Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse

Alzheimer's and Dementia: Translational Research and Clinical Interventions - Tập 4 - Trang 37-45 - 2018
Andrew F. Teich1, Ekta Sharma2, Eliza Barnwell2, Hong Zhang1, Agnieszka Staniszewski1, Tadanobu Utsuki2, Vasudevaraju Padmaraju2, Cheryl Mazell2, Apostolia Tzekou3, Kumar Sambamurti2, Ottavio Arancio1, Maria L. Maccecchini3
1Department of Pathology and Cell Biology, Taub Institute, Columbia University, New York City, NY, USA
2Department of Neurosciences and Ophthalmology, Medical University of South Carolina, Charleston, SC, USA
3QR Pharma Inc., Berwyn, PA, USA

Tóm tắt

AbstractIntroductionTranslational inhibition of amyloid precursor protein (APP) by Posiphen has been shown to reduce APP and its fragments in cell culture, animal models, and mildly cognitively impaired patients, making it a promising drug candidate for the treatment of Alzheimer's disease.MethodsWe used a mouse model of Alzheimer's disease (APP/presenilin‐1) to examine Posiphen's efficacy, pharmacodynamics, and pharmacokinetics.ResultsPosiphen treatment normalized impairments in spatial working memory, contextual fear learning, and synaptic function in APP/presenilin‐1 mice, without affecting their visual acuity, motor skills, or motivation and without affecting wild‐type mice. Posiphen had a prolonged effect in reducing APP and all related peptides for at least 9 hours after the last dose. Its concentration was higher in the brain than in plasma, and the most abundant metabolite was N8‐norPosiphen.DiscussionThis is the first study demonstrating the therapeutic efficacy of inhibiting the translation of APP and its fragments in an Alzheimer's disease model.

Tài liệu tham khảo

10.1126/scitranslmed.3002369 10.1146/annurev-neuro-061010-113613 10.1038/nature07767 10.1007/s00401-014-1347-2 10.1038/74656 10.1046/j.1471-4159.2003.02059.x 10.4161/pri.1.1.4055 10.1111/j.1471-4159.2011.07213.x 10.1212/WNL.35.7.957 10.1038/ng1718 10.1002/ana.24149 10.2174/1567205054367829 10.1124/jpet.106.112102 Mikkilineni S., 2012, The anticholinesterase phenserine and its enantiomer posiphen as 5′untranslated‐region‐directed translation blockers of the Parkinson's alpha synuclein expression, Parkinsons Dis, 2012, 142372 10.1371/journal.pone.0058752 10.1371/journal.pone.0054887 10.1073/pnas.0705346104 Lilja A.M., 2015, Neural stem cell transplant‐induced effect on neurogenesis and cognition in Alzheimer Tg2576 mice is inhibited by concomitant treatment with amyloid‐lowering or cholinergic α7 nicotinic receptor drugs, Neural Plast, 2015, 370432, 10.1155/2015/370432 Salehi A., 2008, Posiphen Treatment is Able to Reduce AAP Levels in Ts65Dn Mouse Model of Down Syndrome 10.1136/jnnp-2012-302589 10.1073/pnas.131152998 10.1196/annals.1332.003 10.1016/j.bbagen.2008.12.001 10.1074/jbc.M110.149161 Rogers J.T., 1996, The alpha‐synuclein 5′untranslated region targeted translation blockers: anti‐alpha synuclein efficacy of cardiac glycosides and Posiphen, J Neural Transm (Vienna), 2011, 493 10.3390/ijms10031226 Yu Q.S., 2013, Synthesis of the Alzheimer drug Posiphen into its primary metabolic products (+)‐N1‐norPosiphen, (+)‐N8‐norPosiphen and (+)‐N1, N8‐bisnorPosiphen, their inhibition of amyloid precursor protein, α‐Synuclein synthesis, interleukin‐1β release, and cholinergic action, Antiinflamm Antiallergy Agents Med Chem, 12, 117, 10.2174/1871523011312020003 10.1016/j.brainresbull.2011.11.017 10.1172/JCI34254 10.1016/j.ejmech.2012.12.009 10.1371/journal.pone.0091531
Thông tin
Thông tin xuất bản

Alzheimer's and Dementia: Translational Research and Clinical Interventions

Tập 4

37-45

Thông tin tác giả