title: Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer's disease.
abstract: 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-1beta. Despite these similarities, only curcumin was effective in reducing amyloid plaque burden, insoluble beta-amyloid peptide (Abeta), and carbonyls. TC had no impact on plaques or insoluble Abeta, but both reduced Tris-buffered saline-soluble Abeta and phospho-c-Jun NH(2)-terminal kinase (JNK). Curcumin but not TC prevented Abeta 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 Abeta, 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.
authors.affiliation: Department of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Aynun N
authors.initials: AN
authors.lastname: Begum
authors.forename: Mychica R
authors.initials: MR
authors.lastname: Jones
authors.forename: Giselle P
authors.initials: GP
authors.lastname: Lim
authors.forename: Takashi
authors.initials: T
authors.lastname: Morihara
authors.forename: Peter
authors.initials: P
authors.lastname: Kim
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Heath
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Rock
authors.forename: Mila A
authors.initials: MA
authors.lastname: Pruitt
authors.forename: Fusheng
authors.initials: F
authors.lastname: Yang
authors.forename: Beverly
authors.initials: B
authors.lastname: Hudspeth
authors.forename: Shuxin
authors.initials: S
authors.lastname: Hu
authors.forename: Kym F
authors.initials: KF
authors.lastname: Faull
authors.forename: Bruce
authors.initials: B
authors.lastname: Teter
authors.forename: Greg M
authors.initials: GM
authors.lastname: Cole
authors.forename: Sally A
authors.initials: SA
authors.lastname: Frautschy
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001682:Biological Availability; D003474:Curcumin / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013329:Structure-Activity Relationship
chemical_list: D003474:Curcumin