title: Involvement of oxidative stress and impaired lysosomal degradation in amiodarone-induced schwannopathy.
abstract: Amiodarone hydrochloride (AMD), an anti-arrhythmic agent, has been shown to cause peripheral neuropathy; however, its pathogenesis remains unknown. We examined the toxic effects of AMD on an immortalized adult rat Schwann cell line, IFRS1, and cocultures of IFRS1 cells and adult rat dorsal root ganglion neurons or nerve growth factor-primed PC12 cells. Treatment with AMD (1, 5, and 10 μm) induced time- and dose-dependent cell death, accumulation of phospholipids and neutral lipids, upregulation of the expression of gangliosides, and oxidative stress (increased nuclear factor E2-related factor in nuclear extracts and reduced GSH/GSSG ratios) in IFRS1 cells. It also induced the upregulation of LC3-II and p62 expression, with phosphorylation of p62, suggesting that deficient autolysosomal degradation is involved in AMD-induced IFRS1 cell death. Furthermore, treatment of the cocultures with AMD induced detachment of IFRS1 cells from neurite networks in a time- and dose-dependent manner. These findings suggest that AMD-induced lysosomal storage accompanied by enhanced oxidative stress and impaired lysosomal degradation in Schwann cells might be a cause of demyelination in the peripheral nervous system.
authors.affiliation: Diabetic Neuropathy Project (Former ALS/Neuropathy Project), Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, 156-8506, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Niimi
authors.affiliation: Diabetic Neuropathy Project (Former ALS/Neuropathy Project), Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, 156-8506, Japan.
authors.forename: Hideji
authors.initials: H
authors.lastname: Yako
authors.affiliation: Diabetic Neuropathy Project (Former ALS/Neuropathy Project), Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, 156-8506, Japan.|Division of Diabetes, Metabolism & Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Tsukamoto
authors.affiliation: Diabetic Neuropathy Project (Former ALS/Neuropathy Project), Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, 156-8506, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Takaku
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Yamauchi
authors.affiliation: Diabetic Neuropathy Project (Former ALS/Neuropathy Project), Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, 156-8506, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Kawakami
authors.affiliation: Diabetic Neuropathy Project (Former ALS/Neuropathy Project), Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, 156-8506, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yanagisawa
authors.affiliation: Diabetic Neuropathy Project (Former ALS/Neuropathy Project), Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, 156-8506, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Watabe
authors.affiliation: Division of Diabetes, Metabolism & Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Utsunomiya
authors.affiliation: Diabetic Neuropathy Project (Former ALS/Neuropathy Project), Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, 156-8506, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Sango
mesh_terms: D000638:Amiodarone / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000633:toxicity; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D008247:Lysosomes / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D016716:PC12 Cells; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000638:Amiodarone; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D010743:Phospholipids; C526109:Anxa3 protein, rat
keywords: Schwann cells; demyelination; in vitro; neurotoxicology; peripheral neuropathy