Authors: Malik M1, Rangel-Barajas C, Sumien N, Su C, Singh M, Chen Z, Huang RQ, Meunier J, Maurice T, Mach RH, Luedtke RR.

1University of North Texas Health Science Center, the Department of Pharmacology and Neuroscience, 3500 Camp Bowie Boulevard, Fort Worth, Texas 76107 USA.


Abstract: Background and purpose > Cognitive deficits in patients with Alzheimer’s Disease, Parkinson’s Disease, traumatic brain injury and stroke often involve alterations in cholinergic signaling. Currently available therapeutic drugs provide only symptomatic relief. Therefore, novel therapeutic strategies are needed to retard and/or arrest the progressive loss of memory.
Experimental approach > Scopolamine-induced memory impairment provides a rapid and reversible phenotypic screening paradigm for cognition enhancement drug discovery. Male C57BL/6J mice administered scopolamine (1mg/kg) were used to evaluate the ability of LS-1-137, a novel sigma-1 receptor selective agonist, to improve the cognitive deficits associated with muscarinic antagonist administration.
Key results > LS-1-137 is a high affinity (Ki = 3.2 nM) sigma-1 receptor agonist that is 80-fold selective for sigma-1 compared to sigma-2 receptor. LS-1-137 binds with low affinity at D2-like (D2, D3 and D4) dopamine and muscarinic receptors. LS-1-137 was found to partially reverse the learning deficits associated with scopolamine administration using a water maze test and an active avoidance task. LS-1-137 treatment was also found to trigger the release of BDNF from rat astrocytes.
Conclusions and implications > The sigma-1 receptor selective compound such as LS-1-137 may represent a novel candidate cognitive enhancer for the treatment of cholinergic muscarinic-dependent cognitive deficits.

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