J Alzheimers Dis. 2009 Jul 20; Hou Y, Yu YB, Liu G, Luo YSubstantial evidence supports a central role of Abeta in the pathogenesis of Alzheimer's disease (AD). We have demonstrated that FLZ, a synthetic cyclic analogue of natural squamosamide, exhibits neuroprotective actions in cells and mouse models, suggesting future investigation of FLZ as a candidate compound for the treatment of AD. In this study, we found that production of amyloid-beta (Abeta) was reduced by FLZ in Abeta-expressing neuroblastoma cells, which correlates with an increase in the soluble alpha-secretase derived fragment of the amyloid-beta protein precursor (sAbetaPPalpha) in the medium. Moreover, the active form of ADAM10 and AbetaPP were elevated at the cell surface of FLZ-treated cells, consistent with an enhanced co-localization of ADAM10 and AbetaPP on the membrane. Pretreatment with brefeldin, a protein trafficking inhibitor, blocked FLZ-induced translocation of ADAM10 to the cell surface and release of sAbetaPPalpha to the culture medium. Furthermore, oral administration of FLZ to APPswe/PS1 transgenic mice significantly reduced the levels of Abeta, parallel with activation of ADAM10, in the hippocampus. In silico prediction indicates that the structure of FLZ agree with the drug-like rules for absorption and permeability. These findings suggest that reducing Abeta production by FLZ may be mediated by its promotion of AbetaPP non-amyloidogenic alpha-secretase processing, and FLZ has therapeutic potential for the treatment of AD.

Zhongguo Zhong Yao Za Zhi. 2009 Mar; 34(6): 766-9Yan H, He W, Li X, Nie C, Wang L, Li X, Wu L, Tu POBJECTIVE: To establish a HPLC method to determine the carnosic acid in the stomach and intestine of rats and study its tissue distribution characteristics. METHOD: After intragastric administration of carnosic acid (90 mg x kg(-1)), rats for each time-point were sacrificed by decapitation. After removal of the blood, various tissues were rapidly removed and weighted, all tissues were treated with a series of pretreatment before HPLC. Chromatographic separation was achieved on a Kromasil C18 column (4.6 mm x 150 mm, 5 microm) protected by an ODS guard column at 25 degrees C, using acetonitrile-0.1% phosphoric acid solution (55:45) as mobile phase, at a flow rate of 1 mL x min(-1). The wavelength of the UV detector was set at 210 nm for carnosic acid and internal standard. RESULT: Good linearities were obtained in every tissue over a range of 0.3212-160.6 mg x L(-1). The recovery, intra-day and inter-day precision and accuracy of three concentrations of carnosic acid in tissues met the requirements of methodology. And the stability of the tissue samples were also validated. The results of distribution in stomach and intestine showed that the highest concentration was (307.1 +/- 119.2) microg x g(-1) in stomach and (33.32 +/- 17.70) microg x g(-1) in intestine after intragastric administration of carnosic acid. CONCLUSION: The HPLC method was established to determine the concentration of carnosic acid in tissues. This method is quick, precise, and reproducible. It is the first time to study the tissue distribution of carnosic acid in rats after intragastric administration.