P7C3-A20 treatment one year after TBI in mice repairs the blood-brain barrier, arrests chronic neurodegeneration, and restores cognition.

Autor:	Vázquez-Rosa E; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106.; Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106.; Geriatric Research Education and Clinical Centers, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106., Shin MK; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106.; Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106.; Geriatric Research Education and Clinical Centers, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106., Dhar M; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106.; Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106.; Geriatric Research Education and Clinical Centers, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106., Chaubey K; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106.; Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106.; Geriatric Research Education and Clinical Centers, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106., Cintrón-Pérez CJ; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106.; Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106.; Geriatric Research Education and Clinical Centers, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106., Tang X; Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106.; Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106., Liao X; Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106.; Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106., Miller E; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106.; Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106.; Geriatric Research Education and Clinical Centers, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106., Koh Y; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106.; Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106.; Geriatric Research Education and Clinical Centers, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106., Barker S; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106.; Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106.; Geriatric Research Education and Clinical Centers, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106., Franke K; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106.; Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106.; Geriatric Research Education and Clinical Centers, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106., Crosby DR; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106.; Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106.; Geriatric Research Education and Clinical Centers, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106., Schroeder R; The Department of Psychiatry, University of Iowa, Iowa City, IA 52242., Emery J; The Department of Psychiatry, University of Iowa, Iowa City, IA 52242., Yin TC; The Department of Psychiatry, University of Iowa, Iowa City, IA 52242., Fujioka H; Cryo-Electron Microscopy Core, Case Western Reserve University School of Medicine, Cleveland, OH 44106., Reynolds JD; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106.; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106.; Department of Anesthesiology and Perioperative Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH 44106., Harper MM; Center for the Prevention and Treatment of Visual Loss, Veterans Affairs Medical Center, Iowa City, IA 52246.; Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA 52242., Jain MK; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106.; Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106.; Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106., Pieper AA; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106; Andrew.Pieper@HarringtonDiscovery.org.; Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106.; Geriatric Research Education and Clinical Centers, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106.; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106.; Weill Cornell Autism Research Program, Weill Cornell Medicine of Cornell University, New York, NY 10065.; Department of Neuroscience, School of Medicine, Case Western Reserve University, Cleveland, OH 44106.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Nov 03; Vol. 117 (44), pp. 27667-27675. Date of Electronic Publication: 2020 Oct 21.
DOI:	10.1073/pnas.2010430117
Abstrakt:	Chronic neurodegeneration in survivors of traumatic brain injury (TBI) is a major cause of morbidity, with no effective therapies to mitigate this progressive and debilitating form of nerve cell death. Here, we report that pharmacologic restoration of the blood-brain barrier (BBB), 12 mo after murine TBI, is associated with arrested axonal neurodegeneration and cognitive recovery, benefits that persisted for months after treatment cessation. Recovery was achieved by 30 d of once-daily administration of P7C3-A20, a compound that stabilizes cellular energy levels. Four months after P7C3-A20, electron microscopy revealed full repair of TBI-induced breaks in cortical and hippocampal BBB endothelium. Immunohistochemical staining identified additional benefits of P7C3-A20, including restoration of normal BBB endothelium length, increased brain capillary pericyte density, increased expression of BBB tight junction proteins, reduced brain infiltration of immunoglobulin, and attenuated neuroinflammation. These changes were accompanied by cessation of TBI-induced chronic axonal degeneration. Specificity for P7C3-A20 action on the endothelium was confirmed by protection of cultured human brain microvascular endothelial cells from hydrogen peroxide-induced cell death, as well as preservation of BBB integrity in mice after exposure to toxic levels of lipopolysaccharide. P7C3-A20 also protected mice from BBB degradation after acute TBI. Collectively, our results provide insights into the pathophysiologic mechanisms behind chronic neurodegeneration after TBI, along with a putative treatment strategy. Because TBI increases the risks of other forms of neurodegeneration involving BBB deterioration (e.g., Alzheimer's disease, Parkinson's disease, vascular dementia, chronic traumatic encephalopathy), P7C3-A20 may have widespread clinical utility in the setting of neurodegenerative conditions. Competing Interests: Competing interest statement: A.A.P. is an inventor on patents related to P7C3. No other authors declare competing interests. (Copyright © 2020 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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