The inhibition of the kynurenine pathway prevents behavioral disturbances and oxidative stress in the brain of adult rats subjected to an animal model of schizophrenia.

Abstract

Evidence has shown that the kynurenine pathway (KP) plays a role in the onset of oxidative stress and also in the pathophysiology of schizophrenia. The aim of this study was to use a pharmacological animal model of schizophrenia induced by ketamine to investigate if KP inhibitors could protect the brains of Wistar rats against oxidative stress and behavioral changes. Ketamine, injected at the dose of 25mg/kg, increased spontaneous locomotor activity. However, the inhibitors of tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO) and kynurenine-3-monooxygenase (KMO) were able to reverse these changes. In addition, the IDO inhibitor prevented lipid peroxidation, and decreased the levels of protein carbonyl in the prefrontal cortex (PFC), hippocampus and striatum. It also increased the activity of superoxide dismutase (SOD) in the hippocampus, as well as increasing the levels of catalase activity in the PFC and hippocampus. The TDO inhibitor prevented lipid damage in the striatum and reduced the levels of protein carbonyl in the hippocampus and striatum. Also, the TDO inhibitor increased the levels of SOD activity in the striatum and CAT activity in the hippocampus of ketamine-induced pro-oxidant effects. Lipid damage was not reversed by the KMO inhibitor. The KMO inhibitor increased the levels of SOD activity in the hippocampus, and reduced the levels of protein carbonyl while elevating the levels of CAT activity in the striatum of rats that had been injected with ketamine. Our findings revealed that the KP pathway could be a potential mechanism by which a schizophrenia animal model induced by ketamine could cause interference by producing behavioral disturbance and inducing oxidative stress in the brain, suggesting that the inhibition of the KP pathway could be a potential target in treating schizophrenia.

• Authors: Gislaine Z Réus, Indianara R T Becker, Giselli Scaini, Fabricia Petronilho, Jean P Oses, Rima Kaddurah-Daouk, Luciane B Ceretta, Alexandra I Zugno, Felipe Dal-Pizzol, João Quevedo, Tatiana Barichello
• Journal: Progress in neuro-psychopharmacology & biological psychiatry (Prog Neuropsychopharmacol Biol Psychiatry) Vol. 81 Pg. 55-63 (Feb 02 2018) ISSN: 1878-4216 [Electronic] England
• PMID: 29030243 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Antipsychotic Agents
• Enzyme Inhibitors
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Kynurenine
• Ketamine
• Tryptophan Oxygenase
• Kynurenine 3-Monooxygenase

Topics

• Animals
• Antipsychotic Agents (pharmacology)
• Brain (drug effects, metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Indoleamine-Pyrrole 2,3,-Dioxygenase (antagonists & inhibitors, metabolism)
• Ketamine
• Kynurenine (metabolism)
• Kynurenine 3-Monooxygenase (antagonists & inhibitors, metabolism)
• Male
• Motor Activity (drug effects, physiology)
• Oxidative Stress (drug effects, physiology)
• Rats, Wistar
• Schizophrenia (drug therapy, metabolism)
• Signal Transduction (drug effects)
• Tryptophan Oxygenase (antagonists & inhibitors, metabolism)