Neurovascular Unit Dysfunction and Blood–Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence
Schizophrenia is a psychotic disorder characterized by delusions, hallucinations, negative symptoms, as well as behavioral and cognitive dysfunction. It is a pathoetiologically heterogeneous disorder involving complex interrelated mechanisms that include oxidative stress and neuroinflammation. Neuro...
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doaj-d4e19a59f2ff4f93b8c89f7b3dbbdf992020-11-25T00:20:28ZengFrontiers Media S.A.Frontiers in Psychiatry1664-06402017-05-01810.3389/fpsyt.2017.00083239625Neurovascular Unit Dysfunction and Blood–Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental EvidenceSouhel Najjar0Souhel Najjar1Silky Pahlajani2Virginia De Sanctis3Joel N. H. Stern4Joel N. H. Stern5Amanda Najjar6Derek Chong7Department of Neurology, Hofstra Northwell School of Medicine, New York, NY, USANeuroinflammation Division, Department of Neurology, Lenox Hill Hospital, New York, NY, USANeuroinflammation Division, Department of Neurology, Lenox Hill Hospital, New York, NY, USANeuroinflammation Division, Department of Neurology, Lenox Hill Hospital, New York, NY, USADepartment of Neurology, Hofstra Northwell School of Medicine, New York, NY, USANeuroinflammation Division, Department of Neurology, Lenox Hill Hospital, New York, NY, USADepartment of Psychology and Human Development, Peabody College, Vanderbilt University, Nashville, TN, USADepartment of Neurology, Hofstra Northwell School of Medicine, New York, NY, USASchizophrenia is a psychotic disorder characterized by delusions, hallucinations, negative symptoms, as well as behavioral and cognitive dysfunction. It is a pathoetiologically heterogeneous disorder involving complex interrelated mechanisms that include oxidative stress and neuroinflammation. Neurovascular endothelial dysfunction and blood–brain barrier (BBB) hyperpermeability are established mechanisms in neurological disorders with comorbid psychiatric symptoms such as epilepsy, traumatic brain injury, and Alzheimer’s disease. Schizophrenia is frequently comorbid with medical conditions associated with peripheral vascular endothelial dysfunction, such as metabolic syndrome, cardiovascular disease, and diabetes mellitus. However, the existence and etiological relevance of neurovascular endothelial dysfunction and BBB hyperpermeability in schizophrenia are still not well recognized. Here, we review the growing clinical and experimental evidence, indicating that neurovascular endotheliopathy and BBB hyperpermeability occur in schizophrenia patients. We present a theoretical integration of human and animal data linking oxidative stress and neuroinflammation to neurovascular endotheliopathy and BBB breakdown in schizophrenia. These abnormalities may contribute to the cognitive and behavioral symptoms of schizophrenia via several mechanisms involving reduced cerebral perfusion and impaired homeostatic processes of cerebral microenvironment. Furthermore, BBB disruption can facilitate interactions between brain innate and peripheral adaptive immunity, thereby perpetuating harmful neuroimmune signals and toxic neuroinflammatory responses, which can also contribute to the symptoms of schizophrenia. Taken together, these findings support the “mild encephalitis” hypothesis of schizophrenia. If neurovascular abnormalities prove to be etiologically relevant to the neurobiology of schizophrenia, then targeting these abnormalities may represent a promising therapeutic strategy.http://journal.frontiersin.org/article/10.3389/fpsyt.2017.00083/fullschizophreniablood–brain barrierneurovascular unitendothelial cellneuroinflammationoxidative stress |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Souhel Najjar Souhel Najjar Silky Pahlajani Virginia De Sanctis Joel N. H. Stern Joel N. H. Stern Amanda Najjar Derek Chong |
spellingShingle |
Souhel Najjar Souhel Najjar Silky Pahlajani Virginia De Sanctis Joel N. H. Stern Joel N. H. Stern Amanda Najjar Derek Chong Neurovascular Unit Dysfunction and Blood–Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence Frontiers in Psychiatry schizophrenia blood–brain barrier neurovascular unit endothelial cell neuroinflammation oxidative stress |
author_facet |
Souhel Najjar Souhel Najjar Silky Pahlajani Virginia De Sanctis Joel N. H. Stern Joel N. H. Stern Amanda Najjar Derek Chong |
author_sort |
Souhel Najjar |
title |
Neurovascular Unit Dysfunction and Blood–Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence |
title_short |
Neurovascular Unit Dysfunction and Blood–Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence |
title_full |
Neurovascular Unit Dysfunction and Blood–Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence |
title_fullStr |
Neurovascular Unit Dysfunction and Blood–Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence |
title_full_unstemmed |
Neurovascular Unit Dysfunction and Blood–Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence |
title_sort |
neurovascular unit dysfunction and blood–brain barrier hyperpermeability contribute to schizophrenia neurobiology: a theoretical integration of clinical and experimental evidence |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Psychiatry |
issn |
1664-0640 |
publishDate |
2017-05-01 |
description |
Schizophrenia is a psychotic disorder characterized by delusions, hallucinations, negative symptoms, as well as behavioral and cognitive dysfunction. It is a pathoetiologically heterogeneous disorder involving complex interrelated mechanisms that include oxidative stress and neuroinflammation. Neurovascular endothelial dysfunction and blood–brain barrier (BBB) hyperpermeability are established mechanisms in neurological disorders with comorbid psychiatric symptoms such as epilepsy, traumatic brain injury, and Alzheimer’s disease. Schizophrenia is frequently comorbid with medical conditions associated with peripheral vascular endothelial dysfunction, such as metabolic syndrome, cardiovascular disease, and diabetes mellitus. However, the existence and etiological relevance of neurovascular endothelial dysfunction and BBB hyperpermeability in schizophrenia are still not well recognized. Here, we review the growing clinical and experimental evidence, indicating that neurovascular endotheliopathy and BBB hyperpermeability occur in schizophrenia patients. We present a theoretical integration of human and animal data linking oxidative stress and neuroinflammation to neurovascular endotheliopathy and BBB breakdown in schizophrenia. These abnormalities may contribute to the cognitive and behavioral symptoms of schizophrenia via several mechanisms involving reduced cerebral perfusion and impaired homeostatic processes of cerebral microenvironment. Furthermore, BBB disruption can facilitate interactions between brain innate and peripheral adaptive immunity, thereby perpetuating harmful neuroimmune signals and toxic neuroinflammatory responses, which can also contribute to the symptoms of schizophrenia. Taken together, these findings support the “mild encephalitis” hypothesis of schizophrenia. If neurovascular abnormalities prove to be etiologically relevant to the neurobiology of schizophrenia, then targeting these abnormalities may represent a promising therapeutic strategy. |
topic |
schizophrenia blood–brain barrier neurovascular unit endothelial cell neuroinflammation oxidative stress |
url |
http://journal.frontiersin.org/article/10.3389/fpsyt.2017.00083/full |
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