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Synthetic Triterpenoid CDDO Derivatives Modulate Cytoprotective or Immunological Properties in Astrocytes, Neurons, and Microglia

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Abstract

2-Cyano-3,12-dioxoolean-1, 9-dien-28-oic acid (CDDO) is a semisynthetic triterpenoid. CDDO derivatives with an amide, butyl ester (BE), imidazolide (IM), or trifluoroethyl amide (TFEA) group at position C-28 of CDDO were evaluated in glial and neuronal cells, in vitro. Changes in intracellular NADPH:quinone oxidoreductase (NQO1) levels, protection against oxidative toxicity, endotoxin-induced free-radical production, and the median lethal concentration (LC50) were assessed. All four CDDO derivatives at nanomolar concentrations increased NQO1 levels in astrocytes and moderately in neurons, but not in microglial cells. Pretreatment with 100 nM of CDDO-amide, CDDO-TFEA, or CDDO-IM protected astrocytes from hydrogen peroxide toxicity. Only CDDO-amide protected neuronal cells. Pretreatment of microglial cells with CDDO derivatives at nanomolar concentrations attenuated endotoxin-induced nitric oxide protection. The effectiveness for NQO1 induction, protection against oxidative toxicity, and attenuation of nitric oxide production, as well as cell viability at higher concentrations, varied among the derivatives with different functional groups at C-28. CDDO-amide had comparable or even a greater effectiveness at altering cytoprotective and immunomodulatory properties while having higher LC50 values for each neural cell type examined. These results indicate that derivatives of CDDO modulate important pathways relevant to many neurological diseases that involve both chronic inflammation and free-radical damage with variable effects based on the functional group at C-28 and cell type.

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Acknowledgements

This work was supported in part by the ALS Center at Dartmouth Hitchcock Medical Center. The CDDO derivatives used in this study were generously supplied by Drs. Michael Sporn and Karen Liby of Dartmouth Medical School. We would also like to thank Dr. Joyce Deleo (Dartmouth Medical School) for supplying the BV-2 cells and Mr. Justin Trombley (Dartmouth Medical School) for the blinded quantification of primary spinal neurons.

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

    David J. Graber, Paul J. Park, William F. Hickey & Brent T. Harris

  2. Department of Pathology, Med/Dent SW201, Georgetown University School of Medicine, 3900 Reservoir Rd, NW, Washington, DC, 20007, USA

    Brent T. Harris

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  1. David J. Graber
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David J. Graber, Paul J. Park, William F. Hickey, and Brent T. Harris have no conflicts of interest.

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

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Work was supported by the ALS Center at Dartmouth Hitchcock Medical Center.

Synthetic triterpenoids were supplied by Drs. Michael Sporn and Karen Liby of Dartmouth Medical School.

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Graber, D.J., Park, P.J., Hickey, W.F. et al. Synthetic Triterpenoid CDDO Derivatives Modulate Cytoprotective or Immunological Properties in Astrocytes, Neurons, and Microglia. J Neuroimmune Pharmacol 6, 107–120 (2011). https://doi.org/10.1007/s11481-010-9240-9

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