Glial scars are permeable to the neurotoxic environment of chronic stroke infarcts

Neurobiology of Disease

Tao Yang¹  Kristina Stepanovic²  Maj Krumberger³  Megan Hayes³  Frank M. Longo³  Justine Mona³  Omar Hussain³  Thuy-Vi V. Nguyen³  W. Anthony Day³  Amanda Chung³  Jacob C. Zbesko³  Kristian P. Doyle⁴  Jennifer Beischel Frye⁴ 

[1]Department of Neurology, University of Arizona, Tucson, AZ 85719, USA

[2]Arizona Health Sciences Center Imaging Core Facility, Arizona Research Labs, University of Arizona, Tucson, AZ 85719, USA

[3]Department of Immunobiology, University of Arizona, Tucson, AZ 85719, USA

[4]Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA

关键词: Chronic stroke;    Neurodegeneration;    Liquefactive necrosis;    Glial scar;    Inflammation;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown