37.4 IMMUNOMODULATORY STRATEGIES FOR SCHIZOPHRENIA: PRECLINICAL EVIDENCES FOR DRUG REPURPOSING

• Published in: Schizophrenia bulletin 2019-04, Vol.45 (Supplement_2), p.S148-S149
• Main Authors: Macedo, Danielle, Araujo, Tatiane, Filho, Adriano Chaves, Lucena, David de, Monte, Aline, Lima, Ricardo
• Format: Article
• Language: English
• Subjects: Plenary/Symposia
• ISSN: 0586-7614; 1745-1701
• DOI: 10.1093/schbul/sbz022.152

Abstract Background Schizophrenia is associated with immune-inflammatory and oxidative stress mechanisms leading to activation of the tryptophan catabolite (TRYCAT) pathway, which ultimately together with dysfunctional N-methyl-D-aspartate receptors (NMDAR) may cause neuroprogression and all symptom clusters of this mental disorder. Tryptophan metabolism is triggered by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). By the enzymatic action of IDO, tryptophan is converted to quinolinic acid, a potent neurotoxin, related to NMDA receptors activation. Conversely, TDO enzymatic activity is related to the synthesis of kynurenic acid, an NMDA and nicotine alpha7 receptors antagonist. While IDO is expressed in microglial cells, astrocytes express TDO. The activation of TRYCAT pathway is being related to schizophrenia symptoms such as cognitive decline. 1-Methyl-D-tryptophan (MDT) is an IDO inhibitor. MDT is being tested as an immunomodulatory strategy for cancer treatment. Melatonin, another immunomodulatory drug is metabolized by IDO while inhibiting TDO. In the present preclinical study, we evaluated the reversal of ketamine-induced schizophrenia-like behavioral and neurochemical alterations in mice, a validated pharmacological animal model of schizophrenia. Methods Male Swiss mice were administered MDT (20 or 40 mg/kg, intraperitoneal) or melatonin (15 mg/kg, per os). We tested oxidative alterations by the evaluations of myeloperoxidase activity (MPO), reduced glutathione (GSH) and lipid peroxidation as well as inflammatory changes, by the measures of interleukin (IL)-4 and IL-6 in brain areas related to schizophrenia neurobiology namely, prefrontal cortex (PFC), hippocampus and striatum. Risperidone was used as standard antipsychotic. Results Our results showed that ketamine triggered positive- (PPI deficits and hyperlocomotion), cognitive- (working memory deficits) and negative-like (social interaction deficits) symptoms of schizophrenia. These symptoms were accompanied by increased MPO activity, decreased GSH and increased lipid peroxidation in all brain areas tested and by increments in hippocampal IL-4 and IL-6 levels. MDT and melatonin reversed all ketamine-induced behavioral alterations, while the antipsychotic risperidone did not reverse working memory deficits. MDT and melatonin reversed the alterations in MPO activity and GSH levels. Lipid peroxidation was reversed only by melatonin and risperidone. Risperidone was not able t