Morroniside alleviates neuroinflammation in ischemic injury by mediating microglial pyroptosis via the...

Ischemic stroke (IS) remains a major cause of global mortality and disability, with neuroinflammation driven by microglial pyroptosis representing a key pathological mechanism. This study examined the neuroprotective efficacy of morroniside-an iridoid glycoside from Cornus officinalis-in experimental model of IS, focusing on its regulation of microglial inflammasome activation, pyroptosis and associated signaling cascades. Using a transient middle cerebral artery occlusion/reperfusion (tMCAO/R) model in Sprague-Dawley rats and an oxygen-glucose deprivation/reperfusion (OGD/R) model in BV2 microglia, morroniside was administered at 270 mg/kg intragastrically in vivo and at concentrations of 1-100 μmol/L in vitro. Protein expression was assessed by Western blotting, cellular markers by immunofluorescence, cytokine levels by enzyme-linked immunosorbent assay (ELISA), and pathway alterations by transcriptomic profiling. Morroniside treatment significantly attenuated microglial activation, as evidenced by reduced ionized calcium-binding adapter molecule 1 (IBA-1) expression, and suppressed pyroptosis through downregulation of gasdermin D (GSDMD), NOD-like receptor family pyrin domain containing 3 (NLRP3), caspase-1, interleukin-1β (IL-1β), and interleukin-18 (IL-18) in both models. Transcriptomic analysis revealed marked enrichment in inflammatory and immune response pathways, with notable suppression of interleukin-17 (IL-17) signaling. Mechanistic analyses showed that morroniside concurrently suppressed IL-17 expression, nuclear factor-κB (NF-κB) phosphorylation, and NLRP3 inflammasome assembly, implicating coordinated inhibition of the IL-17/NF-κB/NLRP3 cascade. Functional in vitro assays confirmed the pathway's essential role: recombinant IL-17 partially reversed, whereas selective IL-17 blockade enhanced, morroniside-mediated suppression of pyroptosis, demonstrating that IL-17 signaling is both necessary and targetable in this cascade. Collectively, these findings identify morroniside as a regulator of IS-associated neuroinflammation that mitigates microglial pyroptosis by interrupting the IL-17/NF-κB/NLRP3 axis, underscoring its potential as a therapeutic candidate for stroke.