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: Karin E Sandoval, Susan A Farr, William A Banks, Michael L Niehoff, John E Morley, Albert M Crider, Ken A Witt
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 654 Issue 1 Pg. 53-9 (Mar 01 2011) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 21185826 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2010 Elsevier B.V. All rights reserved.

Chemical References

• Aminopyridines
• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• NNC 26-9100
• Peptide Fragments
• Receptors, Somatostatin
• amyloid beta-protein (1-42)
• somatostatin receptor subtype-4
• Thiourea

Topics

• Aminopyridines (administration & dosage, pharmacokinetics, pharmacology)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Blood-Brain Barrier (metabolism)
• Brain (metabolism)
• Gene Expression Regulation (drug effects)
• Male
• Maze Learning (drug effects)
• Memory (drug effects)
• Mice
• Peptide Fragments (metabolism)
• Receptors, Somatostatin (agonists, genetics)
• Thiourea (administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology)
• Time Factors
• Tissue Distribution