Uncaria rhynchophylla exerts a neuroprotective effect against febrile seizures by inhibiting NMDAR-mediated neuronal excitability

Uncaria rhynchophylla (UR) is a traditional Chinese medicine widely used for disorders of the nervous and cardiovascular systems. Febrile seizures (FS), the most prevalent cause of seizures in young children, remain lacking effective clinical therapies. This study aimed to explore UR’s neuroprotective effect against FS-induced neuronal injury and its mechanism. We used animal behavioral to evaluate the severity of FS; hematoxylin-eosin (HE) staining, Nissl staining, and immunohistochemistry (IHC) to assess the neuroprotective effect of UR by detecting neuronal injury; molecular docking and molecular dynamics (MD) simulations to verify target binding sites; the CCK-8 assay to assess UR-mediated neuroprotection and cell viability in SH-SY5Y cells; and patch-clamp technique to analyze neuronal excitability. Results showed that UR significantly reduced the severity of FS, especially the incidence of generalized tonic-clonic seizures, and decreased neuronal necrosis and apoptosis in FS models. It also downregulated myelin formation marker MBP and glial activation marker S100β, and decreased neuronal excitability in a dose-dependent manner. UR’s active components, rhynchophylline (RHY) and isorhynchophylline (IRHY), stably bound to NMDARs, downregulated NMDAR 2A/2B subunits, and inhibited NMDAR-mediated evoked excitatory postsynaptic currents (eEPSCs). In conclusion, UR effectively protects neurons from FS-induced neurotoxicity, holding promising potential as a preventive agent for FS.