Pretreatment of aripiprazole and minocycline, but not haloperidol, suppresses oligodendrocyte damage from interferon-γ-stimulated microglia in co-culture model
Introduction
Multiple theories have been put forth regarding the pathogenesis of schizophrenia, while the underlying mechanisms remain to be identified (Fatemi and Folsom, 2009, Jaaro-Peled et al., 2009). Recent imaging studies have shown that first-episode schizophrenia patients have a significant volume reduction in white matter with abnormal brain connectivity (Price et al., 2006, Schlosser et al., 2007). Deviant myelination of schizophrenia patients has been evident in postmortem studies (Uranova et al., 2004, Uranova et al., 2007, Bernstein et al., 2009) and imaging studies (Miyata et al., 2009, Kubota et al., 2011, Kubota et al., 2013). Combined with evidence of dysregulation of myelination-related genes, a disruption of oligodendrocyte function in schizophrenia has been strongly implicated (McCullumsmith et al., 2007).
Mittelbronn et al. demonstrated that local distribution of microglia in the normal adult human brain differs by up to one order of magnitude and that there is significantly more microglia in white matter than in gray matter (Mittelbronn et al., 2001). Therefore, microglial activation plays an important role especially in white matter disorders (Schnieder and Dwork, 2011). Microglial cytotoxicity of oligodendrocytes is mediated through free radical-related molecules (nitric oxide (NO) and/or peroxynitrite) and pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) (Buntinx et al., 2004, Steelman and Li, 2011). TNF-α is known to compromise the growth of oligodendrocytes and the expression of mRNA for myelin basic protein (MBP) in cultures (Cammer and Zhang, 1999). Furthermore, TNF-α is reported to inhibit the survival and proliferation of oligodendrocyte progenitors and their subsequent differentiation into mature myelinating phenotypes (Feldhaus et al., 2004). Recent postmortem and imaging studies have suggested the microglial activation (Radewicz et al., 2000, Steiner et al., 2006, Steiner et al., 2008c, van Berckel et al., 2008, Doorduin et al., 2009, Takano et al., 2010) and oligodendrocyte dysfunction (Uranova et al., 2004, Uranova et al., 2007, Bernstein et al., 2009) in schizophrenia patients. Based on the above evidence, microglial activation may be involved in the pathological process of schizophrenia by damaging oligodendrocytes.
Various antipsychotics, which had classically been regarded to modulate solely neurons and synaptic networks, have recently been revealed to have direct anti-inflammatory properties on activated microglia from a series of in vitro studies (Kato et al., 2007, Kato et al., 2011a, Kato et al., 2013). We have reported that not only antipsychotics with dopamine D2 receptor (D2R) antagonism but also aripiprazole with D2R partial agonism inhibit microglial activation in vitro (Kato et al., 2008, Kato et al., 2011b). In spite of a different pharmacological profile, aripiprazole is effective against the positive and negative symptoms of patients with schizophrenia like other antipsychotics with lower side effects (Kasper et al., 2003, Potkin et al., 2003, Tandon et al., 2006). In addition, aripiprazole has been proved to be effective not only for schizophrenia but also for other psychiatric disorders such as major depressive disorders and bipolar disorders (Keck et al., 2006, Berman et al., 2007). On the other hand, minocycline, a semi-synthetic tetracycline antibiotic, is known to be one of the most well-known inhibitors of microglial activation (Yrjanheikki et al., 1998, Du et al., 2001). Minocycline, which can easily cross the blood–brain barrier, has been reported to provide neuroprotection via suppressing microglial activation in a number of neuronal disorders including amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease and Alzheimer's disease (Kriz et al., 2002, Van Den Bosch et al., 2002, Plane et al., 2010). Recent studies using animal models of schizophrenia have suggested that minocycline can be beneficial for the treatment of schizophrenia (Zhang et al., 2007, Fujita et al., 2008, Mizoguchi et al., 2008, Levkovitz et al., 2010). Furthermore, therapeutic improvement in psychotic symptoms has been demonstrated by minocycline in patients with schizophrenia (Ahuja and Carroll, 2007, Miyaoka et al., 2007, Miyaoka, 2008, Chaves et al., 2010, Levkovitz et al., 2010, Kelly et al., 2011, Chaudhry et al., 2012).
To the best of our knowledge, the protective effects of antipsychotics and minocycline on oligodendrocytes via the modulation of microglial inflammatory responses have never been reported. Our previous investigations have suggested that aripiprazole is the most effective antipsychotic, which directly and significantly inhibits microglial activation in vitro (Kato et al., 2008, Kato et al., 2011b). In the present study, we thus investigate the underlying mechanism of how aripiprazole, haloperidol and minocycline affect the degenerative process of oligodendrocytes via the modulation of microglial activation utilizing a co-culture model with microglia and oligodendrocytes.
Section snippets
Materials and methods
All experimental procedures were conducted in accordance with the Standard Guidelines for Animal Experiments of the Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Cell viability
In the present experiments, the cell viability of HAPI microglial cells was not affected by aripiprazole (20 μM), haloperidol (20 μM) and minocycline (10 μM) (data not shown). Therefore, we used these drugs under this concentration in the present study.
Protective effects of minocycline and antipsychotics on oligodendrocyte damage
IFN-γ is a typical Th1 cytokine and a major immuno-activator released by infiltrating T cells as well as activated microglia in the CNS (Kawanokuchi et al., 2006). Elevated mRNA levels of IFN-γ have been reported in the brain of schizophrenia
Discussion
This is the first report to demonstrate that pretreatment of aripiprazole and minocycline inhibits oligodendrocyte damage by suppressing IFN-γ-activated microglial cells.
We have already demonstrated that aripiprazole inhibits TNF-α production from IFN-γ-activated microglial cells via suppressing the elevation of intracellular calcium signaling, not via D2R receptor-related signaling (Kato et al., 2008). In the present study, we have proved that aripiprazole and minocycline have the potential to
Role of funding source
This work was financially supported by Grant-in-Aids from the Japan Society for the Promotion of Science (JSPS) [to YS, TAK, AM, YM and SK], and from the Mitsubishi Pharma Research Foundation [to TAK and HH].
Contributors
All authors contributed substantially to the scientific process leading up to the writing of the present paper. TAK and AM, the principal investigators of the present research, and YS, the first author, made the conception and design of the project and wrote the protocol. The performance of experiments and the data analysis/interpretation were done by YS, TAK, AM, YM, HH and MSK. YS wrote the first draft of the manuscript. Critical revisions of the manuscript were made by TAK, AM, DY and SK.
Conflict of interest
All authors declare that they have no financial conflict of interest.
Acknowledgments
The authors would like to thank Dr. Masahiro Ohgidani, Dr. Noriaki Sagata, Dr. Yusuke Yamauchi, and Dr. Kohei Hayakawa (Molecular & Translational Psychiatry Unit, Department of Neuropsychiatry, Kyushu University) and Dr. Daichi Muratsu (Division of Oral and Maxillofacial Oncology, Faculty of Dental Science, Kyushu University) for fruitful comments and technical supports.
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