RT Journal Article
SR Electronic
T1 Curcumin Structure-Function, Bioavailability, and Efficacy in Models of Neuroinflammation and Alzheimer's Disease
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 196
OP 208
DO 10.1124/jpet.108.137455
VO 326
IS 1
A1 Aynun N. Begum
A1 Mychica R. Jones
A1 Giselle P. Lim
A1 Takashi Morihara
A1 Peter Kim
A1 Dennis D. Heath
A1 Cheryl L. Rock
A1 Mila A. Pruitt
A1 Fusheng Yang
A1 Beverly Hudspeth
A1 Shuxin Hu
A1 Kym F. Faull
A1 Bruce Teter
A1 Greg M. Cole
A1 Sally A. Frautschy
YR 2008
UL http://jpet.aspetjournals.org/content/326/1/196.abstract
AB Curcumin can reduce inflammation and neurodegeneration, but its chemical instability and metabolism raise concerns, including whether the more stable metabolite tetrahydrocurcumin (TC) may mediate efficacy. We examined the antioxidant, anti-inflammatory, or anti-amyloidogenic effects of dietary curcumin and TC, either administered chronically to aged Tg2576 APPsw mice or acutely to lipopolysaccharide (LPS)-injected wild-type mice. Despite dramatically higher drug plasma levels after TC compared with curcumin gavage, resulting brain levels of parent compounds were similar, correlating with reduction in LPS-stimulated inducible nitric-oxide synthase, nitrotyrosine, F2 isoprostanes, and carbonyls. In both the acute (LPS) and chronic inflammation (Tg2576), TC and curcumin similarly reduced interleukin-1β. Despite these similarities, only curcumin was effective in reducing amyloid plaque burden, insoluble β-amyloid peptide (Aβ), and carbonyls. TC had no impact on plaques or insoluble Aβ, but both reduced Tris-buffered saline-soluble Aβ and phospho-c-Jun NH2-terminal kinase (JNK). Curcumin but not TC prevented Aβ aggregation. The TC metabolite was detected in brain and plasma from mice chronically fed the parent compound. These data indicate that the dienone bridge present in curcumin, but not in TC, is necessary to reduce plaque deposition and protein oxidation in an Alzheimer's model. Nevertheless, TC did reduce neuroinflammation and soluble Aβ, effects that may be attributable to limiting JNK-mediated transcription. Because of its favorable safety profile and the involvement of misfolded proteins, oxidative damage, and inflammation in multiple chronic degenerative diseases, these data relating curcumin dosing to the blood and tissue levels required for efficacy should help translation efforts from multiple successful preclinical models. The American Society for Pharmacology and Experimental Therapeutics