Attenuation of neurodegenerative phenotypes in Alzheimer-like presenilin 1/presenilin 2 conditional double knockout mice by EUK1001, a promising derivative of xanomeline.

Abstract

The M1/M4-preferring muscarinic agonist xanomeline was found to have some benefit in the treatment of the memory impairment of Alzheimer's disease (AD), but side effects precluded further development. EUK1001, a fluorinated derivative of xanomeline, because of greater affinity for M1 muscarinic receptors, is likely to have a significantly better side effect profile than xanomeline. We have now studied the effects of 3-month chronic administration of EUK1001 and xanomeline (0.5mg/kg/day) in AD-like presenilin 1/presenilin 2 conditional double knockout (PS cDKO) mice. Only EUK1001 was found to significantly ameliorate the deficit in recognition memory. Histological analysis demonstrated partial attenuation of the brain atrophy in EUK1001-treated PS cDKO mice and minimal effect in the xanomeline-treated mice. Both compounds effectively suppressed the elevation of brain tau phosphorylation in the PS cDKO mice, but neither inhibited the increased inflammatory responses. These results indicate that EUK1001 showed superiority to xanomeline with regard to attenuation of several AD-like neurodegenerative phenotypes in PS cDKO mice. These results suggest further investigation of the development of EUK1001 for the treatment of AD is indicated.

• Authors: Dong Wang, Liguo Yang, Jingjing Su, Yan Niu, Xiaoping Lei, Juan Xiong, Xiaohua Cao, Yinghe Hu, Bing Mei, Jin-Feng Hu
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 410 Issue 2 Pg. 229-34 (Jul 01 2011) ISSN: 1090-2104 [Electronic] United States
• PMID: 21651893 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• 3-(3-(3-florophenyl-2-propyn-1-ylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6- tetrahydro-1-methylpyridine oxalate
• Glial Fibrillary Acidic Protein
• Muscarinic Agonists
• Nerve Tissue Proteins
• Presenilin-1
• Presenilin-2
• Psen2 protein, mouse
• Pyridines
• Thiadiazoles
• glial fibrillary astrocytic protein, mouse
• tau Proteins
• xanomeline

Topics

• Alzheimer Disease (drug therapy, genetics, pathology)
• Animals
• Brain (metabolism)
• Disease Models, Animal
• Glial Fibrillary Acidic Protein
• Mice
• Mice, Knockout
• Muscarinic Agonists (therapeutic use)
• Nerve Tissue Proteins (metabolism)
• Phosphorylation (drug effects)
• Presenilin-1 (genetics)
• Presenilin-2 (genetics)
• Pyridines (chemistry, therapeutic use)
• Thiadiazoles (chemistry, therapeutic use)
• tau Proteins (metabolism)