Glucocorticoid toxicity in the hippocampus: reversal by supplementation with brain fuels

Glucocorticoids (GCs) can damage neurons of the hippocampus, the principal target tissue in the brain for the hormone. Hippocampal neuron loss during aging in the rat is accelerated by prolonged GC exposure and decelerated by adrenalectomy. GCs appear to damage these neurons indirectly by inducing a state of vulnerability and thus impairing their capacity to survive a variety of metabolic challenges. As such, high physiological concentrations of the steroid increase hippocampal damage induced by an antimetabolite toxin, an excitotoxin, or hypoxia-ischemia. Conversely, adrenalectomy attenuates the damage caused by these insults. This study suggests that GCs endanger hippocampal neurons by impairing their energy metabolism. Neurons are extremely vulnerable to such disruption, all the insults potentiated by GCs either impair energy production or pathologically increase energy consumption, and GCs inhibit glucose utilization in the hippocampus. Administration of different brain fuels--glucose, mannose, fructose, or the ketone beta-hydroxybutyrate--reduced hippocampal damage induced by coadministration of GCs and either of 2 different neurotoxins (kainic acid and 3-acetylpyridine). This appeared to be due to a reduction in the damaging synergy between GCs and the toxin; as evidence, a dose of mannose that attenuated damage induced by kainic acid plus GCs failed to reduce damage induced by the same dose of kainic acid alone. Glucose (whose utilization is noncompetitively inhibited by GCs) and fructose (which does not readily penetrate the blood-brain barrier) were less effective at reducing damage than the other 2 fuels.