Effect of MK-801 and ketamine on hydroxyl radical generation in the posterior cingulate and retrosplenial cortex of free-moving mice, as determined by in vivo microdialysis

Zuo, Daiying; Wu, Yingliang; Yao, Wenxue; Cao, Yue; Wu, Chunfu; Tanaka, Masatoshi

doi:10.1016/j.pbb.2006.05.010

Cited by 57 publications

(32 citation statements)

References 36 publications

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“…Thus, it could be assumed that the effects of transient activation of the IL-6/Nox2 pathway may be a consequence of normal regulatory mechanisms in brain, where brief activation of the pathway does not lead to enduring effects on inhibitory circuits. Indeed, this is what is observed 24 h after one injection of NMDA-R antagonists ( Figure 1a and Zuo et al, 2007;Behrens et al, 2008). Repetitive exposures in adulthood, however, through disinhibitioninduced activation of the IL-6/Nox2 pathway induce an enduring, albeit reversible, dysfunction of the PV-interneuronal system (Figure 1b).…”

Section: Redox Dysregulation Of Nmda-r Mediated Transmission In Pv-insupporting

confidence: 55%

“…Furthermore, the inhibition of Nox2 with apocynin or eliminating superoxide with a brain-penetrant SOD-mimetic prevented the loss of phenotype of PV-interneurons in vitro and in vivo, and the ketamine effects were absent in Nox2-deficient animals (Behrens et al, 2007. Exposure to PCP and more selective NMDA-R antagonists such as MK801 and CPP were shown to produce a rapid increase in reactive oxygen-and nitrogen-species (ROS) in vitro (Xia et al, 2002), and in vivo (Zuo et al, 2007;Fejgin et al, 2008) and repetitive exposures in vivo led to a substantial elevation of baseline levels of free radicals, suggesting that this treatment results in a persistent change in the oxidative state of the cortex (Zuo et al, 2007). Interestingly, recent results have shown that NMDA receptor activity is required for the expression of antioxidant enzymes (Papadia et al, 2008), further supporting the idea that prolonged blockade of NMDA receptors produces an increased oxidative state.…”

Section: The Role Of Superoxide In the Persistent Effects Of Nmda-r Amentioning

confidence: 99%

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Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

2009

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An imbalance in the redox-state of the brain may be part of the underlying pathophysiology in schizophrenia. Inflammatory mediators, such as IL-6, which can tip the redox balance into a prooxidant state, have been consistently found to be altered in schizophrenia patients. However, the relationship of altered redox-state to altered brain functions observed in the disease has been unclear. Recent data from a pharmacological model of schizophrenia suggest that redox and inflammatory imbalances may be directly linked to the pathophysiology of the disease by alterations in fast-spiking interneurons. Repetitive adult-exposure to the NMDA-R antagonist ketamine increases the levels of the proinflammatory cytokine interleukin-6 in brain which, through activation of the superoxide-producing enzyme NADPH-oxidase (Nox2), leads to the loss of the GABAergic phenotype of PV-interneurons and to decreased inhibitory activity in prefrontal cortex. This effect is not observed after a single exposure to ketamine, suggesting that the first exposure to the NMDA-R antagonist primes the brain such that deleterious effects on PVinterneurons appear upon repetitive exposures. The effects of activation of the IL-6/Nox2 pathway on the PV-interneuronal system are reversible in the adult brain, but permanent in the developing cortex. The slow development of PV-interneurons, while essential for shaping of neuronal circuits during postnatal brain development, increases their vulnerability to deleterious insults that can permanently affect their maturational process. Thus, in individuals with genetic predisposition, the persistent activation of the IL-6/Nox2 pathway may be an environmental factor that tips the redoxbalance leading to schizophrenia symptoms in late adolescence and early adulthood.

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Section: Redox Dysregulation Of Nmda-r Mediated Transmission In Pv-insupporting

confidence: 55%

Section: The Role Of Superoxide In the Persistent Effects Of Nmda-r Amentioning

confidence: 99%

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

2009

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“…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.…”

Section: Discussionmentioning

confidence: 87%

“…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.…”

Section: Stress-related Markers After Ketamine Injectionmentioning

confidence: 99%

“…These two different animal models induce chronic neural stress and, in both cases, NOX2 upregulation appears to be responsible for the prolonged oxidative insult on GABAergic neurons. However, it has been reported that acute ketamine administration causes immediate formation of ROS (Zuo et al, 2007) and oxidative damage (de Oliveira et al, 2009). The mechanism of this rapid ROS generation is not known.…”

Section: Introductionmentioning

confidence: 99%

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

Sorce¹,

Schiavone²,

Tucci³

et al. 2010

J. Neurosci.

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Subanesthetic doses of NMDA receptor antagonist ketamine induce schizophrenia-like symptoms in humans and behavioral changes in rodents. Subchronic administration of ketamine leads to loss of parvalbumin-positive interneurons through reactive oxygen species (ROS), generated by the NADPH oxidase NOX2. However, ketamine induces very rapid alterations, in both mice and humans. Thus, we have investigated the role of NOX2 in acute responses to subanesthetic doses of ketamine. In wild-type mice, ketamine caused rapid (30 min) behavioral alterations, release of neurotransmitters, and brain oxidative stress, whereas NOX2-deficient mice did not display such alterations. Decreased expression of the subunit 2A of the NMDA receptor after repetitive ketamine exposure was also precluded by NOX2 deficiency. However, neurotransmitter release and behavioral changes in response to amphetamine were not altered in NOX2-deficient mice. Our results suggest that NOX2 is a major source of ROS production in the prefrontal cortex controlling glutamate release and associated behavioral alterations after acute ketamine exposure. Prolonged NOX2-dependent glutamate release may lead to neuroadaptative downregulation of NMDA receptor subunits.

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The Neurobiology of Schizophrenia

et al. 2015

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Effect of MK-801 and ketamine on hydroxyl radical generation in the posterior cingulate and retrosplenial cortex of free-moving mice, as determined by in vivo microdialysis

Cited by 57 publications

References 36 publications

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

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

The Neurobiology of Schizophrenia

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