title: Ascorbate attenuates trimethyltin-induced oxidative burden and neuronal degeneration in the rat hippocampus by maintaining glutathione homeostasis.
abstract: The specific role of endogenous glutathione in response to neuronal degeneration induced by trimethyltin (TMT) in the hippocampus was examined in rats. A single injection of TMT (8 mg/kg, i.p.) produced a rapid increase in the formation of hydroxyl radical and in the levels of malondialdehyde (MDA) and protein carbonyl. TMT-induced seizure activity significantly increased after this initial oxidative stress, and remained elevated for up to 2 weeks post-TMT. Although a significant loss of hippocampal Cornus Ammonis CA1, CA3 and CA4 neurons was observed at 3 weeks post-TMT, the elevation in the level of hydroxyl radicals, MDA, and protein carbonyl had returned to near-control levels at that time. In contrast, the ratio of reduced to oxidized glutathione remained significantly decreased at 3 weeks post-TMT, and the glutathione-like immunoreactivity of the pyramidal neurons was decreased. However glutathione-positive glia-like cells proliferated mainly in the CA1, CA3, and CA4 sectors and were intensely immunoreactive. Double labeling demonstrated the co-localization of glutathione-immunoreactive glia-like cells and reactive astrocytes, as indicated by immunostaining for glial fibrillary acidic protein. This suggests that astroglial cells were mobilized to synthesize glutathione in response to the TMT insult. The TMT-induced changes in glutathione-like immunoreactivity appear to be concurrent with changes in the expression levels of glutathione peroxidase and glutathione reductase. Ascorbate treatment significantly attenuated TMT-induced seizures, as well as the initial oxidative stress, impaired glutathione homeostasis, and neuronal degeneration in a dose-dependent manner. These results suggest that ascorbate is an effective neuroprotectant against TMT. The initial oxidative burden induced by TMT may be a causal factor in the generation of seizures, prolonged disturbance of endogenous glutathione homeostasis, and consequent neuronal degeneration.
authors.affiliation: Neurotoxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea.
authors.forename: E-J
authors.initials: EJ
authors.lastname: Shin
authors.forename: S K
authors.initials: SK
authors.lastname: Suh
authors.forename: Y K
authors.initials: YK
authors.lastname: Lim
authors.forename: W-K
authors.initials: WK
authors.lastname: Jhoo
authors.forename: O P
authors.initials: OP
authors.lastname: Hjelle
authors.forename: O P
authors.initials: OP
authors.lastname: Ottersen
authors.forename: C Y
authors.initials: CY
authors.lastname: Shin
authors.forename: K H
authors.initials: KH
authors.lastname: Ko
authors.forename: W-K
authors.initials: WK
authors.lastname: Kim
authors.forename: D S
authors.initials: DS
authors.lastname: Kim
authors.forename: W
authors.initials: W
authors.lastname: Chun
authors.forename: S
authors.initials: S
authors.lastname: Ali
authors.forename: H-C
authors.initials: HC
authors.lastname: Kim
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D017665:Hydroxyl Radical / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014298:Trimethyltin Compounds / Q000633:toxicity
chemical_list: D000975:Antioxidants; D005904:Glial Fibrillary Acidic Protein; D014298:Trimethyltin Compounds; C046488:trimethyltin; D017665:Hydroxyl Radical; D008315:Malondialdehyde; D005978:Glutathione; D001205:Ascorbic Acid; D019803:Glutathione Disulfide