Cited by 241Tryptophan and brain disordersSchizophrenia research and treatmentTreatment of Major Depression

Interleukin-6 Mediates the Increase in NADPH-Oxidase in the Ketamine Model of Schizophrenia

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Behrens, M. Margarita, Ali, Sameh S., Dugan, Laura L.·2008·The Journal of Neuroscience

Abstract

Adult exposure to NMDA receptor antagonists, such as ketamine, produces psychosis in humans, and exacerbates symptoms in schizophrenic patients. We recently showed that ketamine activates the innate immune enzyme NADPH-oxidase in brain, and that the superoxide produced leads to dysfunction of a subset of fast-spiking inhibitory interneurons expressing the calcium-binding protein parvalbumin (PV). Here we show that neuronal production of interleukin-6 (IL-6) is necessary and sufficient for ketamine-mediated activation of NADPH-oxidase in brain. Removal of IL-6 in neuronal cultures by anti-IL-6 blocking antibodies, or in vivo by use of IL-6-deficient mice, prevented the increase in superoxide by ketamine and rescued the interneurons. Accumulating evidence suggests that schizophrenia patients suffer from diminished antioxidant defenses, and a recent clinical trial showed that enhancing these defenses may ameliorate symptoms of the disease. Our results showing that ketamine-induced IL-6 is responsible for the activation of NADPH-oxidase in brain suggest that reducing brain levels of this cytokine may protect the GABAergic phenotype of fast-spiking PV-interneurons and thus attenuate the propsychotic effects of ketamine.

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Crossref · 10.1523/jneurosci.4457-08.2008

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  • Ketamine, a pro-inflammatory stimulus, injures PV-INs in vitro and in vivo.

    “For example, the NMDA receptor antagonist ketamine, a pro-inflammatory stimulus, injures PV-INs in vitro and in vivo [16,95].”

    From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [95]

  • This PV-IN injury is linked to IL-6-mediated, Nox2-dependent NADPH oxidase activation and superoxide production.

    “This injury is connected to IL-6mediated Nox2-dependent NADPH oxidase activation and production of superoxide [16,95].”

    From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [95]

  • Noncompeting NMDA antagonists affect inhibitory interneuron function by altering redox mechanisms, an effect that depends on interleukin 6 and other cytokines.

    “Noncompeting NMDA antagonists affect inhibitory interneuron function by altering redox mechanisms, 74 an effect that depends on interleukin 6 and other cytokines.75”

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Authors
Behrens, M. M., Ali, S. S., & Dugan, L. L.
Affiliations
University of California San Diego (US)
Venue
The Journal of Neuroscience
Published
2008-12-17
Volume
28
Issue
51
Pages
13957-13966
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W2062030838
Cited by
241
References
52
Citations by year
2026: 5 · 2025: 7 · 2024: 7 · 2023: 9 · 2022: 11 · 2021: 9 · 2020: 14 · 2019: 8 · 2018: 13 · 2017: 13 · 2016: 18 · 2015: 20 · 2014: 23 · 2013: 17 · 2012: 28
FWCI
4.37
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Hartford Foundation for Public Giving
  • Larry L. Hillblom Foundation
  • National Institute on Aging (K25AG026379, R21AG030320)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
interleukin-6, NADPH oxidase, ketamine, schizophrenia, NMDA receptor antagonists, superoxide, parvalbumin interneurons, fast-spiking interneurons, GABAergic interneurons, antioxidant defense, cytokine inhibition, IL-6-deficient mice
MeSH terms
Animals, Antibodies, Cells, Cultured, Disease Models, Animal, Enzyme Activation, gamma-Aminobutyric Acid, Interneurons, Ketamine, Male, Mice, Inbred C57BL, RNA, Messenger, Schizophrenia, Superoxides, Interleukin-6, Prefrontal Cortex, Mice, Knockout, NADPH Oxidases, Mice

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