title: Treatment with the antipsychotic agent, risperidone, reduces disease severity in experimental autoimmune encephalomyelitis.
abstract: Recent studies have demonstrated that atypical antipsychotic agents, which are known to antagonize dopamine D2 and serotonin 5-HT2a receptors, have immunomodulatory properties. Given the potential of these drugs to modulate the immune system both peripherally and within the central nervous system, we investigated the ability of the atypical anti-psychotic agent, risperidone, to modify disease in the animal model of multiple sclerosis (MS)4, experimental autoimune encephalomyelitis (EAE). We found that chronic oral administration of risperidone dose-dependently reduced the severity of disease and decreased both the size and number of spinal cord lesions. Furthermore, risperidone treatment substantially reduced antigen-specific interleukin (IL)-17a, IL-2, and IL-4 but not interferon (IFN)-γ production by splenocytes at peak disease and using an in vitro model, we show that treatment of macrophages with risperidone alters their ability to bias naïve T cells. Another atypical antipsychotic agent, clozapine, showed a similar ability to modify macrophages in vitro and to reduce disease in the EAE model but this effect was not due to antagonism of the type 1 or type 2 dopamine receptors alone. Finally, we found that while risperidone treatment had little effect on the in vivo activation of splenic macrophages during EAE, it significantly reduced the activation of microglia and macrophages in the central nervous system. Together these studies indicate that atypical antipsychotic agents like risperidone are effective immunomodulatory agents with the potential to treat immune-mediated diseases such as MS.
authors.affiliation: School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
authors.forename: David
authors.initials: D
authors.lastname: O'Sullivan
authors.affiliation: School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
authors.forename: Laura
authors.initials: L
authors.lastname: Green
authors.affiliation: School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
authors.forename: Sarrabeth
authors.initials: S
authors.lastname: Stone
authors.affiliation: School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
authors.forename: Pirooz
authors.initials: P
authors.lastname: Zareie
authors.affiliation: School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
authors.forename: Marie
authors.initials: M
authors.lastname: Kharkrang
authors.affiliation: School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
authors.forename: Dahna
authors.initials: D
authors.lastname: Fong
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Bronwen
authors.initials: B
authors.lastname: Connor
authors.affiliation: School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand; Malaghan Institute of Medical Research, Wellington, New Zealand.
authors.forename: Anne Camille
authors.initials: AC
authors.lastname: La Flamme
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002470:Cell Survival; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000175:diagnosis / Q000188:drug therapy*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000009:adverse effects; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000009:adverse effects; D018967:Risperidone / Q000008:administration & dosage / Q000494:pharmacology*; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000941:Antigens; D014150:Antipsychotic Agents; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D009569:Nitric Oxide; D018967:Risperidone