Ethylmethylhydroxypyridine succinate (Mexidol®): Mechanisms and clinical evidence in ischemic stroke

Ethylmethylhydroxypyridine succinate (Mexidol®) is a medication whose efficacy is due to the combination of antioxidant, antihypoxic, and membrane-stabilizing effects. Ethylmethylhydroxypyridine succinate displays antioxidant activity by binding superoxide anion radicals, increasing the activity of antioxidant enzymes (superoxide dismutase and glutathione peroxidase), and activating the transcription factor NRF2. This compound also increases cellular resistance to hypoxia by supporting the mitochondrial respiratory chain under reduced oxygen tension, activating the succinate receptor (SUCNR1), and influencing the HIF1a transcription factor (doi: 10.17116/jnevro201811812287). Experimental studies have shown that ethylmethylhydroxypyridine succinate reduces neuroinflammation and apoptosis, and stimulates neuroplasticity (doi: 10.17116/jnevro2025125021107). Acute focal cerebral stroke was modeled in rats and the compound was administered intravenously, intramuscularly, and orally at three dosages. When comparing the clinical symptom severity among groups receiving the investigational drug and placebo, statistically significant reduction in symptoms was noted 24 hours after surgery, with all experimental groups showing more pronounced symptoms than the sham-operated group. Micro-CT data indicated positive dynamics with a decrease in hemorrhagic lesion size in treated animals.

In a double-blind, placebo-controlled MIR study, 304 patients in the acute and early recovery periods of ischemic stroke were randomized (ClinicalTrials.gov ID NCT06437626; doi: 10.17116/jnevro202512508240). Groups were balanced by sex, age, and anthropometric parameters. Statistically significant differences supported the efficacy of ethylmethylhydroxypyridine succinate therapy: the active drug group showed a reduction in disability (mRS scale), improved neurological functions (NIHSS), enhanced mobility (Rivermead Index), and a trend toward reduced cognitive deficits (MoCA test). Significant results favoring the drug were observed for median changes in mRS at Visit 4 (p = 0.003), NIHSS (p < 0.001), and Rivermead Index (p = 0.014). The rate of disabled patients decreased (p = 0.016), and the proportion of patients scoring 0–1 on mRS at Visit 4 increased (p = 0.002) compared with placebo. Adverse events occurred in 35 (23%) patients in both the drug and placebo groups (total 42 vs. 43 AEs, p = 1.000). The long-term sequential therapy profile in terms of safety was similar for ethylmethylhydroxypyridine succinate and placebo.

Therefore, ethylmethylhydroxypyridine succinate (Mexidol®) is viewed as a promising drug for ischemic stroke therapy.

Dr. PhD Aleksey Shchulkin is a professor of the Pharmacology Department and head of the Pharmacokinetics Laboratory at the Ryazan State Medical University, Russia. Dr. A. Shchulkin is a specialist in the fields of pharmacokinetics and neuroprotection.