A Novel Phenylpyrrolidine Derivative: Synthesis and Effect on Cognitive Functions in Rats with Experimental Ishemic Stroke

Denis A Borozdenko,Yaroslav V Golubev,Anastasia D Shagina,Ilya L Gubskiy,Maxim A Gureev,Sophia S Borisevich,Dmitri V Tarasenko,Tatiana A Shmigol,Daria D Namestnikova,Vladimir P Chekhonin,Dmitri N Lyakhmun,Elvira A Cherkashova,Darya I Gonchar,Vadim V Negrebetsky,Yuri I Baukov,Nina M Kiseleva,Leonid V Gubsky,Aiarpi A Ezdoglian,Alexey A Lagunin

doi:10.3390/molecules26206124

Abstract

We performed an in silico, in vitro, and in vivo assessment of a potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (compound 1) as a potential prodrug for cognitive function improvement in ischemic brain injury. Using in silico methods, we predicted the pharmacological efficacy and possible safety in rat models. In addition, in silico data showed neuroprotective features of compound 1, which were further supported by in vitro experiments in a glutamate excitotoxicity-induced model in newborn rat cortical neuron cultures. Next, we checked whether compound 1 is capable of crossing the blood–brain barrier in intact and ischemic animals. Compound 1 improved animal behavior both in intact and ischemic rats and, even though the concentration in intact brains was low, we still observed a significant anxiety reduction and activity escalation. We used molecular docking and molecular dynamics to support our hypothesis that compound 1 could affect the AMPA receptor function. In a rat model of acute focal cerebral ischemia, we studied the effects of compound 1 on the behavior and neurological deficit. An in vivo experiment demonstrated that compound 1 significantly reduced the neurological deficit and improved neurological symptom regression, exploratory behavior, and anxiety. Thus, here, for the first time, we show that compound 1 can be considered as an agent for restoring cognitive functions.

Highlights

Neurological disorders are one of the leading sources of premature mortality, ranking second after cardiovascular diseases, and have become the major problem in terms of the percentage of temporary or permanent disabilities among survivors [1]
We further investigated blood–brain permeability using in silico and in vivo models of middle cerebral artery occlusion (MCAO)
Afterward we studied the neuroprotective activity of the identified compound in intact and MCAO rats by looking at the activity and behavioral patterns of the animals, and accessing the neurological deficit

Summary

Introduction

Neurological disorders are one of the leading sources of premature mortality, ranking second after cardiovascular diseases, and have become the major problem in terms of the percentage of temporary or permanent disabilities among survivors [1]. Post-ischemic stroke plays a huge role in the disability level and significantly decreases the quality of life of the patients who have survived a stroke. Infarct zone formation is associated with a local and systemic immune response, including brain edema, proinflammatory cytokine activation, and brain cell apoptosis [2] All of these mechanisms are considered potential targets for new therapy. Reperfusion therapy, intravenous thrombolysis with a tissue plasminogen activator, and endovascular mechanical thrombectomy are the only available efficacious treatments [3]. These methods are not safe and have a very limited time for administration. During the COVID-19 pandemic, many neurological effects of the viral infection were described, dramatically increasing the importance of the identification of new therapeutic agents for cognitive and memory dysfunction, in post-ischemic stroke management

Methods

Results

Conclusion