Study of the new 4-phenylpyrrolidinone-2 derivative pharmacokinetics and neuroprotective effect in the ischemic stroke animal model

D.A Borozdenko,D.N Lyakhmun,D.V Tarasenko,Ya.V Golubev,N.M Kiseleva,V.V Negrebetsky

doi:10.24075/brsmu.2020.010

D.A Borozdenko, D.N Lyakhmun + Show 4 more

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https://doi.org/10.24075/brsmu.2020.010

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Abstract

The development of methods of drug therapy and rehabilitation in different periods of ischemic cerebral lesion is currently an urgent problem. Our study was aimed to investigate the pharmacokinetics and anti-ischemic effect of the new 4-phenylpyrrolidone-2 derivative in rats. To study the drug pharmacokinetics, the Wistar rats were once administered with the substance at a dose of 250 mg/kg, then, the substance distribution in blood and cerebral cortex was evaluated. Elimination half-life value was determined, which was 83.2 min. The substance remained in the brain tissue for 24 hours. To assess the anti-ischemic effect, the stroke was modeled by endovascular middle brain artery transition occlusion, and the drug was administered intravenously for 5 days at two doses, 250 and 125 mg/kg. After that the lesion focus volume was evaluated by MRI, as well as the neurological deficit severity, locomotor and explorative behavior. The studied drug significantly decreased the neurological deficit in model animals compared to control group (1.72 vs 4.4, p < 0.05). According to the MRI data, the effect on the ischemic focus was negligible, while the explorative behavior significantly increased under the influence of the 4-phenylpyrrolidone-2 derivative (hole board test, horizontal activity 12.1 ± 6.8, 22.5 ±10.5, p < 0.05). The data obtained allow us to conclude that the studied substance penetrates the blood-brain barrier (BBB), and accumulates in the brain tissue promoting the neurological deficit correction and increasing the explorative behavior in the ischemic stroke model animals.

Highlights

Stroke is the second leading cause of death in Russia, by the number of cases it follows the myocardial infarction
In the Department of Medical Chemistry and Toxicology of the Institute of Translational Medicine of Pirogov Russian National Research Medical University the new compound has been synthesized, which contains 4-phenylpyrrolidone-2 derivative as a pharmacophore [6]
The VRF_11 pharmacokinetics study results (Table 4) allow us to state that the drug penetrates the blood-brain barrier (BBB) and remains in the cerebral cortex during the day

Summary

Introduction

Stroke is the second leading cause of death in Russia, by the number of cases it follows the myocardial infarction. Thrombolytic therapy has proven pharmacological efficacy in the acute period of ischemic stroke, but it has a whole range of restrictions, the main of which is a narrow time interval. 5% of patients with acute ischemic stroke receive the thrombolytic therapy [1]. Rehabilitation therapy covers a much wider time interval, measured in weeks and months, so many researchers develop drugs in the context of rehabilitation medicine. To confirm the anti-ischemic effect of the new substance it was necessary to define the dose regimen and to estimate the main pharmacokinetic parameters. The study was aimed to investigate the VRF_11 pharmacokinetics and to deduce the most effective dose regimen for the correction of neurological symptoms in the rat model of focal cerebral ischemia. Concentration of the substance in the blood plasma and brain tissue was determined at different time points.

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