title: Synthetic triterpenoid CDDO derivatives modulate cytoprotective or immunological properties in astrocytes, neurons, and microglia.
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.
authors.affiliation: Department of Pathology, Dartmouth Medical School, Lebanon, NH 03756, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Graber
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Park
authors.forename: William F
authors.initials: WF
authors.lastname: Hickey
authors.forename: Brent T
authors.initials: BT
authors.lastname: Harris
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D000975:Antioxidants; D018696:Neuroprotective Agents; D009828:Oleanolic Acid
references.citation: J Neurosci. 1986 Aug;6(8):2163-78
references.pmid: 3018187
references.citation: Proc Natl Acad Sci U S A. 1990 Feb;87(4):1620-4
references.pmid: 2154753
references.citation: PLoS One. 2009 Jun 01;4(6):e5757
references.pmid: 19484125
references.citation: J Neuroinflammation. 2008 May 12;5:14
references.pmid: 18474101
references.citation: J Biol Chem. 2000 May 26;275(21):16023-9
references.pmid: 10821856
references.citation: Mol Endocrinol. 2000 Oct;14(10):1550-6
references.pmid: 11043571
references.citation: Bioorg Med Chem Lett. 2005 May 2;15(9):2215-9
references.pmid: 15837296
references.citation: Biochem Biophys Res Commun. 2009 Mar 13;380(3):449-53
references.pmid: 19174151
references.citation: J Neurooncol. 1994;22(3):191-200
references.pmid: 7760095
references.citation: Anal Biochem. 1988 Mar;169(2):328-36
references.pmid: 3382006
references.citation: Cancer Res. 1998 Feb 15;58(4):717-23
references.pmid: 9485026
references.citation: Cancer Res. 2003 Sep 1;63(17):5551-8
references.pmid: 14500394
references.citation: Front Biosci. 2004 Jan 01;9:763-76
references.pmid: 14766406
references.citation: Free Radic Biol Med. 2010 Jul 15;49(2):147-58
references.pmid: 20338236
references.citation: Mol Pharmacol. 2001 May;59(5):1094-9
references.pmid: 11306692
references.citation: J Med Chem. 2000 Nov 2;43(22):4233-46
references.pmid: 11063620
references.citation: Cell. 2010 Mar 19;140(6):798-804
references.pmid: 20303871
references.citation: Methods Enzymol. 2004;382:243-58
references.pmid: 15047106
references.citation: Mol Cancer Ther. 2006 Dec;5(12):3232-9
references.pmid: 17148759
references.citation: J Immunoassay Immunochem. 2006;27(1):31-44
references.pmid: 16450867
references.citation: Cell. 2010 Mar 19;140(6):805-20
references.pmid: 20303872
references.citation: J Neurochem. 2009 Apr;109(2):502-12
references.pmid: 19200343
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11908-13
references.pmid: 12193649
references.citation: Eur J Pharmacol. 2005 Oct 3;521(1-3):9-20
references.pmid: 16171798
references.citation: Antioxid Redox Signal. 2003 Jun;5(3):319-35
references.pmid: 12880486
references.citation: Free Radic Biol Med. 2007 Sep 1;43(5):809-17
references.pmid: 17664144
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4584-9
references.pmid: 15767573
references.citation: Alcohol. 1999 Feb;17(2):163-8
references.pmid: 10064385
references.citation: J Med Chem. 2000 May 4;43(9):1866-77
references.pmid: 10794703
references.citation: Neurochem Res. 1997 Oct;22(10):1187-92
references.pmid: 9342721
references.citation: Cancer Res. 1999 Jan 15;59(2):336-41
references.pmid: 9927043
references.citation: Neuroscience. 2007 May 25;146(3):1013-9
references.pmid: 17418957
references.citation: J Immunol Methods. 1983 Dec 16;65(1-2):55-63
references.pmid: 6606682
references.citation: Cancer Res. 2004 Nov 1;64(21):7927-35
references.pmid: 15520199
references.citation: J Neurosci. 2008 Dec 10;28(50):13574-81
references.pmid: 19074031
references.citation: Bioorg Med Chem Lett. 1998 Oct 6;8(19):2711-4
references.pmid: 9873608
references.citation: Mol Cancer Ther. 2007 Jan;6(1):154-62
references.pmid: 17237276
references.citation: J Neurosci. 1998 Sep 15;18(18):7361-71
references.pmid: 9736656
references.citation: J Neuroimmunol. 1990 May;27(2-3):229-37
references.pmid: 2110186
references.citation: Glia. 2007 Oct;55(13):1362-73
references.pmid: 17654704
references.citation: J Neurochem. 2001 Mar;76(6):1670-8
references.pmid: 11259485
references.citation: Curr Pharm Des. 2004;10(8):879-91
references.pmid: 15032691
references.citation: J Immunol. 2004 Sep 15;173(6):3916-24
references.pmid: 15356140
references.citation: Mol Cell Biol. 2006 Jan;26(1):221-9
references.pmid: 16354693
references.citation: Cancer Res. 2005 Jun 1;65(11):4789-98
references.pmid: 15930299
references.citation: Neurosci Lett. 2006 Sep 25;405(3):168-71
references.pmid: 16857315
references.citation: Biochem Pharmacol. 2010 Feb 1;79(3):350-60
references.pmid: 19782051
references.citation: Biochem Biophys Res Commun. 2006 Dec 29;351(4):883-9
references.pmid: 17097057
references.citation: J Neurosci. 2003 Apr 15;23(8):3394-406
references.pmid: 12716947
references.citation: Biochem Pharmacol. 2008 Oct 15;76(8):967-73
references.pmid: 18755157
references.citation: Free Radic Biol Med. 2009 Aug 1;47(3):300-6
references.pmid: 19410644
references.citation: J Clin Biochem Nutr. 2009 Jan;44(1):79-84
references.pmid: 19177192
references.citation: Free Radic Biol Med. 2001 Feb 15;30(4):389-92
references.pmid: 11182294
references.citation: Inflamm Res. 2010 Jun;59(6):443-50
references.pmid: 19924513
references.citation: J Neuroimmunol. 1995 Dec 31;63(2):163-74
references.pmid: 8550814
references.citation: Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4288-93
references.pmid: 16857804
references.citation: J Neurosci. 2004 Feb 4;24(5):1101-12
references.pmid: 14762128
references.citation: Glia. 2005 Oct;52(1):78-84
references.pmid: 15920727
references.citation: J Neurochem. 2002 Jun;81(6):1233-41
references.pmid: 12068071
references.citation: Cancer Res. 2008 Apr 15;68(8):2920-6
references.pmid: 18413761
references.citation: J Immunol. 2008 Jul 1;181(1):680-9
references.pmid: 18566435
references.citation: Cancer Res. 2007 Mar 15;67(6):2414-9
references.pmid: 17363558
references.citation: Dev Dyn. 1992 Jul;194(3):209-21
references.pmid: 1467557