Psychoneuroimmunology and Schizophrenia Therapeutics
Psychoneuroimmunology and Schizophrenia Therapeutics
Immune system dysfunctions have closely and consistently been associated with schizophrenia pathogenesis. Converging translational evidence implicates immuno-inflammatory processes congruent with oxidative and nitrosative stress (O&NS) pathway as one of the important mechanisms underlying the psychoneuroimmunological facets of schizophrenia. The source of the activated inflammatory responses has been linked to elevated levels of systemic pro-inflammatory markers, for example cytokines, chemokines, acute phase proteins, O&NS markers and so on in schizophrenia. In addition, an appreciable body of evidence from post-mortem brain studies suggests upregulated inflammation-related gene signatures in various brain regions including dorsolateral prefrontal cortex (DLPFC) of schizophrenia patients. This strongly implies that, along with systemic inflammatory responses, neuroinflammatory processes might also contribute to schizophrenia pathogenesis and exacerbate its progression.
Although a causal relationship between inflammation and schizophrenia prodrome is yet to be ascertained, a plethora of epidemiological studies in humans and experimental animals have recently established that activated immuno-inflammatory processes could also be elicited in response to a variety of risk factors, including prenatal infection, stress, nutrition, obstetric complications and so on. Such immune insults during the earliest and critical stages of brain development could cause neurodevelopmental changes and the implications of these pathways are being widely implicated in the risk and progression of schizophrenia. Although the specific mechanisms of fetal immune perturbations contributing to adult presentation of schizophrenia are unclear, a growing body of evidence suggests that gestational infection-induced immuno-inflammatory responses could modulate brain cytokine profile, O&NS pathway, tryptophan/kynurenine metabolism, oligodendrocyte and microglia activities, gamma-aminobutyric acid ergic neurotransmission, dopaminergic activity, hippocampal circuitry, cognitive attributes and so on and manifest schizophrenia-like symptoms. Of these, microglia-mediated neuropathological changes are remarkably more significant, as microglia constitute an important source of pro-inflammatory mediators and respond rapidly to even minor pathological changes in the brain and also contribute directly to the neuronal degeneration as well as cognitive impairments. Microglia also sustain and propagate inflammation by responding to pro-inflammatory signals released from nonneuronal cells, principally those of immune origin, implying that systemic inflammation can lead to microglia activation. This is achieved by extensive communication between immune system and central nervous system (CNS), especially through an integrative network between microglia and various immune cells including mast cells. Activated microglia have been shown to cause hypoxic injuries in the developing brain, including periventricular white matter damage, disruption of immature blood–brain barrier (BBB) and chronic neurodegeneration. Recent studies have established that schizophrenia is closely associated with microglia activation, as evidenced by increased density of microglia as well as HLA-DR+ microglia in hippocampus. Importantly, the higher density of HLA-DR+ microglia was found to be linked with psychotic positive symptoms in paranoid schizophrenia.
Recent Advances in Psychoneuroimmunology: Implications for Schizophrenia
Immune system dysfunctions have closely and consistently been associated with schizophrenia pathogenesis. Converging translational evidence implicates immuno-inflammatory processes congruent with oxidative and nitrosative stress (O&NS) pathway as one of the important mechanisms underlying the psychoneuroimmunological facets of schizophrenia. The source of the activated inflammatory responses has been linked to elevated levels of systemic pro-inflammatory markers, for example cytokines, chemokines, acute phase proteins, O&NS markers and so on in schizophrenia. In addition, an appreciable body of evidence from post-mortem brain studies suggests upregulated inflammation-related gene signatures in various brain regions including dorsolateral prefrontal cortex (DLPFC) of schizophrenia patients. This strongly implies that, along with systemic inflammatory responses, neuroinflammatory processes might also contribute to schizophrenia pathogenesis and exacerbate its progression.
Although a causal relationship between inflammation and schizophrenia prodrome is yet to be ascertained, a plethora of epidemiological studies in humans and experimental animals have recently established that activated immuno-inflammatory processes could also be elicited in response to a variety of risk factors, including prenatal infection, stress, nutrition, obstetric complications and so on. Such immune insults during the earliest and critical stages of brain development could cause neurodevelopmental changes and the implications of these pathways are being widely implicated in the risk and progression of schizophrenia. Although the specific mechanisms of fetal immune perturbations contributing to adult presentation of schizophrenia are unclear, a growing body of evidence suggests that gestational infection-induced immuno-inflammatory responses could modulate brain cytokine profile, O&NS pathway, tryptophan/kynurenine metabolism, oligodendrocyte and microglia activities, gamma-aminobutyric acid ergic neurotransmission, dopaminergic activity, hippocampal circuitry, cognitive attributes and so on and manifest schizophrenia-like symptoms. Of these, microglia-mediated neuropathological changes are remarkably more significant, as microglia constitute an important source of pro-inflammatory mediators and respond rapidly to even minor pathological changes in the brain and also contribute directly to the neuronal degeneration as well as cognitive impairments. Microglia also sustain and propagate inflammation by responding to pro-inflammatory signals released from nonneuronal cells, principally those of immune origin, implying that systemic inflammation can lead to microglia activation. This is achieved by extensive communication between immune system and central nervous system (CNS), especially through an integrative network between microglia and various immune cells including mast cells. Activated microglia have been shown to cause hypoxic injuries in the developing brain, including periventricular white matter damage, disruption of immature blood–brain barrier (BBB) and chronic neurodegeneration. Recent studies have established that schizophrenia is closely associated with microglia activation, as evidenced by increased density of microglia as well as HLA-DR+ microglia in hippocampus. Importantly, the higher density of HLA-DR+ microglia was found to be linked with psychotic positive symptoms in paranoid schizophrenia.
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