Quetiapine, an Atypical Antipsychotic, Is Protective against Autoimmune-Mediated Demyelination by Inhibiting Effector T Cell Proliferation Feng Mei1., Sheng Guo2., Yangtao He1, Linyun Wang 1 , Hongkai Wang1, Jianqin Niu1, Jiming Kong 3 , Xinmin Li4, Yuzhang Wu2, Lan Xiao1* 1 Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing, China, 2 Department of Immunology, Third Military Medical University, Chongqing, China, 3 Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada, 4 Department of Psychiatry, University of Manitoba, Winnipeg, Canada Abstract Quetiapine (Que), a commonly used atypical antipsychotic drug (APD), can prevent myelin from breakdown without immune attack. Multiple sclerosisis (MS), an autoimmune reactive inflammation demyelinating disease, is triggered by activated myelin-specific T lymphocytes (T cells). In this study, we investigated the potential efficacy of Que as an immune- modulating therapeutic agent for experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. Que treatment was initiated on the onset of MOG35–55 peptide induced EAE mice and the efficacy of Que on modulating the immune response was determined by Flow Cytometry through analyzing CD4+/CD8+ populations and the proliferation of effector T cells (CD4+CD252) in peripheral immune organs. Our results show that Que dramatically attenuates the severity of EAE symptoms. Que treatment decreases the extent of CD4+/CD8+ T cell infiltration into the spinal cord and suppresses local glial activation, thereby diminishing the loss of mature oligodendrocytes and myelin breakdown in the spinal cord of EAE mice. Our results further demonstrate that Que treatment decreases the CD4+/CD8+ T cell populations in lymph nodes and spleens of EAE mice and inhibits either MOG35–55 or anti-CD3 induced proliferation as well as IL-2 production of effector T cells (CD4+CD252) isolated from EAE mice spleen. Together, these findings suggest that Que displays an immune- modulating role during the course of EAE, and thus may be a promising candidate for treatment of MS. Citation: Mei F, Guo S, He Y, Wang L, Wang H, et al. (2012) Quetiapine, an Atypical Antipsychotic, Is Protective against Autoimmune-Mediated Demyelination by Inhibiting Effector T Cell Proliferation. PLoS ONE 7(8): e42746. doi:10.1371/journal.pone.0042746 Editor: Yue Feng, Emory University, United States of America Received May 24, 2012; Accepted July 12, 2012; Published August 13, 2012 Copyright: 2012 Mei et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work is in part supported by the National Natural Science Foundation of China (NSCF, 81071084), International Science & Technology Cooperation Program of China (2010DFB30820) and Natural Science Foundation Project of Chongqing (CQ CSTC, 2009BB5157, 2010BB5157). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: xiaolan35@hotmail.com . These authors contributed equally to this work. Introduction Disseminated demyelination in the central nervous system (CNS) mediated by autoimmune reactive inflammation is the primary pathological hallmark in multiple sclerosis (MS) and in various animal models, including experimental autoimmune encephalomyelitis (EAE), which results in axonal injury, synaptic dysfunctions and neurological impairments [1,2]. The activated myelin-specific CD4+ lymphocytes (T cells) that infiltrated into CNS nerve tissue have been considered as the initiator or early effector cells in the development of both EAE and MS [3,4]. For therapy of MS or EAE, a series of strategies including immunoregulation, anti-inflammation and enhancement in neuro- protection and/or neuroregeneration mediated by small molecules or mesenchymal stem cells have been applied to re-balance/control the immune response and protect myelin from breakdown [5–9]. Currently, interferon b (IFNb) and glatiramer acetate (GA) are commonly used to treat MS [10,11]. These drugs act mainly to rebalance the immune response and are capable of slowing down disease progress and ameliorating the frequency of recurrence of MS, but the efficacy is still limited and the long-term outcome is not satisfactory, most likely due to the inefficiency in myelin repair and neuronal degeneration [1]. Therefore, to rescue myelin from breakdown and to promote remyelination should be incorporated into the approach and treatment of demyelinating diseases including MS. Quetiapine (Que) is a commonly used atypical antipsychotic drug (APD) that has superior therapeutic effects on negative and cognitive symptoms in patients with schizophrenia and other neurological disorders like depression. Previous in vivo and in vitro studies have demonstrated that Que exerts protective effects on neurons [12]. Recently, oligodendrocyte dysfunction or demye- lination has been implicated in the pathophysiology of schizo- phrenia, bipolar disorder and major depression [13]. In trying to reveal the cellular mechanisms underlying the therapeutic actions of Que, recent studies indicate that Que can effectively prevent myelin breakdown in the cerebral cortex and the concomitant spatial working memory impairment in cuprizone induced demyelination mouse model without immune attacks [14–16]. Furthermore, Que can inhibit the activation of microglia in the PLOS ONE | www.plosone.org 1 August 2012 | Volume 7 | Issue 8 | e42746