Nobiletin alleviates cerebral ischemic-reperfusion injury via MAPK signaling pathway

Nobiletin (NOB), isolated from Citrus nobilis, has been reported to inhibit cerebral ischemia/reperfusion (I/R) induced cell apoptosis in the brain. The mechanisms and the protective ability of NOB on cerebral I/R rats are unclear.

A middle cerebral artery occlusion (MCAO) rat model was established and treated with different doses of NOB. The neurological deficits, brain water content and brain index were explored after reperfusion, and TTC staining was applied to assess the infarct area. The production of reactive oxygen species (ROS) related enzymes in the ischemic cortex samples from each group was measured. TUNEL staining was performed to evaluate neuronal cell apoptosis in brain tissues. The expression of cell apoptosis related proteins, p-p38 and MAPKAP-2 and the levels of inflammatory factors were examined by western blotting assay and ELISA.

NOB treatment notably improved the neurological deficits, brain water content and brain index in an MCAO model, accompanied by decreased infarct area in the brain tissue. Apoptosis induced by cerebral I/R was also decreased by NOB administration via upregulating Bcl-2 and downregulating Bax and caspase3. The levels of pro-inflammatory mediators TNF-α, IL-6 were reduced and anti-inflammatory cytokine IL-10 was increased by NOB treatment in MCAO rats. Further, we found that the expression of p-p38 and MAPKAP-2 was reduced by NOB treatment in MCAO rats.

The present results suggest that NOB serves a protective role in I/R-induced cerebral-neuron injury. The mechanisms underlying these effects may be associated with the MAPK signaling pathway.