title: Neuroprotective effect of 3-morpholinosydnonimine against Zn²⁺-induced PC12 cell death.
abstract: Excessive intracellular accumulation of zinc (Zn(2+)) is neurotoxic and contributes to a number of neuropathological conditions. Here, we investigated the protective effect of 3-morpholinosydnonimine (SIN-1) against Zn(2+)-induced neuronal cell death in differentiated PC12 cells. We found that Zn(2+)-induced PC12 cell death was reduced in a concentration-dependent manner by pretreatment with SIN-1. The intracellular accumulation of Zn(2+) was not affected by pretreatment with SIN-1, indicating that SIN-1-induced neuroprotection was not attributable to reduced influx of Zn(2+) into cells. SIN-1C, the stable decomposition product of SIN-1, failed to prevent Zn(2+)-induced cell death. Furthermore, the protective effect of SIN-1 against Zn(2+)-induced PC12 cell death was almost completely abolished by uric acid, a free radical scavenger, suggesting that reactive oxygen and nitrogen species generated by SIN-1 may contribute to the protective effect. SIN-1 prevented the inactivation of glutathione reductase (GR) and the increase in the ratio of oxidized glutathione/total glutathione (GSSG/total GSH) induced by Zn(2+). Addition of membrane permeable GSH ethyl ester (GSH-EE) to PC12 cells prior to Zn(2+) treatment significantly increased cell viability. We therefore conclude that SIN-1 may exert neuroprotective effect against Zn(2+)-induced cell death in differentiated PC12 cells by preventing inhibition of GR and increase in GSSG/total GSH ratio.
authors.affiliation: Department of Oral Biology, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea.
authors.forename: Jeong Mi
authors.initials: JM
authors.lastname: An
authors.affiliation: Department of Oral Biology, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea.
authors.forename: Seong Ah
authors.initials: SA
authors.lastname: Moon
authors.affiliation: Department of Oral Biology, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Hong
authors.affiliation: Department of Oral & Maxillofacial Surgery, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea. Electronic address: jeongwan@yuhs.ac.
authors.forename: Jeong Wan
authors.initials: JW
authors.lastname: Kang
authors.affiliation: Department of Oral Biology, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea. Electronic address: jeong@yuhs.ac.
authors.forename: Jeong Taeg
authors.initials: JT
authors.lastname: Seo
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D019803:Glutathione Disulfide / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D015032:Zinc / Q000009:adverse effects* / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; C002385:linsidomine; D008981:Molsidomine; D005980:Glutathione Reductase; D015032:Zinc; D019803:Glutathione Disulfide
keywords: Glutathione reductase; Neuroprotection; PC12 cells; SIN-1; Zn(2+)