title: A Novel 1,4-Dihydropyridine Derivative Improves Spatial Learning and Memory and Modifies Brain Protein Expression in Wild Type and Transgenic APPSweDI Mice.
abstract: Ca2+ blockers, particularly those capable of crossing the blood-brain barrier (BBB), have been suggested as a possible treatment or disease modifying agents for neurodegenerative disorders, e.g., Alzheimer's disease. The present study investigated the effects of a novel 4-(N-dodecyl) pyridinium group-containing 1,4-dihydropyridine derivative (AP-12) on cognition and synaptic protein expression in the brain. Treatment of AP-12 was investigated in wild type C57BL/6J mice and transgenic Alzheimer's disease model mice (Tg APPSweDI) using behavioral tests and immunohistochemistry, as well as mass spectrometry to assess the blood-brain barrier (BBB) penetration. The data demonstrated the ability of AP-12 to cross the BBB, improve spatial learning and memory in both mice strains, induce anxiolytic action in transgenic mice, and increase expression of hippocampal and cortical proteins (GAD67, Homer-1) related to synaptic plasticity. The compound AP-12 can be seen as a prototype molecule for use in the design of novel drugs useful to halt progression of clinical symptoms (more specifically, anxiety and decline in memory) of neurodegenerative diseases, particularly Alzheimer's disease.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Latvia, Riga, Latvia.
authors.forename: Baiba
authors.initials: B
authors.lastname: Jansone
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Inga
authors.initials: I
authors.lastname: Kadish
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: van Groen
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Latvia, Riga, Latvia.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Beitnere
authors.affiliation: Department of Pharmacology/Toxicology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Doyle Ray
authors.initials: DR
authors.lastname: Moore
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia.
authors.forename: Aiva
authors.initials: A
authors.lastname: Plotniece
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia.
authors.forename: Karlis
authors.initials: K
authors.lastname: Pajuste
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Latvia, Riga, Latvia.
authors.forename: Vija
authors.initials: V
authors.lastname: Klusa
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D004095:Dihydropyridines / Q000494:pharmacology*; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000072233:Homer Scaffolding Proteins; D006801:Humans; D008297:Male; D008568:Memory / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D065853:Spatial Learning / Q000187:drug effects*; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D014151:Anti-Anxiety Agents; D002352:Carrier Proteins; D004095:Dihydropyridines; D000072233:Homer Scaffolding Proteins; C038806:1,4-dihydropyridine; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1