Neuroprotective activity of glucocorticoids against NMDA toxicity in mouse cortical neuron-astrocyte cultures: Potential role of the tPA-PAI-1 axis

Abstract

Given the potent anti-inflammatory effects exerted by glucocorticoids under various pathological situations, their use has been proposed to protect the brain against cerebral ischemia, neuro-inflammatory diseases and trauma. However, the efficiency of these treatments remains a matter of debate, since both neuroprotective and neurotoxic effects have been observed depending on the experimental models used (Abraham et al., J Neuroendocrinol., 13: 749, 2001). First we observed that purified neuron and astrocyte populations both express the mRNA encoding for the glucocorticoid receptor (as determined by RT PCR), suggesting that both cell type might respond to glucocorticoid. In order to further understand the role of glucocorticoids in brain tissues, we have tested the effect of dexamethasone (a potent glucocorticoid) in a model of mixed murine cultures of neurons and glia subjected to N-methyl-D-aspartate (NMDA)-induced excitotoxicity. We observed that pre-treatment of the cultures with dexamethasone significantly reduced NMDA-induced neuronal necrosis. We also described that dexamethasone (dose and time dependently) induced within 12–24 hours of treatment a significant increase in both the synthesis and secretion of type 1 plasminogen activator inhibitor (PAI-1) in astrocyte cultures. Previous experiments in the laboratory have shown in the same paradigm of NMDA-induced toxicity that tPA markedly increases the deleterious action of NMDA and that this potentiating action of tPA is abolished by PAI-1 (Buisson et al., FASEB J, 12: 1683, 1998). Since dexamethasone led to a significant decrease in t-PA activity (as assessed by zymography assay), our results suggest that glucocorticoids might exert a neuroprotective activity against NMDAR-mediated toxicity by interacting with the t-PA/PAI-1 axis.