Compromised Blood–brain Barrier Competence in Remote Brain Areas in Ischemic Stroke Rats at the Chronic Stage

Stroke is a life-threatening disease leading to long-term disability in stroke survivors. Cerebral functional insufficiency in chronic stroke might be due to pathological changes in brain areas remote from the initial ischemic lesion, i.e., diaschisis. Previously, we showed that the damaged blood–brain barrier (BBB) was involved in subacute diaschisis. The present study investigated BBB competence in chronic diaschisis by using a transient middle cerebral artery occlusion (tMCAO) rat model. Our results demonstrated significant BBB damage mostly in the ipsilateral striatum and motor cortex in rats at 30 days after tMCAO. The BBB alterations were also determined in the contralateral hemisphere via ultrastructural and immunohistochemical analyses. Major BBB pathological changes in contralateral remote striatum and motor cortex areas included 1) vacuolated endothelial cells containing large autophagosomes, 2) degenerated pericytes displaying mitochondria with cristae disruption, 3) degenerated astrocytes and perivascular edema, 4) Evans blue extravasation, and 5) appearance of parenchymal astrogliosis. Discrete analyses of striatal and motor cortex areas revealed significantly higher autophagosome accumulation in capillaries of ventral striatum and astrogliosis in dorsal striatum in both cerebral hemispheres. These widespread microvascular alterations in ipsilateral and contralateral brain hemispheres suggest persistent and/or continued BBB damage in chronic ischemia. The pathological changes in remote brain areas likely indicate chronic ischemic diaschisis, which should be considered in the development of treatment strategies for stroke. J. Comp. Neurol. 522:3120–3137, 2014. © 2014 Wiley Periodicals, Inc