E1R, a novel positive modulator of sigma 1 receptors, attenuates scopolamine-induced cognitive impairment in mice

Liga Zvejniece1, Baiba Shvalbe1, Reinis Vilskersts1, Rudolfs Mezhapuke1, Maksims Vorona1, Grigorijs Veinbergs1, Ilga Misane2, Ilmars Stonans2, Ivars Kalvinsh1, Maija Dambrova1. 1Latvian Institute of Organic Synthesis, Aizkraukes Str 21, Riga LV1006, Latvia, 2JSC Grindeks, Krustpils Street 53, Riga LV1057, Latvia

Background. The activation of sigma-1 receptors reportedly ameliorates cognitive deficits in animal models of cholinergic dysfunction used to mimic cognitive symptoms of Alzheimer’s disease. Herein, we describe a novel positive modulator of sigma-1 receptor which attenuates scopolamine-induced impairment of passive avoidance retention in mice.

Methods. Male ICR mice (23 - 25 g) and Wistar rats (230 - 250 g) were housed under standard conditions (21-23 °C, 12 h light-dark cycle) with unlimited access to standard food (Lactamin AB, Sweden) and water. A 4,5-disubstituted piracetam derivative (E1R; 5S-methyl-2-oxo-4R-phenyl- pyrrolidin-1-yl)-acetamide) was synthesized and tested in combination with sigma-1 and sigma-2 receptor agonists for sigma receptor activity in an electrically stimulated rat vas deferens. The effect of E1R on cognitive function was assessed in passive avoidance response (PAR) test in mice. E1R was administered i.p. at doses of 0.1, 1.0 and 10 mg/kg 60 min prior to the acquisition trial (an electrical foot shock: 0.1 mA/ 3s) and 24 hrs later the retention trial was performed. The effect of E1R on scopolamine-induced cognitive deficits was assessed in PAR test in mice. E1R was administered i.p. at doses of 0.5, 1.0, 5 and 10 mg/kg 60 min prior to the acquisition trial (an electrical foot shock: 0.3 mA/ 3s), scopolamine was administered s.c. at a dose of 0.3 mg/kg 20 min after E1R injection. Twenty-four h later retention trial was performed. A selective sigma-1 receptor antagonist NE-100 at a dose of 2 mg/kg was used to study the possible involvement of the sigma-1 receptor in the effects of E1R (5 mg/kg) on scopolamine-induced impairment. NE-100 was administered i.p. 20 min prior to E1R. All results were expressed as the mean ± S.E.M. of data from 12-15 mice per group. The data were evaluated by analysis of variance (ANOVA). Whenever ANOVA was significant, further multiple comparisons were made using Newman-Keuls test as the post-hoc test. The differences were considered significant when p<0.05.

Results. The addition of cumulative doses of E1R did not influence the contractions of electrically stimulated rat vas deferens. Pre-treatment with E1R significantly enhanced the effect of sigma-1 receptor selective agonist PRE-084, but had no influence on effects induced by sigma-2 receptor agonist PB28. Passive avoidance retention was dose dependently enhanced by acute administration of E1R at doses of 1 and 10 mg/kg (p<0.05). At doses of 1, 5 and 10 mg/kg, E1R significantly reversed scopolamine-induced impairment of passive avoidance retention. The effect of E1R on scopolamine-induced cognitive deficit was antagonized by the administration of the selective sigma-1 receptor antagonist NE-100 (p<0.05).

Conclusion. E1R, a novel 4,5-disubstituted derivative of piracetam, possesses significant cognition enhancing properties and efficacy against scopolamine-induced cholinergic dysfunction in mice. These effects of E1R are related to its positive modulatory action on sigma-1 receptors which might be of interest in developing new drugs for treatment of cognitive symptoms of neurodegenerative diseases.

Acknowledgement. The study was supported by the European Regional Development Fund grant No. 2010/0237/2DP/2.1.1.1.0/10/APIA/VIAA/059.