Effect of dexamethasone on elevated cytokine mRNA levels in chemical-induced hippocampal injury.
An acute administration of the hippocampal toxicant trimethyltin (TMT) produced a specific pattern of neuronal necrosis in dentate granule cells with accompanying astrogliosis and initiation of a cytokine response within 24 hours. The purpose of this study was to examine the effects of the anti-inflammatory agent, dexamethasone (DEX), on the pattern of cytokine expression and neuronal degeneration occurring after an acute TMT injection. Dexamethasone (0.2 mg/kg or 10 mg/kg) was administered to 21-day-old male mice 1 hour prior to an injection of TMT hydroxide (2.5 mg/kg, i.p.). Mice receiving 0.2 mg/kg DEX received a second injection 6 hours after TMT. Twenty-four hours later, neuronal necrosis and astrogliosis were assessed and found to be similar in animals treated with TMT, either in the presence or absence of dexamethasone. Pretreatment with dexamethasone failed to prevent the neurodegeneration and astrogliosis. The TMT-induced injury response was represented in elevations of mRNA levels for the injury-associated host response genes glial fibrillary acidic protein (GFAP), EB22/5.3, and intercellular adhesion molecule-1 (ICAM-1). The combination of DEX and TMT produced increased elevation in mRNA levels for EB22/5.3 and ICAM, while GFAP levels remained the same as with TMT alone. The injury response from TMT was accompanied by elevations in mRNA levels for the cytokines tumor necrosis factor (TNF) alpha, TNFbeta, and interleukin (IL)-1alpha. Treatment with dexamethasone prior to TMT resulted in significantly elevated levels of TNFalpha, TNFbeta, and IL-1alpha as compared to TMT alone. These data represent the inability of glucocorticoids to downregulate the injury response in rat hippocampus following a systemic injection of TMT and suggest a stimulation and "priming" of hippocampal cells by dexamethasone.
Bruccoleri
A
A
Neurotoxicology Group, Laboratory of Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Pennypacker
K R
KR
Harry
G J
GJ
D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology*; D005911:Gliosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009336:Necrosis; D009410:Nerve Degeneration; D009498:Neurotoxins / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism*; D012260:Ribonucleases; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014298:Trimethyltin Compounds / Q000633:toxicity
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D009498:Neurotoxins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014298:Trimethyltin Compounds; C046488:trimethyltin; D003907:Dexamethasone; D012260:Ribonucleases