title: 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.affiliation: Key Laboratory of Brain Functional Genomics, Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics (MOE & SBFG), East China Normal University, Shanghai 200062, PR China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.forename: Liguo
authors.initials: L
authors.lastname: Yang
authors.forename: Jingjing
authors.initials: J
authors.lastname: Su
authors.forename: Yan
authors.initials: Y
authors.lastname: Niu
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Lei
authors.forename: Juan
authors.initials: J
authors.lastname: Xiong
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Cao
authors.forename: Yinghe
authors.initials: Y
authors.lastname: Hu
authors.forename: Bing
authors.initials: B
authors.lastname: Mei
authors.forename: Jin-Feng
authors.initials: JF
authors.lastname: Hu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein; D051379:Mice; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000627:therapeutic use*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D053764:Presenilin-1 / Q000235:genetics; D053766:Presenilin-2 / Q000235:genetics; D011725:Pyridines / Q000737:chemistry* / Q000627:therapeutic use*; D013830:Thiadiazoles / Q000737:chemistry* / Q000627:therapeutic use*; D016875:tau Proteins / Q000378:metabolism
chemical_list: C533736:3-(3-(3-florophenyl-2-propyn-1-ylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6- tetrahydro-1-methylpyridine oxalate; D005904:Glial Fibrillary Acidic Protein; D018721:Muscarinic Agonists; D009419:Nerve Tissue Proteins; D053764:Presenilin-1; D053766:Presenilin-2; C095101:Psen2 protein, mouse; D011725:Pyridines; D013830:Thiadiazoles; C528900:glial fibrillary astrocytic protein, mouse; D016875:tau Proteins; C075257:xanomeline