RESEARCH REPORT BETWEEN EXCITOTOXINS AND THE NA+ K+-ATPASE INHIBITOR OUABAIN IN CAUSING NEURONAL LESIONS IN THE RAT HIPPOCAMPUS/

A possible indirect role of glutamate in causing the neuronal death fo und after intracerebral administration of a low dose of ouabain (0.1 n mol) has been evaluated. This dose of ouabain produces a more extensiv e neuronal lesion than those caused by glutamate receptor agonists (ka inate at an equimolar dose, or NMDA (N-methyl-D-aspartate) at a 50-fol d higher dose). The selective glutamate receptor antagonists, dizocilp ine (MK-801) and NBQX ihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline ), in doses which blocked the direct toxicity of glutamate receptor ag onists acting on either the NMDA and non-NMDA classes of glutamate rec eptor, failed to provide more than a minor protection against ouabain- induced neuronal death in the rat dorsal hippocampus. In contrast, the non-selective glutamate receptor antagonist, kynurenate (100 nmol) re duced the damage by around 70%. The difference in neuroprotection foun d between the glutamate receptor antagonists suggests that kynurenate may protect by a non-glutamatergic mechanism. Co-administration of oua bain and glutamate receptor agonists (kainate, NMDA or glutamate) resu lted in additive rather than synergistic damage to hippocampal neurons . The results suggest that in vivo, ouabain and excitotoxins probably cause neuronal death by independent mechanisms.