Transient NMDA Receptor Inactivation Provides Long-Term Protection to Cultured Cortical Neurons from a Variety of Death Signals

Abstract

NMDA receptor antagonists, such as (ϩ)-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 M MK-801, applied up to 96 hr before a "lethal" insult, protected primary cortical neurons from a diverse group of neurotoxic agents, including NMDA, ␤-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 [Ca 2ϩ ] 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.

Original article Delayed preconditioning with NMDA receptor antagonists in a rat model of perinatal asphyxia

“…In addition to and independent of the possible role of NMDA receptor activation in the mechanisms of brain preconditioning, it has been demonstrated that even brief exposure of the primary cultures of hippocampal neurons to antagonists of NMDA receptors induces long lasting tolerance to excitotoxicity and to staurosporine-evoked apoptosis [64]. More recently we confirmed these data in cultured cerebellar granule cells (CGC) [36].…”

“…Indeed, this phenomenon meets the criteria of delayed preconditioning, in which a lag between the preconditioning stimulus and development of tolerance is necessary to induce synthesis of proteins involved in neuroprotection [2,8,13,52]. Tremblay et al [64] in their pioneering in vitro study demonstrated that administration of the protein synthesis inhibitor during the first few hours after preconditioning with (+)MK-801 prevented induction of tolerance in the primary cultures of the rat cortical neurons. The other characteristic feature of preconditioning inducing delayed tolerance against brain ischemia is the involvement of oxidative stress in triggering the neuroprotective mechanisms [52].…”

Killer Proteases and Little Strokes—How the Things that do not Kill You Make You Stronger

“…Moreover, the repertoire of cell defenses is quite versatile. Small hypoxic stressors provide protection against a wide variety of subsequent injuries including more intense hypoxia, ab peptide and ceramide exposure, cytokine activation, excitotoxicity, energetic dysfunction, and other stressors Riepe et al, 1997;Tremblay et al, 2000;Weih et al, 1999). These findings support an appealing therapeutic possibility that a common target or pathway could be manipulated to provide protection from a host of neuropathological conditions including stroke, Parkinson's disease, Alzheimer's disease, head injury, and other insults.…”

Neuroprotective effects of memantine in a mouse model of retinal degeneration induced by rotenone

“…Tremblay et al (2000) demonstrated that pre-exposure of rat cortical neurons to memantine for 30 min is sufficient to protect against NMDA-mediated cell death, even when this lethal insult is applied 48 hr after the brief memantine exposure. Although animal studies have demonstrated that neuroprotection with memantine is achieved after relatively prolonged periods of steady plasma concentrations, it is possible that even transient exposures to the drug result in advantageous cellular effects.…”