title: Reversal of schizophrenia-like symptoms and immune alterations in mice by immunomodulatory drugs.
abstract: Immune dysregulation observed in schizophrenia alters tryptophan metabolism. Tryptophan metabolism is triggered by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Tryptophan is converted to quinolinic acid, a potent neurotoxin, and to kynurenic acid, an NMDA antagonist. 1-Methyl-D-tryptophan (MDT) inhibits IDO. Melatonin is metabolized by IDO while inhibiting TDO. We evaluated the reversal of ketamine-induced schizophrenia-like behavioral and neurochemical alterations in mice by the administration of MDT (20 or 40 mg/kg, i.p.) or melatonin (15 mg/kg, per os). Oxidative stress and inflammatory alterations, i.e. myeloperoxidase activity (MPO), reduced glutathione (GSH), lipid peroxidation (LPO) and interleukin (IL)-4 and IL-6 were measured in the prefrontal cortex (PFC), hippocampus and striatum. Risperidone was used as standard antipsychotic. Ketamine triggered positive- (PPI deficits and hyperlocomotion), cognitive- (working memory deficits) and negative (social interaction deficits) schizophrenia-like symptoms. These symptoms were accompanied by increased MPO activity, decreased GSH and increased LPO in all brain areas and increments in hippocampal IL-4 and IL-6. MDT and melatonin reversed all ketamine-induced behavioral alterations. Risperidone did not reverse working memory deficits. MDT and melatonin reversed alterations in MPO activity and GSH levels. LP was reversed only by melatonin and risperidone. Risperidone could not reverse MPO alterations in the PFC and striatum. All drugs reversed the alterations in IL-4 and IL-6. The hippocampus and striatum of ketamine+melatonin-treated animals had lower levels of IL-6. Our findings provide further preclinical evidence that immune-inflammatory and oxidative pathways are involved in schizophrenia and that targeting these pathways is a valid treatment option in schizophrenia.
authors.affiliation: Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil; Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Tatiane
authors.initials: T
authors.lastname: da Silva Araújo
authors.affiliation: Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil; Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Adriano Jose
authors.initials: AJ
authors.lastname: Maia Chaves Filho
authors.affiliation: Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil; Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Aline Santos
authors.initials: AS
authors.lastname: Monte
authors.affiliation: Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil; Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Ana
authors.initials: A
authors.lastname: Isabelle de Góis Queiroz
authors.affiliation: Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil; Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Rafaela Carneiro
authors.initials: RC
authors.lastname: Cordeiro
authors.affiliation: Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil; Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Michel
authors.initials: M
authors.lastname: de Jesus Souza Machado
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Ricardo
authors.initials: R
authors.lastname: de Freitas Lima
authors.affiliation: Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil; Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: David
authors.initials: D
authors.lastname: Freitas de Lucena
authors.affiliation: Impact Strategic Research Center, Deakin University, Geelong, Australia; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, Brazil.
authors.forename: Michael
authors.initials: M
authors.lastname: Maes
authors.affiliation: Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil; Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil. Electronic address: daniellesilmacedo@gmail.com.
authors.forename: Danielle
authors.initials: D
authors.lastname: Macêdo
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D007155:Immunologic Factors / Q000494:pharmacology*; D056747:Immunomodulation; D015847:Interleukin-4 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007649:Ketamine; D008297:Male; D008550:Melatonin / Q000494:pharmacology; D051379:Mice; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D018967:Risperidone / Q000494:pharmacology; D012559:Schizophrenia / Q000188:drug therapy* / Q000276:immunology*; D012565:Schizophrenic Psychology; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D007155:Immunologic Factors; D015850:Interleukin-6; C577686:interleukin-6, mouse; D015847:Interleukin-4; D007649:Ketamine; D014364:Tryptophan; D008550:Melatonin; D018967:Risperidone; C525396:1-methyltryptophan
keywords: 1-Methyl-D-tryptophan; Immunomodulatory drugs; Ketamine-induced schizophrenia; Melatonin; Schizophrenia; Tryptophan metabolism