Chronic peripheral administration of somatostatin receptor subtype-4 agonist NNC 26-9100 enhances learning and memory in SAMP8 mice

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 ¹³¹I-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.