Iridoids as Multi-target Neuroprotective Agents for Ischemic Stroke: Mechanisms and Therapeutic Potential

Ischemic stroke continues to be a predominant global cause of death and long-term disability, with therapeutic options remaining notably constrained. Against this challenging backdrop, iridoids-natural monoterpenoids abundantly present in various medicinal plants-have gained significant attention as prospective neuroprotective agents for ischemic stroke. This comprehensive review systematically consolidates preclinical evidence regarding the therapeutic potential of ten representative iridoids, namely catalpol, picroside II, oleuropein, morroniside, loganin, aucubin, geniposide, cornin, gentiopicroside, and swertiamarin, utilizing data from diverse experimental stroke models. Accumulated findings reveal that these iridoid compounds mediate multi-modal neuroprotective benefits primarily through the regulation of crucial pathological cascades, such as excitotoxicity, persistent neuroinflammation, oxidative stress, apoptotic pathways, and blood-brain barrier integrity disruption. From a mechanistic standpoint, iridoids exert their influences by modulating a spectrum of vital signaling pathways, including VEGF/PI3K/Akt, Nrf2/HO-1, NF-κB, MAPK, and Bcl-2. These modulatory activities contribute to enhanced angiogenesis and neurogenesis, facilitate microglial polarization toward the protective M2 phenotype, and effectively mitigate oxidative damage and neuronal apoptosis. Given their pleiotropic mechanisms of action, iridoids constitute a highly promising class of natural scaffolds for developing innovative multi-target therapeutics for ischemic stroke. To advance their translational potential, subsequent research should emphasize structural optimization and synthetic derivatization to improve potency and pharmacokinetics. Concurrently, exploring advanced targeted drug delivery platforms appears imperative to maximize their bioavailability and brain penetration, thereby facilitating the transition of iridoid-based candidates from preclinical research to clinical application.