Following
stroke, the damaged tissue undergoes liquefactive
necrosis, a stage of
infarct resolution that lasts for months although the exact length of time is currently unknown. One method of repair involves reactive astrocytes and microglia forming a
glial scar to compartmentalize the area of liquefactive
necrosis from the rest of the brain. The formation of the
glial scar is a critical component of the healing response to
stroke, as well as other central nervous system (CNS)
injuries. The goal of this study was to evaluate the toxicity of the extracellular fluid present in areas of liquefactive
necrosis and determine how effectively it is segregated from the remainder of the brain. To accomplish this goal, we used a mouse model of
stroke in conjunction with an extracellular fluid toxicity assay, fluorescent and electron microscopy, immunostaining, tracer
injections into the
infarct, and multiplex immunoassays. We confirmed that the extracellular fluid present in areas of liquefactive
necrosis following
stroke is toxic to primary cortical and hippocampal neurons for at least 7 weeks following
stroke, and discovered that although
glial scars are robust physical and endocytic barriers, they are nevertheless permeable. We found that molecules present in the area of liquefactive
necrosis can leak across the
glial scar and are removed by a combination of paravascular clearance and microglial endocytosis in the adjacent tissue. Despite these mechanisms, there is delayed
atrophy, cytotoxic
edema, and neuron loss in regions adjacent to the
infarct for weeks following
stroke. These findings suggest that one mechanism of neurodegeneration following
stroke is the failure of
glial scars to impermeably segregate areas of liquefactive
necrosis from surviving brain tissue.