Glucocorticoids Inhibit Glucose Transport and Glutamate Uptake in Hippocampal Astrocytes: Implications for Glucocorticoid Neurotoxicity

Abstract

Glucocorticoids (GCs), the adrenal steroid hormones secreted during stress, can damage the hippocampus and impair its capacity to survive coincident neurological insults. This GC endangerment of the hippocampus is energetic in nature, as it can be prevented when neurons are supplemented with additional energy substrates. This energetic endangerment might arise from the ability of GCs to inhibit glucose transport into both hippocampal neurons and astrocytes. The present study explores the GC inhibition in astrocytes. (1) GCs inhibited glucose transport approximately 15-30% in both primary and secondary hippocampal astrocyte cultures. (2) The parameters of inhibition agreed with the mechanisms of GC inhibition of glucose transport in peripheral tissues: A minimum of 4 h of GC exposure were required, and the effect was steroid specific (i.e., it was not triggered by estrogen, progesterone, or testosterone) and tissue specific (i.e., it was not triggered by GCs in cerebellar or cortical cultures). (3) Similar GC treatment caused a decrease in astrocyte survival during hypoglycemia and a decrease in the affinity of glutamate uptake. This latter observation suggests that GCs might impair the ability of astrocytes to aid neurons during times of neurologic crisis (i.e., by impairing their ability to remove damaging glutamate from the synapse).

Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

“…In our study, plasma corticosterone levels are beyond physiological levels, which is in agreement with the fact that glucocorticoids dose-dependently inhibit brain glucose uptake when they are present in the brain at concentrations above the high physiological range in in vitro (Virgin et al, 1991) and in vivo (Doyle et al, 1994). Interestingly, similar GC treatment caused a decrease in the affinity of glutamate uptake by astrocytes.…”

“…Interestingly, similar GC treatment caused a decrease in the affinity of glutamate uptake by astrocytes. Studies have shown that in hippocampal cell cultures glucocorticoids significantly inhibit glucose transport and glutamate uptake by both neurons and astrocytes (Horner et al, 1990;Virgin et al, 1991). This latter observation suggests that GCs might impair the ability of astrocytes to aid neurons (ie, by impairing their ability to remove damaging glutamate from the synapse), which may be the case of our model.…”

“…A likely functional implication of the stress effects on cerebral glucose transport is an impairment of glutamate uptake (Virgin et al, 1991). Indeed, stress has been shown to increase extracellular glutamate concentrations in many brain areas (Lowy et al, 1993;Moghaddam et al, 1994;SteinBehrens et al, 1994), an effect that is proposed to result from compromised activity of the energy-dependent excitatory amino acid transporters.…”

“…During the physiological activation of the brain areas there is a correlative increase in local glucose uptake (Sokoloff, 1999). However, several studies have found that in stressful situations, supraphysiological levels of corticosterone have inhibitory effects on glucose transport and metabolism in several brain regions in rats (Landgraf et al, 1978;Virgin et al, 1991) and also in humans (De León et al, 1997). In peripheral tissues, glucocorticoids released by stress act by decreasing glucose transport and metabolism and increasing serum glucose levels (Munck, 1971).…”

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

“…This may be due to an enhanced release of the amino acid and/or to a decreased uptake in neuronal or glial tissue. The latter was indeed demonstrated in a preparation of cultured astrocytes (Virgin et al, 1991). The activity of glutamine synthetase, and therefore the availability of glutamate, is not regulated by corticosteroids in the brain (Tombaugh and Sapolsky, 1990), as it is for instance in peripheral tissue (Max et al, 1988).…”