Reduction of Abeta42 in brains of transgenic APPswe mice by 2-3-chlorophenylaminophenylacetate.
1. Imbalanced generation of the Abeta42 peptide from the amyloid beta protein precursor (APP) is implicated in the pathogenesis of Alzheimer's disease. 2. The present study is the first to evaluate the ability of 2-[3-chlorophenylamino]phenylacetic acid (GLY-230), a new drug in clinical development for the treatment of vascular complications of diabetes, to modulate Abeta42 levels in transgenic mice expressing APP. 3. Oral administration of 7.5 mg/kg GLY-230 twice a day for 14 days to APPswe transgenic mice aged 3 months significantly reduced brain Abeta42 and increased plasma Abeta42 levels by 50 and 20%, respectively. 4. GLY-230 readily entered the brain after administration of a dose (7.5 mg/kg) that decreased brain Abeta42. 5. These results are the first to demonstrate that GLY-230, which exhibits antiglycation but no cyclo-oxygenase inhibitory properties, lowers brain Abeta42 levels in this experimental model of Alzheimer's disease.
Cohen
Margo P
MP
Glycadia Inc., Philadelphia, Pennsylvania 19103, USA. drmpcohen@aol.com
Shearman
Clyde W
CW
D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism*
C518289:2-(3-chlorophenylamino)phenylacetic acid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D004008:Diclofenac