Abstract
Astrocytes are claimed to protect neurons against excitotoxicity by clearing glutamate from the extracellular space and rapidly converting it into glutamine. Glutamine, is then released into the extracellular medium, taken up by neurons and transformed back into glutamate which is then stored into synaptic vesicles. Glutamine synthetase (GS), the key enzyme that governs this glutamate/glutamine cycle, is known to be upregulated by glucocorticoids. In the present work we have thus studied in parallel the effects of dexamethasone on glutamine synthetase activity and NMDA-induced neuronal death in cultures derived from the brain cortex of murine embryos. We showed that dexamethasone was able to markedly enhance GS activity in cultures of astrocytes but not in near pure neuronal cultures. The pharmacological characteristics of the dexamethasone action strongly suggest that it corresponds to a typical receptor-mediated effect. We also observed that long lasting incubation (72 h) of mixed astrocyte-neuron cultures in the presence of 100 nM dexamethasone significantly reduced the toxicity of NMDA treatment. Furthermore we demonstrated that methionine sulfoximine, a selective inhibitor of GS, abolished the dexamethasone-induced increase in GS activity and also markedly potentiated NMDA toxicity. Altogether these results suggest that dexamethasone may promote neuroprotection through a stimulation of astrocyte glutamine synthetase.
Highlights
The effects of glucocorticoids on brain cell survival or death remain a matter of controversy since both their neuroprotective and neurotoxic actions were described [1,2,3,4]
Our results show that long term treatment by 100 nM dexamethasone significantly enhanced Glutamine synthetase (GS) activity and protected neurons from NMDA-induced necrosis suggesting that neuroprotection was mediated via an enhancement of the astrocytic glutamine synthetase activity
We measured the effect of dexamethasone (Dex) on glutamine synthetase activity in astrocyte cultures
Summary
The effects of glucocorticoids on brain cell survival or death remain a matter of controversy since both their neuroprotective and neurotoxic actions were described [1,2,3,4]. Several groups have determined that glucocorticoids may significantly increase the deleterious action of various stimuli both in vivo and in vitro These include hypoxia-ischemia-induced brain damage [6], excitotoxicity of glutamate receptors agonists [7], neuronal death triggered by reactive oxygen species [8,9], as well as neurotoxicity induced by β amyloid or gp 120 [10,11]. Sloviter and coworkers [13] demonstrated a long time ago that ablation of the adrenal glands induced a selective degeneration of granule hippocampal neurons in adult rats This cellular loss could be prevented by administration of corticosterone, suggesting that physiological levels of glucocorticoids are required to sustain neuronal survival. Glucocorticoids have been known to exert protective actions against glutamate toxicity [16] and ischemia-induced neuronal degeneration [17,18]
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