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Reversal of schizophrenia-like symptoms and immune alterations in mice by immunomodulatory drugs
- Source :
- Journal of psychiatric research. 84
- Publication Year :
- 2016
-
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.
- Subjects :
- Male
medicine.medical_specialty
Neuroimmunomodulation
Hippocampus
Melatonin
Immunomodulation
03 medical and health sciences
chemistry.chemical_compound
Mice
Random Allocation
0302 clinical medicine
Kynurenic acid
Neurochemical
Internal medicine
medicine
Animals
Immunologic Factors
Biological Psychiatry
Risperidone
biology
business.industry
Interleukin-6
Tryptophan
Brain
030227 psychiatry
Psychiatry and Mental health
Disease Models, Animal
Endocrinology
chemistry
Myeloperoxidase
biology.protein
Schizophrenia
NMDA receptor
Ketamine
Schizophrenic Psychology
Interleukin-4
business
030217 neurology & neurosurgery
Quinolinic acid
medicine.drug
Antipsychotic Agents
Subjects
Details
- ISSN :
- 18791379
- Volume :
- 84
- Database :
- OpenAIRE
- Journal :
- Journal of psychiatric research
- Accession number :
- edsair.doi.dedup.....539b9db0444d38388cbd3f3860062182