A mechanism for glucocorticoid toxicity in the hippocampus: increased neuronal vulnerability to metabolic insults.
Glucocorticoids appear capable of damaging or destroying hippocampal neurons. There is a progressive loss of such neurons with age, and the process can be prevented by adrenalectomy at mid-age or accelerated by prolonged exposure to high circulating titers of glucocorticoids. The present study examines possible mechanisms for this steroid action. Rats were either adrenalectomized, intact, or treated with corticosterone (CORT) sufficient to produce prolonged elevations of titers in the high physiological range. After 1 week, unilateral hippocampal microinfusions were made with either kainic acid (KA) or 3-acetylpyridine (3-AP). Doses of these hippocampal neurotoxins were chosen to produce small-sized lesions. Treatment with CORT exacerbated the extent of damage following neurotoxin infusion, whereas adrenalectomy attenuated the damage. Additional studies eliminated some potential mechanisms for this phenomenon. CORT did not directly alter the intrinsic toxicity of the compounds but, rather, altered the sensitivity of target cells to them. As evidence, no potentiation of damage in CORT-treated animals occurred in KA-sensitive brain regions lacking CORT receptors. Since CORT did not increase the diffusion or binding of [3H]KA in the hippocampus, it appears unlikely that CORT potentiated toxin-induced damage by influencing the specific mechanism of action of any toxin. Finally, the general nature of the CORT potentiation of damage was supported by the markedly different postulated mechanisms of toxicity of KA and 3-AP. We hypothesize that CORT exerts its extensive catabolic effects upon target cells to produce generalized metabolic vulnerability in hippocampal neurons possessing high concentrations of CORT receptors, thereby sensitizing them to varied metabolic insults.
D000818:Animals; D005938:Glucocorticoids / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects*; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects; D009498:Neurotoxins / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
D005938:Glucocorticoids; D009498:Neurotoxins; D011725:Pyridines; C010835:3-acetylpyridine; D007608:Kainic Acid