Objective To investigate the neuroprotective effect of rhein（RHE）on ischemic mice and its potential mechanism of reducing inflammatory response and neuronal apoptosis by inhibiting Notch/nuclear factor(NF)-κB signaling pathway.

Methods The classical middle cerebral artery occlusion (MCAO) method  was used to construct ischemic stroke mouse models. The mice were randomly divided into 5 groups including the sham operation group (sham), the model group (MCAO), the MCAO+edaravone group (Eda), the MCAO+RHE-treated group (RHE), and the MCAO+RHE+Notch activitor Jagged 1 group (RHE+J). Each group has 18 mice. The Bederson scoring system, balance beam walking test and accelerated rotating rod test were used to assess the neurological function and locomotor ability of mice in each group. 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin eosin staining, and TUNEL method  were used to assess cerebral infarction, hippocampal morphological damage, and neuronal apoptosis. ELISA was used to analysis the levels of interleukin (IL)-6 and tumor necrosis factor α (TNF-α) in hippocampal tissue. Western blotting was used to analysis caspase-3, Notch1, Hes1, and NF-κB p65 protein expression.    Results Compared with the sham group, Bederson score, balance beam score, cerebral infarct volume, IL-6 and TNF-α levels, the proportion of TUNEL-positively stained cells, caspase-3, Notch1, Hes1, and p-NF-κB p65 protein expression were significantly increased in the MCAO group, whereas the latency to fall decreased significantly (P<0.05) . Compared with the MCAO group, Bederson score, balance beam score, cerebral infarct volume, IL-6 and TNF-α levels, proportion of TUNEL-positively stained cells, caspase-3, Notch1, Hes1, and p-NF-κB p65 protein expression were significantly lower in both Eda and RHE groups, whereas the latency to fall increased significantly (P<0.05). Compared with the RHE group, Bederson score, balance beam score, cerebral infarction volume, IL-6 and TNF-α levels, the proportion of TUNEL-positively stained cells, caspase-3, Notch1, Hes1, and p-NF-κB p65 protein expression increased significantly in the RHE+J group, whereas the latency to fall decreased significantly (P<0.05).   Conclusion Rhein can significantly improve nerve function in ischemic mice by inhibiting Notch/NF-κB signaling pathway activation, suggesting that rhein has potential clinical application value.