Novel Sigma Receptor Dual Modulator Enhances Memory Behavior in the Senescence-Accelerated Prone Mouse (SAMP8) Model of Age-Related Cognitive Decline

Abstract

<b>Abstract ID 52588</b> <b>Poster Board 214</b> Alzheimer’s disease (AD) is the leading cause of dementia, affecting nearly 50 million people worldwide. Despite an increased understanding of AD pathogenesis, the search for viable disease-modifying therapeutics continues. Sigma-1 and sigma-2 receptors, which are found in regions of the brain highly affected by AD, present novel targets with disease-modifying potential. While little is known about the mechanism of action of the sigma receptors, they are proposed to be involved with the regulation of many AD hallmarks. Investigations of sigma-1 receptor and sigma-2 receptor modulators have independently shown to improve learning and memory behaviors, as well as reduce neuroinflammation and amyloid-beta brain levels in AD mouse models (Antonini et&nbsp;al., <i>Journal of Alzheimer’s Disease</i>, <i>24</i>(3), 569–586, 2011; Izzo et&nbsp;al., <i>PLoS ONE</i>, <i>9</i>(11), 2014) . Herein, we investigated a novel molecule (BBZI) with high receptor affinity for both sigma-1 (Ki = 0.8nM) and sigma-2 (Ki=2.5nM) receptors as to learning and memory behavioral responses with chronic dosing in the senescence-accelerated prone mouse (SAMP8) model of age-related cognitive decline and AD. Twelve-month old SAMP8 were treated with BBZI over 28-days, i.p. daily dosing (0.001, 0.01, 0.1, 1.0, and 10 mg/kg) and vehicle controls. Testing battery included investigation of locomotion and anxiety through the open field activity test (day 15) and the elevated plus test (days 16-17), Y-maze for short term spatial memory (day 22), novel object recognition to test recognition memory (days 23-24), and the T-maze foot-shock avoidance test for long term spatial memory (days 20 &amp; 27). The results indicated there is no difference in distance traveled or level of anxiety like behavior across the dosing groups as indicated by the open field activity test and the elevated plus test, respectively. There was also no significant improvement in Y-maze tested spatial memory or recognition memory as indicated novel object recognition test results. However, the T-maze foot-shock avoidance test results indicated BBZI treatment of 1.0 mg/kg with i.p. injection displayed significant positive results with acquisition learning testing (9.25 +/- 0.91 trials to first avoidance, p &lt; 0.05) and retention memory testing (6.42 +/- 0.84 trials to criterion, p &lt; 0.001). Additionally, BBZI treatment of 0.1 mg/kg with i.p. injection yielded positive results with retention memory testing (8.46 +/- 0.86 trials to criterion, p &lt; 0.05). Our study revealed that at the doses specified, BBZI promotes enhanced long term memory effectiveness with the T Maze foot-shock avoidance test in a mouse model of AD, while having no impact on general activity or anxiety. This corroborates the hypothesis of sigma receptors’ involvement in learning and memory behaviors and further supports the potential of Sigma receptor target therapeutics for AD treatment.