Inhibition of amyloid beta protein aggregation and neurotoxicity by rifampicin. Its possible function as a hydroxyl radical scavenger.
Aggregation of physiologically produced soluble amyloid beta protein (Abeta) to insoluble, neurotoxic fibrils is a crucial step in the pathogenesis of Alzheimer's disease. Aggregation studies with synthetic Abeta1-40 peptide by the thioflavin T fluorescence assay and electron microscopy and cytotoxicity assays using rat pheochromocytoma PC12 cells showed that an antibiotic, rifampicin, and its derivatives, which possess a naphthohydroquinone or naphthoquinone structure, inhibited Abeta1-40 aggregation and neurotoxicity in a concentration-dependent manner. Hydroquinone, p-benzoquinone, and 1,4dihydroxynaphthalene, which represent partial structures of the aromatic chromophore of rifampicin derivatives, also inhibited A beta1 40 aggregation and neurotoxicity at comparable molar concentrations to rifampicin. Electron spin resonance spectrometric analysis revealed that the inhibitory activities of those agents correlated with their radical-scavenging ability on hydroxyl free radical, which was shown to be generated in cell-free incubation of Abeta1-40 peptide. These results suggest that at least one mechanism of rifampicin-mediated inhibition of A beta aggregation and neurotoxicity involves scavenging of free radicals and that rifampicin and/or appropriate hydroxyl radical scavengers may have therapeutic potential for Alzheimer's disease.
Tomiyama
T
T
Teijin Institute for Biomedical Research, 4-3-2 Asahigaoka, Hino, Tokyo 191, Japan.
Shoji
A
A
Kataoka
K
K
Suwa
Y
Y
Asano
S
S
Kaneko
H
H
Endo
N
N
D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004578:Electron Spin Resonance Spectroscopy; D016166:Free Radical Scavengers / Q000494:pharmacology* / Q000627:therapeutic use; D017665:Hydroxyl Radical; D008854:Microscopy, Electron; D009420:Nervous System / Q000187:drug effects; D016716:PC12 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D012293:Rifampin / Q000494:pharmacology* / Q000627:therapeutic use
D016229:Amyloid beta-Peptides; D016166:Free Radical Scavengers; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D017665:Hydroxyl Radical; D012293:Rifampin