title: Memory-enhancing and brain protein expression-stimulating effects of novel calcium antagonist in Alzheimer's disease transgenic female mice.
abstract: The prevalence of Alzheimer's disease (AD) is higher in females than in males, and causes more severe cognitive, memory and behavioral impairments. Previously, in male transgenic (Tg) APPSweDI mice, we reported that the novel lipophilic 1,4-dihydropyridine (DHP) derivative AP-12 crossed the blood-brain barrier, blocked neuronal and vascular calcium channels, changed brain protein expression and improved behavior. In this study, we used female Tg APPSweDI mice to assess the effects of AP-12 on behavior, and brain protein expression, with a particular focus on those of the GABAergic system. The results showed that in female Tg mice, similar to male Tg mice, AP-12 improved spatial learning/memory performance in the water maze test and demonstrated anxiolytic effect in the elevated zero maze (after single administration of AP-12) and elevated plus maze (after chronic injections of AP-12). In addition, we demonstrated upregulated expression of glutamate decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) in the cingulate cortex and hippocampus, pointing to the role of the GABAergic system as one of the neural networks dysregulated in AD. In both female and male mice, AP-12 did not change the expression of hippocampal Homer-1, a protein which is involved in synaptic plasticity. However, in cingulate cortex, the staining density of Homer-1 was significantly increased in female mice. Further, female mice (similar to male mice) did not show changes in brain AChE expression and in the amyloid beta load in the hippocampus and cingulate cortex. In conclusion, the memory enhancing, anxiolytic and protein expression effects of AP-12 did not show sex specificity in APPSweDI mice. Considering the ability of AP-12 to block brain calcium channels and improve memory by enhancing the GABAergic and synaptic plasticity processes, AP-12 is a promising compound which merits further pre-clinical studies to investigate its usefulness in the treatment of AD.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Latvia, Riga, Latvia. Electronic address: baiba.jansone@lu.lv.
authors.forename: Baiba
authors.initials: B
authors.lastname: Jansone
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Inga
authors.initials: I
authors.lastname: Kadish
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
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: 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: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006179:Gyrus Cinguli / Q000187:drug effects* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D014151:Anti-Anxiety Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C038806:1,4-dihydropyridine; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D002118:Calcium
keywords: 1,4-Dihydropyridine derivative; Alzheimer’s disease; Anxiolytic effect; Memory; Mice; Protein expression