title: Chronic peripheral administration of somatostatin receptor subtype-4 agonist NNC 26-9100 enhances learning and memory in SAMP8 mice.
abstract: Selective somatostatin receptor subtype agonists have been proposed as a means to mitigate learning and memory loss associated with Alzheimer's disease. The first aim of this study evaluated blood-to-brain transport and regional brain distribution of NNC 26-9100, a selective somatostatin subtype-4 (sst4) receptor agonist. The entry rate of (131)I-NNC 26-9100 was K(i)=0.25 μl/g min, with an ~93% association with the parenchymal component. The second goal of this study was to evaluate the effect of chronic NNC 26-9100 administration (i.p.) on learning and memory, brain Aβ(x-42) levels, and protein expression of sst4 receptor and amyloid precursor protein (APP) in the senescence-accelerated mouse p8 (SAMP8) model of Alzheimer's disease. Mice chronically treated with NNC 26-9100 showed improved learning (day 21) and memory (day 28) using the T-maze paradigm (20 and 200 μg). Ex vivo tissue analyses showed a decline in Aβ(x-42) levels at the 20 μg dose, while no alterations were observed in sst4 receptor or APP protein expression compared to vehicle controls. These findings indicate NNC 26-9100 is taken up into key brain regions associated with learning and memory. Furthermore, chronic administration of NNC 26-9100 improved learning and memory and decreased Aβ(x-42) brain levels. These results suggest sst4 receptor agonists may provide a viable therapy in the treatment of Alzheimer's disease and other forms of cognitive impairment.
authors.affiliation: Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, 200 University Park Drive, Edwardsville, IL 62026, USA.
authors.forename: Karin E
authors.initials: KE
authors.lastname: Sandoval
authors.forename: Susan A
authors.initials: SA
authors.lastname: Farr
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
authors.forename: Michael L
authors.initials: ML
authors.lastname: Niehoff
authors.forename: John E
authors.initials: JE
authors.lastname: Morley
authors.forename: Albert M
authors.initials: AM
authors.lastname: Crider
authors.forename: Ken A
authors.initials: KA
authors.lastname: Witt
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000235:genetics; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000631:Aminopyridines; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C115929:NNC 26-9100; D010446:Peptide Fragments; D017481:Receptors, Somatostatin; C075222:amyloid beta-protein (1-42); C098681:somatostatin receptor subtype-4; D013890:Thiourea