title: HRD1 levels increased by zonisamide prevented cell death and caspase-3 activation caused by endoplasmic reticulum stress in SH-SY5Y cells.
abstract: Zonisamide, which is commonly prescribed at high doses (200-400 mg/day) for the treatment of partial seizures, has recently been used at a low dose (25 mg/day) for improving parkinsonian syndrome. However, the molecular mechanisms that underlie the antiparkinsonian effects of zonisamide have not been clarified. Here we show that low micromolar concentrations of zonisamide prevented cleavage of caspase-3 and cell death in human dopaminergic SH-SY5Y neuroblastoma cells that were subjected to endoplasmic reticulum stress induced by tunicamycin or 6-hydroxydopamine. Hypodense zonisamide increased the expression levels of SEL1L, which is known to stabilize the ubiquitin ligase HRD1. Indeed, upregulation of HRD1 protein was observed. Thus, the results of this study strongly suggest that low concentrations of zonisamide inhibit neuronal cell death by increasing HRD1 protein levels in patients with Parkinson's disease. Consequently, in addition to the treatment of Parkinson's disease, the therapeutic potential of zonisamide should be considered for the treatment of several neurodegenerative disorders with pathophysiological mechanisms involving endoplasmic reticulum stress.
authors: Department of Pharmacy and Pharmacology, Asahikawa Medical University, Asahikawa, Hokkaido, 078-8510, Japan.
authors: Tomohiro
authors: T
authors: Omura
authors: Masaru
authors: M
authors: Asari
authors: Joe
authors: J
authors: Yamamoto
authors: Naoya
authors: N
authors: Kamiyama
authors: Kumiko
authors: K
authors: Oka
authors: Chisato
authors: C
authors: Hoshina
authors: Chikatoshi
authors: C
authors: Maseda
authors: Toshio
authors: T
authors: Awaya
authors: Yoshikazu
authors: Y
authors: Tasaki
authors: Hiroshi
authors: H
authors: Shiono
authors: Keiko
authors: K
authors: Shimizu
authors: Kazuo
authors: K
authors: Matsubara
mesh_terms: D000927:Anticonvulsants / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D009447:Neuroblastoma / Q000201:enzymology / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics*; D000078305:Zonisamide
chemical_list: D000927:Anticonvulsants; D061945:Caspase Inhibitors; D007555:Isoxazoles; D000078305:Zonisamide; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases; C505407:CASP3 protein, human; D053148:Caspase 3