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NEUROPHARMACOLOGY

Curcumin Structure-Function, Bioavailability, and Efficacy in Models of Neuroinflammation and Alzheimer's Disease

Departments of Medicine (A.N.B., M.R.J., G.P.L., P.K., F.Y., B.H., S.H., B.T., G.M.C., S.A.F.) and Neurology (G.M.C., S.A.F.) and Psychiatry and Biobehavioral Sciences and The Semel Institute (K.F.F.), University of California, Los Angeles, California; Greater Los Angeles Healthcare System, Geriatric Research Education Clinical Center, Sepulveda, California (A.N.B., M.R.J., G.P.L., P.K., F.Y., B.H., S.H., B.T., G.M.C., S.A.F.); Cancer Prevention and Control Program, Moores UCSD Cancer Center, University of California San Diego, La Jolla, California (D.D.H., C.L.R., M.A.P.); and Department of Post-Genomics and Diseases, Division of Psychiatry and Behavioral Proteomics, Osaka University Graduate School of Medicine D3, Osaka, Japan (T.M.)

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.

Address correspondence to: Dr. Sally A. Frautschy, Departments of Medicine/Neurology UCLA, Greater Los Angeles Healthcare System, VA Medical Center, Research 151, 16111 Plummer St., Sepulveda, CA 91343. E-mail: frautsch{at}ucla.edu

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