Neurovascular Unit Dysfunction and Blood–Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence

Abstract

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.

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

“…BBB dysfunction was likewise observed in a boxer suffering from chronic traumatic encephalopathy [127]. In addition to the neurological problems, an aberrant microvasculature as well as abnormal CBF is observed in schizophrenia [128][129][130]. The cause of schizophrenia is not well-understood but may involve disturbed dopamine and NMDA receptor signaling.…”

Atypical Antipsychotic Drug Olanzapine Deregulates Hepatic Lipid Metabolism and Aortic Inflammation and Aggravates Atherosclerosis

“…Schizophrenia is a persistent and disabling psychotic disorder that may be attributed to multiple factors including genetic and environmental aspects and social processes [1,2]. Schizophrenic patients may display abnormal social behavior and be out of touch with reality [1,2].…”

“…Schizophrenic patients may display abnormal social behavior and be out of touch with reality [1,2]. The most common symptoms of schizophrenia include delusions, hallucinations and disorganized thoughts, which are divided into three categories: positive, negative, and cognitive [3].…”

Sodium nitroprusside is effective in preventing and/or reversing the development of schizophrenia‐related behaviors in an animal model: The SHR strain

“…Additionally, the course of these behavioral abnormalities is in accordance with what is seen in the clinic: hyperlocomotion is presented only in adult SHRs while deficits in social interaction and in fear conditioning can be seen in 30‐ and 45‐day‐old SHRs, respectively (S.T.Niigaki, F.F.Peres, D.A.Gouvea, R.Levin, V.Almeida, N.D.Silva, M.C.Diana, M.A.Suiama, V.C.Abilio submitted). Interestingly, cardiovascular comorbidities, including hypertension, are presented in schizophrenia patients . Some functional and neurochemical alterations seen in the SHR strain underlie schizophrenia physiopathology and may lead to neurovascular changes and, putatively, be related to the behavioral abnormalities presented by this strain: an increase in brain and vascular oxidative stress, an increase in neuroinflammation, and a hyperpermeability of the blood‐brain and blood‐cerebrospinal fluid barrier .…”

“…18 Some functional and neurochemical alterations seen in the SHR strain underlie schizophrenia physiopathology and may lead to neurovascular changes and, putatively, be related to the behavioral abnormalities presented by this strain: an increase in brain and vascular oxidative stress, 18,19 an increase in neuroinflammation, 18,20 and a hyperpermeability of the bloodbrain and blood-cerebrospinal fluid barrier. 18,21,22 Considering specifically the nitrergic system, a decrease in brain and endothelial levels of NO and/or NOS activity have been reported in the SHR strain. 23,24 In addition, we have reported in the SHR strain a decrease in the gene expression of glutamate AMPA-R (Gria1) and NMDA-R (Grin1) in the nucleus accumbens as well as in Gad2 (glutamate decarboxylase 2), Chrnb4 (cholinergic receptor, nicotinic, beta 4), Slc5a7 (choline transporter), and Qrfpr (pyroglutamylated RFamide peptide receptor) in the prefrontal cortex.…”