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

Abstract

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.

O eixo hipotálamo-pituitária-adrenal, a função dos receptores de glicocorticóides e sua importância na depressão

“…Indeed, it has been suggested that prolonged overproduction of glucocorticoids, whether as a result of ongoing stress or a genetic predisposition to HPA axis hyperactivity, damages brain structures (especially the hippocampus) essential for HPA axis restraint. 41 Such damage, in turn, has been hypothesized to lead to a feed-forward circuit in which ongoing stressors drive glucocorticoid overproduction indefinitely (the "glucocorticoid cascade hypothesis"). Because of the capacity of high concentrations of glucocorticoids to disrupt cellular functioning in ways that can lead to a host of ills, this glucocorticoid overproduction is believed to contribute directly to many of the adverse behavioral and physiological sequelae associated with chronic stress.…”

Energy Dependency of Glucocorticoid Exacerbation of gp120 Neurotoxicity

“…This agrees with findings that energy supplementation can reverse GC exacerbation of neurotoxicity induced by kainate and ischemia (Tombaugh and Sapo!sky, 1992) in the hippocampus. In these latter articles, the energy supplementation took the form of mannose and ketones as well as glucose (Sapolsky, 1986). The generality of these interventions suggests that the energetic features of glucose supplementation ultimately help maintain ATP levels.…”

Mineralocorticoid and glucocorticoid receptors in the brain. Implications for ion permeability and transmitter systems

“…They do so regardless of their peripheral catabolic actions, since the aggrevation of induced lesions was also observed in isolated brain preparations Tombaugh et al, 1992). Additional administration of energy sources, such as glucose or mannose, effectively protected against the deleterious effects of glucocorucolos (Sapolsky, 1986). Considering the implication of increased excitatory amino acid transmission, particularly through NMDA receptors, and a :~teady elevation of intracellular [Ca] in neuronal damage due to energy shortage, it is not surprising that the glucocorticoid-induced exacerbatmn of neurotoxic agents shows NMDA and Ca dependenc~,: !l) Corticosterone enhanced 3AP toxicity was reduced by a NMDA antagonist (Armanini cz al., 1990): rapid changes in glucose utilization after mild stress are also NMDA-dependent (Schasfoort <: al.. 1988) (2) Kainic acid-evoked rises in [Ca]~ in a hippocampal neuronal culture are enhanced alter 24 hr incubation with 1 #M corticosterone (Elliot and Sapolsky, 1992), at least partly due t~ an impaired Ca-extrtlsion mechanism (Elliot and Sapolsky, 1993).…”