Abstract
BackgroundComprehensive stroke studies reveal diaschisis, a loss of function due to pathological deficits in brain areas remote from initial ischemic lesion. However, blood-brain barrier (BBB) competence in subacute diaschisis is uncertain. The present study investigated subacute diaschisis in a focal ischemic stroke rat model. Specific focuses were BBB integrity and related pathogenic processes in contralateral brain areas.Methodology/Principal FindingsIn ipsilateral hemisphere 7 days after transient middle cerebral artery occlusion (tMCAO), significant BBB alterations characterized by large Evans Blue (EB) parenchymal extravasation, autophagosome accumulation, increased reactive astrocytes and activated microglia, demyelinization, and neuronal damage were detected in the striatum, motor and somatosensory cortices. Vascular damage identified by ultrastuctural and immunohistochemical analyses also occurred in the contralateral hemisphere. In contralateral striatum and motor cortex, major ultrastructural BBB changes included: swollen and vacuolated endothelial cells containing numerous autophagosomes, pericyte degeneration, and perivascular edema. Additionally, prominent EB extravasation, increased endothelial autophagosome formation, rampant astrogliosis, activated microglia, widespread neuronal pyknosis and decreased myelin were observed in contralateral striatum, and motor and somatosensory cortices.Conclusions/SignificanceThese results demonstrate focal ischemic stroke-induced pathological disturbances in ipsilateral, as well as in contralateral brain areas, which were shown to be closely associated with BBB breakdown in remote brain microvessels and endothelial autophagosome accumulation. This microvascular damage in subacute phase likely revealed ischemic diaschisis and should be considered in development of treatment strategies for stroke.
Highlights
Stroke is the fourth leading cause of death in the USA [1], contributing to almost 130,000 fatalities [2] and 5.5 million worldwide yearly [3]
Large autophagosomes were observed in almost all endothelial cells (ECs) (Figure 1D), with some autophagosomes extending from lumen to basal lamina in attenuated portions of the cells
Most damage was detected in the ipsilateral hemisphere, damage which included blood-brain barrier (BBB) alterations characterized by large Evans Blue (EB) parenchymal extravasation, autophagosome accumulation, increased reactive astrocytes and activated microglia, demyelinization, and neuronal damage in various brain structures 7 days after transient middle cerebral artery occlusion (tMCAO)
Summary
Stroke is the fourth leading cause of death in the USA [1], contributing to almost 130,000 fatalities [2] and 5.5 million worldwide yearly [3]. Strokes occur due to interruption of blood flow to the brain and are broadly typed by cause as ischemic or hemorrhagic. 80% of strokes are ischemic [4]. Minutes after ischemic stroke insult, dramatic cerebral pathological changes occur at cellular and molecular levels [7,8]). Ischemic stroke insults can be focal, global, permanent, or transient, primarily leading to deprivations of oxygen, glucose, and essential nutrients in post-ischemic areas. The complexity and heterogeneity of mechanisms underlying post-ischemic brain injury make it difficult to develop effective therapeutic approaches for stroke. Comprehensive stroke studies reveal diaschisis, a loss of function due to pathological deficits in brain areas remote from initial ischemic lesion. The present study investigated subacute diaschisis in a focal ischemic stroke rat model. Specific focuses were BBB integrity and related pathogenic processes in contralateral brain areas
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