Preclinical Characterization of Antioxidant Quinolyl Nitrone QN23 as a New Candidate for the Treatment of Ischemic Stroke

Abstract

Nitrones are encouraging drug candidates for the treatment of oxidative stress-driven diseases such as acute ischemic stroke (AIS). In a previous study, we found a promising quinolylnitrone, QN23, which exerted a neuroprotective effect in neuronal cell cultures subjected to oxygen–glucose deprivation and in experimental models of cerebral ischemia. In this paper, we update the biological and pharmacological characterization of QN23. We describe the suitability of intravenous administration of QN23 to induce neuroprotection in transitory four-vessel occlusion (4VO) and middle cerebral artery occlusion (tMCAO) experimental models of brain ischemia by assessing neuronal death, apoptosis induction, and infarct area, as well as neurofunctional outcomes. QN23 significantly decreased the neuronal death and apoptosis induced by the ischemic episode in a dose-dependent manner and showed a therapeutic effect when administered up to 3 h after post-ischemic reperfusion onset, effects that remained 11 weeks after the ischemic episode. In addition, QN23 significantly reduced infarct volume, thus recovering the motor function in a tMCAO model. Remarkably, we assessed the antioxidant activity of QN23 in vivo using dihydroethidium as a molecular probe for radical species. Finally, we describe QN23 pharmacokinetic parameters. All these results pointing to QN23 as an interesting and promising preclinical candidate for the treatment of AIS.

Development of Pharmacological Strategies with Therapeutic Potential in Ischemic Stroke

“…The obtained results (Figure 7c) showed a significant decrease in neuronal degeneration (Fluoro-Jade B) and apoptosis-positive cells when 2.0 mg/kg of QN23 was administered intravenously up to 3 h post-ischemia-reperfusion onset. The functional evaluation results are in accordance with the findings obtained using the staining techniques, achieving a significant reduction in neurodeficit values in the animals treated up to 3 h after the ischemic insult [45]. (d) Study of the long-term effect of QN23 after cerebral ischemia-reperfusion using the neuronal viability assessment.…”

“…A power analysis (see above) provided a sample size of six subjects per group, and seven animals were used for each experimental group, except for QN23 4.0 mg/kg, which included five animals because of death within the first 24 h after the procedure. Thus, and in accordance with the results obtained from two independent laboratories, a dose of 2.0 mg/kg was selected for further QN23 characterization [45].…”

“…The results obtained in these studies encourage the suggestion of QN23, a candidate with an improved neuroprotective effect relative to RP19 and improved pharmacological characteristics, as our new quinolylnitrone lead. Subsequent preclinical studies for the in-depth biological characterization of QN23 were reported in 2022 [45] with a study of the dose-response relationship after intravenous administration (note that previous in vivo experiments (Figure 6 [44]) were carried out with intraperitoneal administration) in both transient global and focal (tMCAO) cerebral ischemia experimental models. The results shown in Figure 7a show that, within the tested range (1.0-2.5 mg/kg), a dose of 2.0 mg/kg was the one that produced the most significant decrease in neuronal death (as observed via Fluoro-Jade B; Figure 7a) and apoptosis-positive cells (as observed via the TUNEL assay; Figure 7a), both in the cortex and CA1 hippocampal regions.…”

“…Figures were reprinted (adapted) with permission from Antioxidants. Copyright 2022 by the authors [45].…”

Flavonoid-Conjugated Gadolinium Complexes as Anti-Inflammatory Theranostic Agents

“…Furthermore, as highly water-soluble agents, gadolinium compounds can enhance the solubility of flavonoids, which is an important consideration, as the solubility of drug candidates, including theranostic agents, is among the pivotal physicochemical properties of drugs [ 14 ]. Indeed, candidate drugs are commonly required to have solubilities of approximately 10 µM for preclinical evaluation [ 15 ]. Consequently, gadolinium compounds are considered good candidates for enhancing the solubility of flavonoids to optimize theranostic agents as promising drug candidates.…”