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.
Highlights
Schizophrenia is a pathoetiologically heterogeneous psychotic disorder characterized by delusions, hallucinations, negative symptoms, as well as behavioral and cognitive dysfunction
We suggest that oxidation and inflammation associated with schizophrenia can contribute to uncoupling and reduced activity of endothelial endothelial nitric oxide synthase (eNOS) [16] (Figure 1); reactive oxygen species (ROS) promotes oxidative conversion of the eNOS cofactor BH4 to dihydrobiopterin (BH2), thereby reducing endothelial BH4 bioavailability, which in turn inhibits eNOS activity [16]
We suggest that uncoupling and reduced activity of endothelial eNOS may contribute to the increased risk of cardiovascular disease and neurovascular endothelial dysfunction in schizophrenia
Summary
Schizophrenia is a pathoetiologically heterogeneous psychotic disorder characterized by delusions, hallucinations, negative symptoms, as well as behavioral and cognitive dysfunction. Schizophrenia-relevant behavioral abnormalities in infection-mediated neurodevelopmental mouse model were associated with reduced central TSPO binding despite increased pro-inflammatory cytokine levels [10] Together, these findings suggest that the lack of increased TSPO expression or ligand binding by human PET imaging in first-episode psychosis and recent-onset schizophrenia may not reliably exclude the presence of low-grade neuroinflammatory process [10]. Multiple neuropathological and neuroimaging studies have established the effects of neuroinflammation and oxidative stress on the neurovascular unit and blood–brain barrier (BBB), especially in neurologic disorders with comorbid psychiatric symptoms [16] These disorders include epilepsy, stroke, traumatic brain injury, multiple sclerosis, and Alzheimer’s disease [16]. We aimed to characterize the human evidence by performing a systematic review of neuropathological, neuroimaging, serological, CSF, and genetic studies relevant to this effect (Table 1)
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