High levels of stress or stress hormones have been reported to exacerbate human disorders of several physiological systems. As a model of stress, male mice were implanted with 0, 10, 35 or 100 mg/21d release corticosterone (CORT) pellets (0, 19, 67, and 190 mg/kg/d). After 7d, mice were injected with saline or 25 mg/kg kainic acid (KA), were scored for seizures (Racine scale), and were allowed to recover for 12 or 24h (histology), 7d (ELISA for GFAP), or 1, 3, 6, or 12h (western blot for IgG). Tissue was prepared for histological analysis of neurodegeneration by the cupric-silver stain; astrogliosis by ELISA and immunohistochemistry for GFAP; and microglial activation by Iba-1, CD11c, isolectin, and reactive silver staining. Treatment of mice with CORT caused no neuronal death, and attenuated damage caused by KA. GFAP levels were elevated seven-fold in KA-treated mice. Increasing doses of CORT caused greater decreases in basal GFAP, and CORT pre-treatment attenuated KA-induced protein elevation. GFAP staining revealed hypertrophic astrocytes with thick processes following KA treatment. Astrocytic hypertrophy was attenuated by CORT pre-treatment. Iba-1 and silver staining revealed a population of resting microglia in all brain regions. Basal Iba-1 staining was attenuated by high doses of CORT. Lectin and CD11c stained microglia were observed in regions that displayed KA-induced neurodegeneration and were rarely observed in control or CORT-treated animals. KA treatment caused a breach of the blood-brain barrier (BBB) and resulted in hippocampal levels of IgG that were increased by one hour. IgG levels were maximal at six hours post-treatment, and returned to baseline by 12 hours. CORT pre-treatment attenuated KA-induced BBB opening and IgG influx. Our data indicate CORT does not cause neuronal damage, and attenuates excitotoxic neurodegeneration and glial activation that has BBB disruption as a component of the pathological mechanism.
The Toxicologist. Society of Toxicology 48th Annual Meeting and ToxExpo, March 15-19, 2009, Baltimore, Maryland