Abstract
Schizophrenia is a complex psychiatric disorder that exhibits an interconnection between the immune system and the brain. Experimental and clinical studies have suggested the presence of neuroinflammation in schizophrenia. In the present study, the effect of antipsychotic drugs, including clozapine, risperidone, and haloperidol (10, 20 and 20 μM, respectively), on the production of IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, IL-18, INF-γ, and TNF-α was investigated in the unstimulated and polyriboinosinic-polyribocytidilic acid [poly (I:C)]-stimulated primary microglial cell cultures. In the unstimulated cultures, clozapine, risperidone, and haloperidol did not influence the cytokine levels. Nevertheless, in cell cultures under strong inflammatory activation by poly (I:C), clozapine reduced the levels of IL-1α, IL-1β, IL-2, and IL-17. Risperidone and haloperidol both reduced the levels of IL-1α, IL-1β, IL-2, and IL-17, and increased the levels of IL-6, IL-10, INF-γ, and TNF-α. Based on the results that were obtained with the antipsychotic drugs and observing that clozapine presented with a more significant anti-inflammatory effect, clozapine was selected for the subsequent experiments. We compared the profile of cytokine suppression obtained with the use of NLRP3 inflammasome inhibitor, CRID3 to that obtained with clozapine, to test our hypothesis that clozapine inhibits the NLRP3 inflammasome. Clozapine and CRID3 both reduced the IL-1α, IL-1β, IL-2, and IL-17 levels. Clozapine reduced the level of poly (I:C)-activated NLRP3 expression by 57%, which was higher than the reduction thay was seen with CRID3 treatment (45%). These results suggest that clozapine might exhibit anti-inflammatory effects by inhibiting NLRP3 inflammasome and this activity is not typical with the use of other antipsychotic drugs under the conditions of strong microglial activation.
Highlights
Schizophrenia (SCZ) is a progressive neurodevelopmental disorder that leads to severe mental illness and it is a major cause of adult disease burden [1]
We evaluated the anti-inflammatory effect of the antipsychotic drugs by determining the cytokine levels (IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, IL-18, INF-γ, and tumor necrosis factor (TNF)-α) in primary microglial cell cultures activated by poly (I:C)
Risperidone increased the levels of IL-6, IL-10, INF-γ, and TNF-α when compared to the vehicle
Summary
Schizophrenia (SCZ) is a progressive neurodevelopmental disorder that leads to severe mental illness and it is a major cause of adult disease burden [1]. Changes in cerebral dopaminergic and glutamatergic transmissions are the well-established neurobiological explanations for SCZ pathophysiology [2]. Increasing evidence from genetic, transcriptome, postmortem, peripheral biomarker, and therapeutic studies have postulated that the dysregulation of the immune system actively contributes to SCZ symptoms and progression [3]. Recent reports have demonstrated an imbalance in the host immune response that is associated with the activation of microglia in the pathophysiology of SCZ [4]. Imaging and postmortem studies have reaffirmed the presence of microglial activation in SCZ patients during the acute psychotic phase [5,6].
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