Guanine nucleotides inhibit NMDA and kainate-induced neurotoxicity in cultured rat hippocampal and neocortical neurons.

Previous evidence suggests that guanine nucleotides can directly inhibit N-methyl-d-aspartate (NMDA) and AMPA/kainate receptors and antagonize a variety of cellular functions elicited by these glutamate receptor agonists. We investigated the possibility that the guanine nucleotides GTP, GDP, and GMP exert a neuroprotective effect on cultured rat hippocampal or neocortical neurons exposed to the excitotoxicants NMDA (30 microM) or kainate (300 microM). On co-application with NMDA all three nucleotides revealed a comparable rescue effect from 100 microM nucleotide concentrations onwards, with a higher inhibitory potential in hippocampal than in neocortical cultures. Similarly, kainate-induced neurotoxicity was inhibited by all three nucleotides but the inhibitory potential was lower than after application of NMDA. Guanosine had no effect on either culture system. GTP and GDP where hydrolyzed by hippocampal and cortical cultures with GMP accumulating in the medium, suggesting that hydrolysis of GTP had no effect on the effective nucleotide concentration. Our results show that GTP, GDP, and GMP inhibit NMDA- and kainate-mediated neurotoxicity in cultured hippocampal and neocortical neurons. They suggest that guanine nucleotides may be candidates for broadly antagonizing glutamate receptor-mediated neurotoxicity.