TY - JOUR T1 - Transient NMDA Receptor Inactivation Provides Long-Term Protection to Cultured Cortical Neurons from a Variety of Death Signals JF - The Journal of Neuroscience JO - J. Neurosci. SP - 7183 LP - 7192 DO - 10.1523/JNEUROSCI.20-19-07183.2000 VL - 20 IS - 19 AU - Roger Tremblay AU - Balu Chakravarthy AU - Kimberley Hewitt AU - Joseph Tauskela AU - Paul Morley AU - Trevor Atkinson AU - Jon P. Durkin Y1 - 2000/10/01 UR - http://www.jneurosci.org/content/20/19/7183.abstract N2 - NMDA receptor antagonists, such as (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801), potently block glutamate-induced neuronal death in myriad in vitro cell models and effectively attenuate ischemic damage in vivo. In this report, a novel role for MK-801 and other 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 μmMK-801, applied up to 96 hr before a “lethal” insult, protected primary cortical neurons from a diverse group of neurotoxic agents, including NMDA, β-amyloid, staurosporine, etoposide, and oxygen–glucose deprivation. This neuroprotective preconditioning by MK-801 arose from transient NMDA receptor inactivation, because the noncompetitive NMDA receptor antagonists memantine and nylindin and the competitive antagonist AP-5 gave similar effects. MK-801 protection was dependent on new protein synthesis during the first 2 hr, but not from 2 to 5 hr, after MK-801 exposure. The MK-801 transient 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 activation 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 receptors triggered a rapid compensatory survival response that provided long-term protection from a spectrum of insults, inducing apoptotic and nonapoptotic death. The possibility that MK-801 preconditioning blocks an event common to seemingly diverse death mechanisms suggests it will be an important tool for obtaining a clearer understanding of the salient molecular events at work in neuronal death and survival pathways. ER -