A number of studies have already established the role of the subventricular zone in sustaining adult neurogenesis in different brain regions and under different pathological conditions, but nothing is reported about the role of this germinal area in preserving cell viability. In this work, we developed an organotypic culture model of the forebrain structures that comprise the neocortex, striatum, subventricular zone, and corpus callosum. With this model, we investigated the role of the subventricular zone in modulating cell viability in the cortex after oxygen/glucose deprivation. Here we have demonstrated that soluble heat-labile factors released by the subventricular zone in the media can lead to protection specifically in the cortical area. No protection was observed when medium, conditioned with factors released during the insult was administered to the hippocampal slices. Moreover, the use of different modifications of the slice cultures showed that the removal of the subventricular zone increased the cellular damage induced by oxygen/glucose deprivation. Furthermore, by using pharmacological experiments to investigate the possible mechanisms that regulate this subventricular function, we found evidence of purinergic involvement. We postulate that extracellular ATP signaling in the subventricular zone exacerbates cortical damage induced by hypoxia/hypoglycemia. For the first time, we demonstrate in vitro that the germinal subventricular zone can release factors that can be protective after exposure to a metabolic stressor. These released factors are not yet characterized but we identified in the extracellular ATP a factor that may interfere with the protective role of the subventricular zone during metabolic cortical damage.