Rapid degeneration of neurons in the penumbra region following a small, focal ischemic stroke

Ischemic stroke causes immediate cell death within the infarct core, whereas cells in the surrounding penumbra region are damaged but can be salvaged. Rapid restoration of blood flow can rescue these cells in the first few hours post-stroke. It remains unclear how long cells within the penumbra region can survive. To address this, we compared the acute cellular response within the ischemic core versus the penumbra region following an Endothelin-1-induced focal ischemic stroke in mice. We used vascular labelling to distinguish the three regions of blood perfusion: the non-perfused core; the hypo-perfused penumbra; and the perfused region. Within 4 hr post-stroke ~80% of neurons died in the non-perfused core, while 40% of neurons died in the hypo-perfused region. From 4 to 24 hr post-stroke, surviving neurons within the hypo-perfused region underwent extensive dendritic and axonal degeneration. Breakdown of the blood brain barrier, microglia activation, monocyte/neutrophil infiltration and astrogliosis, however, was not observed until 24 hr post-stroke. The cellular response within the hypo-perfused region was distinct from the non-perfused core. The core was comprised primarily of infiltrating peripheral monocytes and leukocytes, whereas the hypo-perfused region contained activated microglia and astrocytes. This study shows that small, localized ischemic strokes exhibit altered breakdown of the BBB in comparison with larger strokes. Furthermore, the massive degeneration of neuronal processes within the penumbra region suggests that the timeline to salvage surviving neurons is limited. In summary, the findings from this study reinforce the urgent need for therapeutic strategies targeting the acute hours post-stroke.