Anoxic depolarization mediates acute damage independent of glutamate in neocortical brain slices

An important but poorly understood event associated with ischemia is anoxic depolarization (AD), a sudden and profound depolarization of neurons and g lia in cortical and subcortical gray matter. Leao first measured the AD as a wave of electrical silence moving across the cerebral cortex in 1947 and noted its similarity to spreading depression (SD), SD is harmless when cour sing through normoxic cortical tissue as during migraine aura. However for 3-4 h following focal ischemia, the additional metabolic stress arising fro m recurring SD in the penumbra expands the ischemic core, so SD blockade is potentially beneficial therapeutically. In the present study, we measured intrinsic optical signals (IOSs) to monitor anoxic depolarization in submer ged rat neocortical slices during O-2/glucose deprivation (OGD), After simi lar to6 min of OGD, the AD was imaged as a focal increase in light transmit tance which then propagated across neocortical gray at similar to2 mm/min. Although the slice was globally stressed, the AD always initiated focally, sometimes at multiple sites. Its propagation was coincident with a transien t negative shift in the extracellular potential, the electrical signature o f AD. Acute damage to neocortex (measured as a delayed decrease in LT and a s a loss of the evoked field potential) followed only where the AD had prop agated, so it is the combined metabolic demands of AD and OGD that acutely damages all layers of the neocortex, Glutamate receptor antagonists (2 mM k ynurenate or 25 muM AP-5/10 muM CNQX) did not block AD initiation, slow its propagation or prevent post-AD damage. This study shows that acute ischemi c damage is greatly exacerberated by AD during metabolic stress and that gl utamate receptor antagonists are not protective. Using this slice model, th erapeutically tolerable drugs that block the AD and SD can be investigated.