Chemical adrenalectomy reduces hippocampal damage induced by kainic acid.
Glucocorticoids (GCs), the adrenal steroids secreted during stress, have numerous catabolic effects which include damage to neurons of the hippocampus, a principal neural target site for the steroids. In the rat, the extent of GC exposure over the lifespan is a major determinant of the rate of hippocampal neuron death during aging. GCs also modulate the severity of hippocampal damage in the rat following insults such as seizure or hypoxia-ischemia. As evidence, exogenous GCs exacerbate, while adrenalectomy attenuates hippocampal damage after these insults. Thus, it is possible that diminution of endogenous GC secretion might protect the human hippocampus after similar neurological insults; adrenalectomy under such circumstances is obviously not a viable clinical option. We demonstrate the protective effects of transient chemical adrenalectomy with the GC synthesis inhibitor, metyrapone. Rats were microinfused with the excitotoxin kainic acid in order to induce status epilepticus seizures; this insult caused a significant GC stress-response. Attenuation of that response with metyrapone reduced the CA3 hippocampal damage produced by kainic acid. Metyrapone did not change the intensity of seizures, but rather, apparently, changed the capacity of neurons to withstand the seizure. Thus, metyrapone, which is used safely and efficaciously in other clinical contexts, might prove protective of the brain following seizure in the human.
Stein
B A
BA
Department of Biological Sciences, Stanford University, CA 94305.
Sapolsky
R M
RM
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D004569:Electroencephalography; D005938:Glucocorticoids / Q000378:metabolism / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology
D005938:Glucocorticoids; D007608:Kainic Acid; D008797:Metyrapone