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Supraphysiological levels of the stress hormone corticosterone attenuate blood-brain barrier disruption and microglial activation in hippocampus of C57BL/6J mice treated with kainic acid.
Benkovic-SA; O'Callaghan-JP; Miller-DB
Toxicologist 2004 Mar; 78(S-1):87
Kainic acid intoxication in C57BL/6J mice causes neuronal damage and the activation of glial cells. Neurotoxicants can alter blood-brain barrier integrity, and the in-flux of blood-borne factors may contribute to the total toxicity profile. We evaluated the consequences of kainate treatment on the blood-brain barrier and microglial activation, and the ability of high levels of corticosterone to modulate pathology. Male mice were implanted with a corticosterone pellet (192 mg/kg/d) to mimic the sustained activation of the HPA axis associated with chronic stress, and allowed to recover for seven days. Control and implanted mice were injected intraperitoneally with saline or 25 mg/kg kainic acid, and sacrificed at 1, 3, 6, and 12 hours post treatment. Kainate-induced seizures were scored at Stage 1 (Racine scale), and corticosterone pretreatment did not alter seizure activity. Analysis of hippocampal IgG levels by Western blotting revealed a kainate-induced breach of the blood-brain barrier, and subsequent influx of plasma-derived IgG by one hour, which continued to increase and achieved significant elevation at six hours post-treatment. Corticosterone pretreatment attenuated the kainate-induced influx of IgG at all time points. Immunohistochemical localization of IgG in hippocampal parenchyma paralleled blot data. Microglial activation following kainate treatment was evaluated by silver staining and revealed activated cells at one hour post treatment. Staining with Isolectin B4 revealed numerous microglial cells throughout the hippocampal parenchyma at 12 hours post treatment, and an attenuation in the quantity of microglia by corticosterone pretreatment. The interactions of chronic stress and chemical intoxication, and subsequent effects on neuroanatomy and physiology are complicated, and though many literature reports describe exacerbation of neurotoxicity by stress, our data suggest steroid treatment can be protective.
Stress; Hormones; Laboratory-animals; Animals; Animal-studies; Acids; Neurotoxins; Neurotoxicity; Bloodborne-pathogens; Physiology; Physiological-factors
The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland
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