N-methyl-D-aspartate receptor desensitisation is neuroprotective by inhibiting glutamate-induced apoptotic-like death

Glutamate excitotoxicity is implicated in several neurodegenerative diseases; consequently, considerable effort has been made to elucidate neuroprotective mechanisms against such toxicity. N-Methyl-D-aspartate (NMDA) receptor desensitisation is one potential mechanism for controlling glutamate-mediated neuronal cell death. Pretreatment of rat cerebellar granule cells with subtoxic concentrations of NMDA caused a marked reduction in the calcium signals generated by subsequent glutamate stimulation, and, furthermore, this receptor desensitisation was coupled to a reduction in glutamate-induced apoptotic-like death. These effects were reduced by either D-2-amino-5-phosphonopentanoic acid, an NMDA receptor antagonist, or cyclosporin A, an inhibitor of calcineurin. Thus, the results support a role for receptor desensitisation in protection from glutamate-mediated apoptotic-like neuronal cell death.