Assessing the cognitive‐enhancing effect of desformylflustrabromine in rat model of Aβ‐induced cognitive impairment

Accumulation of β‐Amyloid peptides (Aβ)‐containing plaques, perturbation of the neocortical cholinergic pathways, and loss of brain acetylcholine receptors (AChR) are hallmark characteristics of Alzheimer's disease (AD). Several AChR subtypes are expressed in the cortex and the hippocampus and play essential role in learning, memory, and neuronal survival during ageing. Indeed, three out of the only four FDA‐approved drugs for AD are inhibitors of acetylcholinesterase, the enzyme responsible for ACh degradation. In addition, stimulation of α4β2 nAChRs have been shown to protect against Aβ1‐42‐induced cell death in cultured cortical neurons and to improve working memory and cognition in abstinent smokers. Because drugs that enhance the α4β2 nAChR would be beneficial for the treatment of the cognitive decline associated with many neuropathologies including AD, we focus on selective targeting of the α4β2 nAChR using positive allosteric modulators (PAM). PAMs of nAChR enhance ACh signaling without alteration of cholinergic transmission due to the prolonged activation and desensitization of nAChRs seen with agonists. In this study, we examine the cognitive‐enhancing effect of the α4β2 nAChRs PAM, desformylflustrabromine (dFBr), in a rat model of cognitive impairment. dFBr isolated originally from the marine bryozoan Flustra foliacea then its chemical synthesis and interaction with nAChRs in vitro were illustrated. In two‐electrode voltage clamp recording from Xenopus oocyte, dFBr potentiated ACh‐induced currents of low‐sensitivity (α4)3(β2)2 and high‐sensitivity (α4)2(β2)3 nAChRs maximally by ~300 and ~400% and with IC 50 s of ~0.4 and ~2 μM, respectively. In preliminary study, we tested the effect of two daily treatments of 10 mg/kg dFBr on rats' performance in passive avoidance test measured 10 days after intracerebroventricular (ICV) injection of vehicle (sham) or Aβ1‐42. dFBr treatment increased retention time (the time spent in the light compartment before entering the dark compartment that is associated with mild foot shock) in both naive (sham injected) and rats with AD‐like cognitive impairment (Aβ1‐42 injected). Experiments are in progress to evaluate the effects of dFBr on rats' performance in other learning and memory paradigms such as the 8‐arm radial maze. Support or Funding Information University of Texas System Rising STARs Program Fund This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .