Different sub-anesthetic doses of ketamine increase oxidative stress in the brain of rats

Abstract

Schizophrenia is a complex neuropsychiatric disorder in which symptoms can be classified as either positive, such as delusions and hallucinations, or negative, such as blunted affect and social withdrawal. However, the mechanisms underlying this disease are poorly understood. There is evidence that reactive oxygen species (ROS) play an important role in the pathogenesis of many diseases, particularly those which are neurological and psychiatric in nature. Ketamine has been used to induce a schizophrenia-like condition as an animal model in which to study this condition. In the present study we tested the effects of sub-anesthetic doses of ketamine on various parameters of oxidative stress in the brain of rats. Our results indicate that lipid peroxidation and tissue protein oxidation were affected by varying sub-anesthetic doses of ketamine in multiple cerebral structures. Additionally, the activity of the antioxidant enzymes CAT and SOD was measured and was also found to be altered in most of the structures tested. In conclusion, we observe an increase in oxidative damage marked by an increase in lipid peroxidation, oxidative protein damage and a decrease in enzymatic defenses, in an animal model of schizophrenia. Given that oxidative stress could be related to schizophrenia, these findings may explain, at least in part, the mechanisms underlying in this disease.

The NADPH Oxidase NOX2 Controls Glutamate Release: A Novel Mechanism Involved in Psychosis-Like Ketamine Responses

“…Basically, the ketamine-induced NOX2 activation could be either a direct consequence of NMDA receptor inhibition or attributable to another pathway. The fact that two NMDA receptor antagonists, ketamine and dizocilpine [(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate], both induce cerebral ROS generation during injection in rats (de Oliveira et al, 2009) and mice (Zuo et al, 2007) support the former possibility. However, given the lack of cellular studies specifically addressing this issue, it is, at this point, difficult to exclude that ketamine activates NOX2 through other mechanisms.…”

“…Ketamine administration causes an increase in ROS production (Zuo et al, 2007) and oxidative damage (de Oliveira et al, 2009) in the brain. However, the source of the ROS generation is not known.…”

Effect of folic acid on oxidative stress and behavioral changes in the animal model of schizophrenia induced by ketamine

“…Also, increased levels of markers for lipid per oxidation were observed in a similar population (Dadheech et al, 2008;Padurariu et al, 2010). Additionally, a study performed by our group suggested that the animal model of schizophrenia induced by ketamine showed changes in the activity of superoxide dismutase (SOD), catalase (CAT) and GPx, resulting in protein and lipid damage (De Oliveira et al, 2009). …”

Oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part 2. Depression, anxiety, schizophrenia and autism

“…#SOD (cerebellum, prefrontal cortex, hippocampus) #CAT (cerebellum, prefrontal cortex, hippocampus) [126] G72/G30 transgenic schizophrenia mice " lipid peroxidation (brain) #GSH (brain) [128] G72/G30 transgenic schizophrenia mice -#CAT (cerebellum) [131] Social isolation/Ppp1r2-Cre/ fGluN1 knockout mice " ROS production (medial prefrontal cortex, S1 cortex)…”