title: Compromised blood-brain barrier competence in remote brain areas in ischemic stroke rats at the chronic stage.
abstract: 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.
authors.affiliation: Center of Excellence for Aging and Brain Repair, University of South Florida, Morsani College of Medicine, Tampa, Florida, 33612; Department of Neurosurgery and Brain Repair, University of South Florida, Morsani College of Medicine, Tampa, Florida, 33612; Department of Molecular Pharmacology and Physiology, University of South Florida, Morsani College of Medicine, Tampa, Florida, 33612; Department of Pathology and Cell Biology, University of South Florida, Morsani College of Medicine, Tampa, Florida, 33612.
authors.forename: Svitlana
authors.initials: S
authors.lastname: Garbuzova-Davis
authors.forename: Edward
authors.initials: E
authors.lastname: Haller
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Williams
authors.forename: Eithan D
authors.initials: ED
authors.lastname: Haim
authors.forename: Naoki
authors.initials: N
authors.lastname: Tajiri
authors.forename: Diana G
authors.initials: DG
authors.lastname: Hernandez-Ontiveros
authors.forename: Aric
authors.initials: A
authors.lastname: Frisina-Deyo
authors.forename: Sean M
authors.initials: SM
authors.lastname: Boffeli
authors.forename: Paul R
authors.initials: PR
authors.lastname: Sanberg
authors.forename: Cesario V
authors.initials: CV
authors.lastname: Borlongan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001253:Astrocytes / Q000473:pathology / Q000648:ultrastructure; D000071186:Beclin-1; D001812:Blood-Brain Barrier / Q000503:physiopathology* / Q000648:ultrastructure; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D007839:Functional Laterality; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology*; D008297:Male; D046529:Microscopy, Electron, Transmission; D055806:Microvessels / Q000473:pathology / Q000648:ultrastructure; D009044:Motor Cortex / Q000473:pathology* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C512829:Becn1 protein, rat; D005904:Glial Fibrillary Acidic Protein
keywords: BBB; MCAO; astrocytes; autophagosomes; chronic diaschisis; rats