title: Blood-brain barrier alterations provide evidence of subacute diaschisis in an ischemic stroke rat model.
abstract: BACKGROUND
  Comprehensive 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.
  
  
  RESULTS
  In 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
  These 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.
authors.affiliation: Center of Excellence for Aging & Brain Repair, University of South Florida, Morsani College of Medicine, Tampa, Florida, United States of America. sgarbuzo@health.usf.edu
authors.forename: Svitlana
authors.initials: S
authors.lastname: Garbuzova-Davis
authors.forename: Maria C O
authors.initials: MC
authors.lastname: Rodrigues
authors.forename: Diana G
authors.initials: DG
authors.lastname: Hernandez-Ontiveros
authors.forename: Naoki
authors.initials: N
authors.lastname: Tajiri
authors.forename: Aric
authors.initials: A
authors.lastname: Frisina-Deyo
authors.forename: Sean M
authors.initials: SM
authors.lastname: Boffeli
authors.forename: Jerry V
authors.initials: JV
authors.lastname: Abraham
authors.forename: Mibel
authors.initials: M
authors.lastname: Pabon
authors.forename: Andrew
authors.initials: A
authors.lastname: Wagner
authors.forename: Hiroto
authors.initials: H
authors.lastname: Ishikawa
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Shinozuka
authors.forename: Edward
authors.initials: E
authors.lastname: Haller
authors.forename: Paul R
authors.initials: PR
authors.lastname: Sanberg
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kaneko
authors.forename: Cesario V
authors.initials: CV
authors.lastname: Borlongan
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D002545:Brain Ischemia / Q000150:complications*; D003342:Corpus Striatum / Q000098:blood supply / Q000473:pathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D017628:Microglia / Q000378:metabolism; D055806:Microvessels / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009044:Motor Cortex / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D009186:Myelin Sheath / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010539:Permeability; D010588:Phagosomes; D051381:Rats; D020521:Stroke / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology