title: Glucocorticoids exacerbate peroxynitrite mediated potentiation of glucose deprivation-induced death of rat primary astrocytes.
abstract: Glucocorticoids have been implicated in the exacerbation of several types of neurotoxicity in various neuropathological situations. In this study, we investigated the effect of a glucocorticoid dexamethasone on glucose deprivation induced cell death of immunostimulated rat primary astrocytes, which is dependent on the production of peroxynitrite from the immunostimulated cells [Choi et al. Glia, 31(2001) 155-164; J. Neuroimmunol. 112 (2001) 55-62]. Glucose deprivation in immunostimulated rat primary astrocytes results in the release of lactate dehydrogenase (LDH) after 5 h and co-treatment with dexamethasone (1-1000 nM) dose-dependently increased LDH release. Treatment of the exogenous peroxynitrite generator SIN-1 (20 microM), plus glucose deprivation, also increased LDH release after 6 h and co-treatment with dexamethasone dose-dependently increased LDH release. A glucocorticoid receptor antagonist, RU-486, reversed the potentiation of cell death by dexamethasone. Glucose deprivation in immunostimulated cells decreased the intracellular ATP levels, which preceded LDH release from the cell, and co-treatment with dexamethasone dose-dependently potentiated the depletion of intracellular ATP levels. In addition, dexamethasone further deteriorated SIN-1 plus glucose deprivation-induced decrease in mitochondrial transmembrane potential in rat primary astrocytes, which was reversed by RU-486. The results from the present study suggest that glucocorticoids may be detrimental to astrocytes in situations where activation of glial cells are observed, including ischemia and Alzheimer's disease, by mechanisms involving depletion of intracellular ATP levels and deterioration of mitochondrial transmembrane potentials.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Seoul National University, San 56-1, Shillim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
authors.forename: C Y
authors.initials: CY
authors.lastname: Shin
authors.forename: J W
authors.initials: JW
authors.lastname: Choi
authors.forename: E S
authors.initials: ES
authors.lastname: Jang
authors.forename: J H
authors.initials: JH
authors.lastname: Ryu
authors.forename: W K
authors.initials: WK
authors.lastname: Kim
authors.forename: H C
authors.initials: HC
authors.lastname: Kim
authors.forename: K H
authors.initials: KH
authors.lastname: Ko
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D015735:Mifepristone / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D005938:Glucocorticoids; D006727:Hormone Antagonists; D020030:Nitric Oxide Donors; D030421:Peroxynitrous Acid; D015735:Mifepristone; C002385:linsidomine; D003907:Dexamethasone; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D008981:Molsidomine; D005947:Glucose