Glucocorticoid toxicity in the hippocampus. Temporal aspects of synergy with kainic acid.
Excessive exposure to glucocorticoids can damage neurons of the hippocampus, the principal neural target tissue for the steroid. Glucocorticoids, which are broadly catabolic throughout the body, appear to damage the hippocampus by inducing a metabolic vulnerability in its neurons, impairing their capacity to survive varied neuropathologic challenges which would normally be sublethal. As such, a number of interventions which damage the hippocampus--infusion of an excitotoxin or of an antimetabolite or induction of global ischemia--have their toxicity enhanced in rats with high circulating corticosterone concentrations and attenuated in adrenalectomized animals. The present report examines the temporal parameters with which corticosterone modulates the toxicity of the excitotoxin kainic acid (KA). Rats adrenalectomized and maintained corticosterone-free for 1 week prior to and following microinfusion of KA had minimal volumes of hippocampal damage. Administration of 10 mg/day of corticosterone (which produces circulating concentrations in the upper physiological range for the majority of a day) for as little as 1 day prior to and following KA infusion significantly potentiated damage; increasing periods of exposure to corticosterone bracketing the infusion of the toxin progressively increased damage. Both exposure to corticosterone only during the period prior to KA infusion or only in the aftermath of infusion potentiated damage. Thus, glucocorticoids appear to compromise the capacity of hippocampal neurons to survive KA via both rapid effects (manifest within as little as 24 h) as well as through more persistent actions.
D000315:Adrenalectomy; D000818:Animals; D003345:Corticosterone / Q000633:toxicity*; D004357:Drug Synergism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011712:Pyramidal Tracts / Q000187:drug effects / Q000473:pathology; D051381:Rats
D007608:Kainic Acid; D003345:Corticosterone