Kamojima, Yoshinogawa, Tokushima 776-8585, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Neurology, Tokushima National Hospital, National Hospital Organization, 1354 Shikiji, Kamojima, Yoshinogawa, Tokushima 776-8585, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Inui
authors.affiliation: Department of Neurology, Tokushima National Hospital, National Hospital Organization, 1354 Shikiji, Kamojima, Yoshinogawa, Tokushima 776-8585, Japan; Department of Clinical Research, Tokushima National Hospital, National Hospital Organization, 1354 Shikiji, Kamojima, Yoshinogawa, Tokushima 776-8585, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Mitsui
mesh_terms: D045744:Cell Line, Tumor; D007464:Clioquinol / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009420:Nervous System / Q000187:drug effects*; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000187:drug effects*
chemical_list: D007464:Clioquinol; D013482:Superoxide Dismutase
keywords: Clioquinol; Reactive oxygen species (ROS); Subacute myelo-optico neuropathy (SMON); Superoxide dismutase (SOD)