Cornel iridoid glycosides exerted neuroprotective effects against cerebral ischemia/reperfusion injury in rats via inhibiting TLR4/MyD88/NF-κB pathway.

Inflammatory response plays a key role in the pathophysiological process of Ischemic stroke. Cornel iridoid glycosides (CIG), the primary components of Cornus officinalis Sieb. et Zucc., have demonstrated a wide range of anti-inflammatory pharmacological activities. This study aimed to investigate the neuroprotective effect of CIG against cerebral ischemia/reperfusion injury and to explore its anti-inflammatory mechanisms. Sprague-Dawley rats were pre-treated with CIG at doses of 1.25, 2.5, and 5 mL/kg and then subjected to transient middle cerebral artery occlusion/re-perfusion (tMCAO/R). The effectiveness of prevention was determined based on neurological function, cerebral infarction, edema, histological changes, microglia aggregation, and induction of inflammation cytokines using hematoxylin-eosin staining, TUNEL staining, and real-time quantitative PCR. Proteins involved in the canonical nuclear factor kappa B (NF-κB) signaling pathway were analyzed using immunofluorescence, western blot, and molecular docking analysis. The results showed that CIG could dose-dependently reduce the neurological deficit score, cerebral infarction and edema, and brain cells apoptosis caused by tMCAO/R injury. Additionally, CIG significantly inhibited the aggregation of microglia and decreased levels of tumor necrosis factor-α, interleukin-1β and interleukin-6 in a dose-dependent manner. Furthermore, the tMCAO/R rats pre-treated with CIG displayed inhibition of NF-κB nuclear translocation and down-regulations on TLR4, MyD88, TRAF6, and inhibitory kappa B. Molecular docking analysis revealed that the CIG components (morroniside, loganin, and cornuside I) exhibited good affinities with protein TLR4, MyD88, and TRAF6. CIG could alleviate cerebral ischemia/reperfusion injury by inhibiting microglia aggregation and reducing the neuroinflammatory response, which targets the TLR4/MyD88/NF-κB signaling pathway. Therefore, CIG might potentially serve as a new medicine candidate for the prevention of ischemic stroke.