title: Bryostatin-1 Restores Blood Brain Barrier Integrity following Blast-Induced Traumatic Brain Injury.
abstract: Recent wars in Iraq and Afghanistan have accounted for an estimated 270,000 blast exposures among military personnel. Blast traumatic brain injury (TBI) is the 'signature injury' of modern warfare. Blood brain barrier (BBB) disruption following blast TBI can lead to long-term and diffuse neuroinflammation. In this study, we investigate for the first time the role of bryostatin-1, a specific protein kinase C (PKC) modulator, in ameliorating BBB breakdown. Thirty seven Sprague-Dawley rats were used for this study. We utilized a clinically relevant and validated blast model to expose animals to moderate blast exposure. Groups included: control, single blast exposure, and single blast exposure + bryostatin-1. Bryostatin-1 was administered i.p. 2.5 mg/kg after blast exposure. Evan's blue, immunohistochemistry, and western blot analysis were performed to assess injury. Evan's blue binds to albumin and is a marker for BBB disruption. The single blast exposure caused an increase in permeability compared to control (t = 4.808, p < 0.05), and a reduction back toward control levels when bryostatin-1 was administered (t = 5.113, p < 0.01). Three important PKC isozymes, PKCα, PKCδ, and PKCε, were co-localized primarily with endothelial cells but not astrocytes. Bryostatin-1 administration reduced toxic PKCα levels back toward control levels (t = 4.559, p < 0.01) and increased the neuroprotective isozyme PKCε (t = 6.102, p < 0.01). Bryostatin-1 caused a significant increase in the tight junction proteins VE-cadherin, ZO-1, and occludin through modulation of PKC activity. Bryostatin-1 ultimately decreased BBB breakdown potentially due to modulation of PKC isozymes. Future work will examine the role of bryostatin-1 in preventing chronic neurodegeneration following repetitive neurotrauma.
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV, 26506, USA.|The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, 26506, USA.
authors.forename: Brandon P
authors.initials: BP
authors.lastname: Lucke-Wold
authors.affiliation: The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, 26506, USA.|Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WV, 26506, USA.
authors.forename: Aric F
authors.initials: AF
authors.lastname: Logsdon
authors.affiliation: The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, 26506, USA.|Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WV, 26506, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Smith
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV, 26506, USA.|The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, 26506, USA.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Turner
authors.affiliation: Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, 26506, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Alkon
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV, 26506, USA.|The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, 26506, USA.
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV, 26506, USA.|The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, 26506, USA.|Office of Professional Studies in Health Sciences, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Naser
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV, 26506, USA.
authors.forename: Chelsea M
authors.initials: CM
authors.lastname: Knotts
authors.affiliation: The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, 26506, USA.|Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WV, 26506, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Huber
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV, 26506, USA. crosen@hsc.wvu.edu.|The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, 26506, USA. crosen@hsc.wvu.edu.|Department of Neurosurgery, West Virginia University School of Medicine, One Medical Center Drive, Suite 4300, Health Sciences Center, PO Box 9183, Morgantown, WV, 26506-9183, USA. crosen@hsc.wvu.edu.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Rosen
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001253:Astrocytes / Q000201:enzymology; D001753:Blast Injuries / Q000188:drug therapy* / Q000503:physiopathology; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001930:Brain Injuries / Q000188:drug therapy* / Q000503:physiopathology; D054713:Bryostatins / Q000494:pharmacology / Q000627:therapeutic use*; D015820:Cadherins / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D008297:Male; D062793:Occludin / Q000378:metabolism; D017397:Prefrontal Cortex / Q000098:blood supply; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019108:Tight Junctions / Q000187:drug effects; D062826:Zonula Occludens-1 Protein / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D054713:Bryostatins; D015820:Cadherins; D062793:Occludin; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D062826:Zonula Occludens-1 Protein; D000099152:Cadherin 5; C568987:Ocln protein, rat; C569044:Tjp1 protein, rat; C046785:bryostatin 1
keywords: Blood brain barrier; Bryostatin-1; Protein kinase C; Tight junction proteins