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

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.

The Antidepressant Activity of a Taurine-Containing Derivative of 4-Phenylpyrrolidone-2 in a Model of Chronic Unpredictable Mild Stress

“…For example, in rats with ethanol-induced CNS depression, taurine was found to increase sleep time, and in a CUMS model, taurine administration reduced anxiety and restored sucrose intake [28,29]. Using a "silyl" method for N-alkylation of lactams, we synthesized Compound I, which incorporates a taurine residue [9,30].…”

“…It is involved in membrane stabilization, osmoregulation, neuroprotection, and neuronal proliferation. We have previously shown that Compound I crosses the blood-brain barrier, accumulates in the cerebral cortex, and positively affects the rate of neurologic deficit elimination in an animal model of ischemic stroke [9].…”

“…Dep_C1 (Compound_ I Dep_C1)-n = 12, therapy with Compound I 125 mg/kg (IP administration), 14 days [9,10].…”

Pyridine Carboxamides Based on Sulfobetaines: Design, Reactivity, and Biological Activity

“…For many years, our group has focused on discovering and developing new heterocyclic compounds that have nootropic, anti-inflammatory, and antidepressant activities. Our main goal is to develop effective medications for treating cognitive impairments, including ischemic stroke and its complications [ 1 , 2 , 3 , 4 ]. The recent COVID-19 pandemic highlighted the emerging need for these kinds of therapeutic agents.…”

New lactam-containing benzenesulfonamides: design, synthesis, and in silico and in vitro studies

“…Preclinical trails of the new 4-phenylpyrrolidone derivative containing the taurine moiety have been completed to the present time. 7 It is assumed that the biological activity of the considered compounds is due to their structural similarity with γ-aminobutyric acid, the neuromediator of central nervous system retardation. 8 The "silyl method" 9 turned out to be a very promising method for synthesis of N-substituted lactams.…”