Reversal of schizophrenia-like symptoms and immune alterations in mice by immunomodulatory drugs

• Published in: Journal of psychiatric research Vol. 84; pp. 49 - 58
• Main Authors: da Silva Araújo, Tatiane, Maia Chaves Filho, Adriano Jose, Monte, Aline Santos, Isabelle de Góis Queiroz, Ana, Cordeiro, Rafaela Carneiro, de Jesus Souza Machado, Michel, de Freitas Lima, Ricardo, Freitas de Lucena, David, Maes, Michael, Macêdo, Danielle
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2017
• Subjects: 1-Methyl-D-tryptophan; Animals; Antipsychotic Agents - pharmacology; Brain - drug effects; Brain - immunology; Disease Models, Animal; Immunologic Factors - pharmacology; Immunomodulation; Immunomodulatory drugs; Interleukin-4 - metabolism; Interleukin-6 - metabolism; Ketamine; Ketamine-induced schizophrenia; Male; Melatonin; Melatonin - pharmacology; Mice; Neuroimmunomodulation - drug effects; Neuroimmunomodulation - physiology; Psychiatry; Random Allocation; Risperidone - pharmacology; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - immunology; Schizophrenic Psychology; Tryptophan - analogs & derivatives; Tryptophan - pharmacology; Tryptophan metabolism; tryptophan 2,3-dioxygenase; Ketamine-induced schizophrenia; Melatonin; IL; Tryptophan metabolism; prefrontal cortex; Schizophrenia; LPO; myeloperoxidase; PFC; lipid peroxidation; MPO; 1-Methyl-D-tryptophan; Immunomodulatory drugs; tryptophan catabolite pathway; reduced glutathione; interleukin; MDT; GSH; TDO; TRYCAT
• ISSN: 0022-3956; 1879-1379
• DOI: 10.1016/j.jpsychires.2016.09.017

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.