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Anti-Inflammatory Efficacy of Dexamethasone and Nrf2 Activators in the CNS Using Brain Slices as a Model of Acute Injury

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Abstract

Limiting excessive production of inflammatory mediators is an effective therapeutic strategy for many diseases. It’s also a promising remedy for neurodegenerative diseases and central nervous system (CNS) injuries. Glucocorticoids are valuable anti-inflammatory agents, but their use is constrained by adverse side-effects. Activators of NF-E2-related factor-2 (Nrf2) signaling represent an attractive anti-inflammatory alternative. In this study, dexamethasone, a synthetic glucocorticoid, and several molecular activators of Nrf2 were evaluated for efficacy in slices of cerebral cortex derived from adult SJL/J mice. Cortical explants increased expression of IL-1β and TNF-α mRNAs in culture within 5 h of sectioning. This expression was inhibited with dexamethasone in the explant medium or injected systemically in mice before sectioning. Semi-synthetic triterpenoid (SST) derivatives, potent activators of the Nrf2 pathway, demonstrated fast-acting anti-inflammatory activity in microglia cultures, but not in the cortical slice system. Quercetin, luteolin, and dimethyl fumarate were also evaluated as molecular activators of Nrf2. While expression of inflammatory mediators in microglia cultures was inhibited, these compounds did not demonstrate anti-inflammatory efficacy in cortical slices. In conclusion, brain slices were amenable to pharmacological modification as demonstrated by anti-inflammatory activity with dexamethasone. The utilization of Nrf2 activators to limit inflammatory mediators within the CNS requires further investigation. Inactivity in CNS tissue, however, suggests their safe use without neurological side-effects in treating non-CNS disorders. Short-term CNS explants may provide a more accurate model of in vivo conditions than microglia cultures since the complex tissue microenvironment is maintained.

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Acknowledgments

DJG, WFH, and BTH were supported by the Department of Pathology, Dartmouth Medical School. DJG and BTH received grant support from Reata Pharmaceutical. DJG, EWS, and BTH received grant support from the ALS Center at Dartmouth Hitchcock Medical Center. The CDDO derivatives were generously supplied by Michael Sporn and Karen Liby of Dartmouth Medical School. Quercetin dihydrate and luteolin were generously supplied by Tom Lahey of ImmunoBiotics.

Conflict of interest disclosure

The authors state that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pathology, Dartmouth Medical School, Lebanon, NH, 03756, USA

    David J. Graber & William F. Hickey

  2. Department of Neurology, Dartmouth Medical School, Lebanon, NH, 03756, USA

    Elijah W. Stommel & Brent T. Harris

  3. Department of Neurology, Georgetown University School of Medicine, Washington, DC, 20007, USA

    Brent T. Harris

  4. Department of Pathology, Georgetown University School of Medicine, Washington, DC, 20007, USA

    Brent T. Harris

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  1. David J. Graber
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  2. William F. Hickey
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  4. Brent T. Harris
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Correspondence to David J. Graber.

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Disclaimers: DJG and BTH received grant support from Reata Pharmaceuticals. The CDDO derivatives were generously supplied by Michael Sporn and Karen Liby of Dartmouth Medical School. Quercetin dihydrate and luteolin were generously supplied by Tom Lahey of ImmunoBiotics.

Sources of support: Work was supported with funds from Reata Pharmaceuticals, ALS Center at Dartmouth Hitchcock Medical Center, and the Dept. of Pathology at Dartmouth Medical School.

David J. Graber and Brent T. Harris authors who are guarantors

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Graber, D.J., Hickey, W.F., Stommel, E.W. et al. Anti-Inflammatory Efficacy of Dexamethasone and Nrf2 Activators in the CNS Using Brain Slices as a Model of Acute Injury. J Neuroimmune Pharmacol 7, 266–278 (2012). https://doi.org/10.1007/s11481-011-9338-8

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