Risperidone significantly inhibits interferon-γ-induced microglial activation in vitro
Introduction
Microglia has recently been regarded to be a mediator of neuroinflammation via the release of proinflammatory cytokines, nitric oxide (NO) and reactive oxygen species (ROS) in the central nervous system (CNS). Microglia has thus been reported to play an important role in the pathology of neurodegenerative disease, such as Alzheimer's disease (AD) and Parkinson's disease (PD) (McGeer et al., 1993, Stoll and Jander, 1999).
The pathological mechanisms of schizophrenia remain unclear while some recent neuroimaging studies suggest that even schizophrenia may be a kind of neurodegenerative disease like AD and PD (Lieberman, 1999, Lieberman et al., 2005b). There have so far been only a few studies on the relationship between microglia and schizophrenia, while in a postmortem brain study, single case analysis revealed highly elevated microglial cell numbers in the anterior cingulate cortex and mediodorsal thalamus of schizophrenic patients who had committed suicide during acute psychosis (Steiner et al., 2006). Furthermore, a transient microglial activation has been demonstrated in the acute psychotic state of schizophrenia with use of a novel in vivo imaging technique, positron emission tomography (PET) with the [11C] PK11195 radioligand, which mainly binds to the peripheral benzodiazepine receptor of activated microglia (Hirsch, 2004, van Berckel et al., 2005). These data support the possibility that microglial activation might have a key role in the pathology of schizophrenia. There is increasing evidence that the pathophysiology of schizophrenia is related to activation of the inflammatory/immunological response system, as indicated by some studies (Drzyzga et al., 2006). Increased serum concentrations of interleukin (IL)-2, IL-6 and IL-8 have been observed in schizophrenic patients (Lin et al., 1998, Zhang et al., 2004) and immunomodulatory drugs such as cyclooxygenase-2 (COX-2) inhibitors have recently been reported to show beneficial effects on schizophrenic symptoms (Muller et al., 2002). Moreover, recent reports have demonstrated that atypical antipsychotics, such as clozapine and risperidone, decreased serum levels of cytokines such as IL-2, IL-6 and tumor necrosis factor (TNF)-α (Lu et al., 2004), whose main source in the CNS is considered to be activated microglia in schizophrenic patients. Another factor is NO and its metabolites, which have been suggested to play important roles in schizophrenia, much like in AD and PD (Bernstein et al., 2005).
Structural brain abnormalities have been extensively and consistently described in schizophrenic patients. Longitudinal studies using high-resolution magnetic resonance imaging (MRI) to examine brain structure have found that MRI volume changes were progressive over time and related to the course of illness and treatment outcome in schizophrenic patients (Davis et al., 2003, Kumra et al., 2005). Atypical antipsychotics are becoming standard drugs for the treatment of schizophrenia due to their less adverse effects and more effectiveness for the negative symptoms of schizophrenia (Buckley, 1997, Blin, 1999, Lieberman et al., 2005a). Some recent reports have suggested the possibility of specific atypical antipsychotics having pharmacological properties that could produce neurotrophic, neurogenetic, or neuroprotective effects. Namely, specific atypical antipsychotics such as olanzapine and risperidone have been reported to decrease the reduction of MRI volume during the clinical course of schizophrenia (Chakos et al., 2005, Lieberman et al., 2005b, Massana et al., 2005, Girgis et al., 2006).
To the best of our knowledge, there have been only a few reports describing the effect of antipsychotics on microglial activation, and the inhibitory effect of olanzapine on microglial activation has recently been reported (Hou et al., 2006). In the present study, we thus investigated the effects of risperidone on the generation of nitric oxide and inflammatory cytokines by interferon-γ-activated microglia.
Section snippets
Materials
Recombinant IFN-γ was purchased from Genzyme (Cambridge, MA, USA). Recombinant mouse granulocyte macrophage colony stimulating factor (GM-CSF) was purchased from R&D systems (Minneapolis, MN, USA). β-actin and iNOS antibodies were purchased by Abcam Inc. (Cambridge, MA, USA) and Upstate Inc. (Lake Placid, NY, USA), respectively. Risperidone was kindly gifted from Jansen research foundation, a division of Janssen Pharmaceutica NV (Beerse, Belgium). Haloperidol and all other main chemicals were
Cell viability
The 6–3 microglial cells were treated with DMSO (0.15%), haloperidol (10, 20 and 30 μM) or risperidone (10, 20 and 30 μM) without IFN-γ for 72 h. A MTT assay showed no significant influence on cell viability by haloperidol or risperidone treatments (Table 1).
The 6–3 microglial cells were pre-treated with DMSO (0.15%), haloperidol (10, 20 and 30 μM) or risperidone (10, 20 and 30 μM) for 12 h, and then the cells were treated with IFN-γ (50 U/mL) for 60 h. A MTT assay showed no significant
Discussion
To the best of our knowledge, there have only been four previous reports which studied the effect of antipsychotics on microglial activation in vitro. Kowalski et al. demonstrated that flupentixol and trifluperidol reduced secretion of TNF-α and NO by activated microglia (Kowalski et al., 2003), and flupentixol, trifluperidol, chlorpromazine and loxapine have been reported to reduce IL-1β and IL-2 release by activated microglia (Kowalski et al., 2004, Labuzek et al., 2005). As for atypical
Acknowledgements
The authors thank Dr. Makoto Sawada at Nagoya University for providing them with the microglial cell line, 6–3.
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