Thymoquinone from Nigella sativa in Experimental Ischemic Stroke: A Systematic Review of Its Neuroprotective Effects

Introduction Ischemic stroke causes substantial mortality and disability, and effective pharmacological neuroprotection remains limited. Naturally derived compounds with multi-target activities have gained increasing attention as potential adjunctive therapies. Among them, thymoquinone, a major active constituent of Nigella sativa, has emerged as a promising candidate in experimental ischemic stroke. This review evaluated the preclinical evidence on thymoquinone as a neuroprotective agent in experimental ischemic stroke. Methods This systematic review followed PRISMA guidelines. PubMed/MEDLINE, Scopus, ScienceDirect, and Europe PMC were searched up to December 30, 2025. Eligible studies investigated thymoquinone or Nigella sativa extract in animal models of ischemic stroke and reported neuroprotective outcomes. Data on animal model, intervention, outcomes, mechanisms, and methodological quality were extracted. Risk of bias was assessed using SYRCLE’s tool. Results From 872 records, 12 preclinical studies were included. Most studies used rodent ischemic stroke models, particularly MCAO. Thymoquinone improved neurological and motor outcomes, reduced infarct volume, brain edema, oxidative stress, inflammation, apoptosis, autophagy, and blood-brain barrier disruption, and promoted neuronal survival. The main mechanisms involved activation of Nrf2/HO-1 signaling, inhibition of TLR4/NF-κB pathways, modulation of microglial polarization, mitochondrial protection, and suppression of apoptotic signaling. Risk of bias assessment showed adequate reporting mainly for baseline characteristics, incomplete outcome data, and sequence generation, while several domains remained unclear. Discussion : Thymoquinone shows promising neuroprotective effects in experimental ischemic stroke through multi-target mechanisms. However, incomplete methodological reporting, heterogeneous models, variable dosing, and pharmacokinetic limitations may affect translational reliability. Further rigorous preclinical studies with optimized delivery systems are needed before clinical development.