No abstract

Glucocorticoids (GCs), the adrenal steroids secreted during stress, endanger the hippocampus, compromising its ability to survive neurological insults. GCs probably do so by disrupting energetics in the hippocampus, thus impairing its ability to contain damaging fluxes of excitatory amino acids and calcium. Superficially, these observations suggest that stress itself should also exacerbate the toxicity of neurological insults. However, most studies have involved unphysiologic GC manipulations, limiting speculations about the endangering effects of stress. In this study, rats were infused with the excitotoxin kainic acid (KA) after either having been adrenalectomized and replaced with a range of physiologic concentrations of GCs, or having been stressed intermittently. We observed that within the CA3 region, increasing CORT concentrations exacerbated the KA-induced neuron loss, the extent of tau immunoreactivity, and of spectrin proteolysis. The transitions from low to high basal GC concentrations and from high basal to stress GC values were both associated with significant exacerbation of neuron loss and tau immunoreactivity; the extent of spectrin proteolysis was less sensitive to increments in GCs. As would be expected from these data, exposure to intermittent stress prior to KA infusion also exacerbated neuron loss, tau immunoreactivity, and spectrin proteolysis in CA3. Thus, physiological elevations of GCs, and stress itself, can exacerbate hippocampal neuron loss and the attendant degenerative markers following an excitotoxic insult. Of significance, seizure and hypoxia-ischemia provoke considerable GC stress responses, which may thus worsen the resultant damage. Furthermore, a number of neuropsychiatric disorders, as well as aging, are associated with elevated basal GC concentrations, which may endanger the hippocampus in the event of neurological insult.

Glucocorticoids (GCs) compromise the ability of hippocampal neurons to survive various insults, and do so, at least in part, by exacerbating steps in the glutamate/N-methyl-D-aspartate (NMDA)/calcium cascade of damage. As evidence, GCs impair uptake of glutamate by hippocampal astrocytes, the GC endangerment of the hippocampus is NMDA receptor dependent, and GCs exacerbate kainic acid (KA)-induced calcium mobilization. These observations predict that GCs should also exacerbate KA-induced accumulation of extracellular glutamate and aspartate. To test this, adrenalectomized rats were given replacement GCs in either the low or high physiological range. Three days later, rats were anesthetized and 1 mM KA was infused through a dialysis probe placed in the dorsal hippocampus. Extracellular amino acid concentrations in the dialysate were then assessed by HPLC. After KA infusion, high-GC rats (30 +/- 3 micrograms/dl) had significantly elevated concentrations of glutamate and aspartate compared with low-GC rats (all less than 0.95 micrograms/dl). The glutamate accumulation was due to GCs raising pre-KA concentrations, whereas the aspartate accumulation was due to GCs exacerbating the KA-induced rise. Glutamine concentrations were unaffected by KA, whereas the high-GC regimen elevated glutamine concentrations both before and after KA. Taurine concentrations rose after infusion of KA, but were unaffected by GC regime, whereas alanine concentrations were unaffected by either manipulation. Serine concentrations were unaffected by KA, but were depressed both before and after KA in high-GC rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucocorticoids (GCs) are secreted during stress and can damage the hippocampus over the course of aging and impair the capacity of hippocampal neurons to survive excitotoxic insults. Using microdialysis, we have previously observed that GCs augment the extracellular accumulation of glutamate and aspartate in the hippocampus following kainic acid‐induced seizures. In that study, adrenalectomized rats maintained on minimal GC concentrations were compared with those exposed to GCs elevated to near‐pharmacological levels. We wished to gain insight into the physiological relevance of these observations. Thus, we have examined the effects of GCs over the normal physiological range on glutamate and aspartate profiles; this was done by implanting adrenalectomized rats with GC‐secreting pellets, which produce stable and controllable circulating GC concentrations. We observe that incremental increases in GC concentrations cause incremental increases in glutamate accumulation before the kainic acid insult, as well as in the magnitude of the glutamate response to kainic acid. Elevating GC concentrations from the circadian trough to peak doubled cumulative glutamate accumulation, whereas a rise into the stress range caused a fourfold increase in accumulation. Similar, although smaller, effects also occurred with aspartate accumulation (as well as with taurine but not glutamine accumulation). These data show that the highly elevated GC concentrations that accompany neurological insults such as seizure or hypoxia‐ischemia will greatly exacerbate the glutamate accumulation at that time. Furthermore, stress levels of GCs augmented glutamate accumulation even in the absence of an excitotoxic insult, perhaps explaining how sustained stress itself damages the hippocampus. Finally, even the moderately ėlevated basal GC concentrations that typically occur in aged rats augmented glutamate accumulation, perhaps explaining how GCs damage the hippocampus over the course of normal aging.

No abstract