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Chronic NMDA Administration Increases Neuroinflammatory Markers in Rat Frontal Cortex: Cross-Talk Between Excitotoxicity and Neuroinflammation

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Abstract

Chronic N-Methyl-d-aspartate (NMDA) administration, a model of excitotoxicity, and chronic intracerebroventricular lipopolysaccharide infusion, a model of neuroinflammation, are reported to upregulate arachidonic acid incorporation and turnover in rat brain phospholipids as well as enzymes involved in arachidonic acid metabolism. This suggests cross-talk between signaling pathways of excitotoxicity and of neuroinflammation, involving arachidonic acid. To test whether chronic NMDA administrations to rats can upregulate brain markers of neuroinflammation, NMDA (25 mg/kg i.p.) or vehicle (1 ml saline/kg i.p.) was administered daily to adult male rats for 21 days. Protein and mRNA levels of cytokines and other inflammatory markers were measured in the frontal cortex using immunoblot and real-time PCR. Compared with chronic vehicle, chronic NMDA significantly increased protein and mRNA levels of interleukin-1beta, tumor necrosis factor alpha, glial fibrillary acidic protein and inducible nitric oxide synthase. Chronic NMDA receptor overactivation results in increased levels of neuroinflammatory markers in the rat frontal cortex, consistent with cross-talk between excitotoxicity and neuroinflammation. As both processes have been reported in a number of human brain diseases, NMDA receptor inhibitors might be of use in treating neuroinflammation in these diseases.

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Abbreviations

NMDA:

N-Methyl-d-aspartate

IL-1β:

Interleukin-1beta

TNFα:

Tumor necrosis factor alpha

GFAP:

Glial fibrillary acid protein

iNOS:

Inducible nitric oxide synthase

LPS:

Lipopolysaccharide

NR:

N-Methyl-d-aspartate receptor

AP-2:

Activator protein-2

NF-κB:

Nuclear factor-kappa B

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Acknowledgement

This work was entirely supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.

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Authors and Affiliations

  1. Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, 9000 Rockville Pike, Bldg. 9, 1S-126, Bethesda, MD, 20892, USA

    Yunyoung C. Chang, Hyung-Wook Kim, Stanley I. Rapoport & Jagadeesh S. Rao

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  1. Yunyoung C. Chang
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  2. Hyung-Wook Kim
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  3. Stanley I. Rapoport
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  4. Jagadeesh S. Rao
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Correspondence to Jagadeesh S. Rao.

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Chang, Y.C., Kim, HW., Rapoport, S.I. et al. Chronic NMDA Administration Increases Neuroinflammatory Markers in Rat Frontal Cortex: Cross-Talk Between Excitotoxicity and Neuroinflammation. Neurochem Res 33, 2318–2323 (2008). https://doi.org/10.1007/s11064-008-9731-8

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  • DOI: https://doi.org/10.1007/s11064-008-9731-8

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