Transient NMDA receptor inactivation provides long-term protection to cultured cortical neurons from a variety of death signals

NMDA receptor antagonists, such as (+)-5-methyl-10,11-dihydro- 5H-dibenzo [ a, d] cyclohepten-5,10-imine maleate (MK-801), potently block glutamate-ind uced neuronal death in myriad in vitro cell models and effectively attenuat e ischemic damage in vivo. In this report, a novel role for MK-801 and othe r NMDA receptor antagonists in preconditioning neurons to withstand a wide range of subsequent lethal insults is described. A brief 30 min exposure to 0.1 mu M MK-801, applied up to 96 hr before a "lethal" insult, protected p rimary cortical neurons from a diverse group of neurotoxic agents, includin g NMDA, beta-amyloid, staurosporine, etoposide, and oxygen-glucose deprivat ion. This neuroprotective preconditioning by MK-801 arose from transient NM DA receptor inactivation, because the noncompetitive NMDA receptor antagoni sts memantine and nylindin and the competitive antagonist AP-5 gave similar effects. MK-801 protection was dependent on new protein synthesis during t he first 2 hr, but not from 2 to 5 hr, after MK-801 exposure. The MK-801 tr ansient did not alter the ability of NMDA to trigger normally lethal [Ca2+] (i) influx 48 hr later, but it did block early downstream signaling events coupled to NMDA neurotoxicity, including PKC inactivation and the activatio n of calpain. Moreover, MK-801 protected neurons from staurosporine-induced apoptosis, although caspase activation in these cells was unimpeded. It is likely that the stress associated with transient inactivation of NMDA rece ptors triggered a rapid compensatory survival response that provided long-t erm protection from a spectrum of insults, inducing apoptotic and nonapopto tic death. The possibility that MK-801 preconditioning blocks an event comm on to seemingly diverse death mechanisms suggests it will be an important t ool for obtaining a clearer understanding of the salient molecular events a t work in neuronal death and survival pathways.