Protective effects of fraxin on cerebral ischemia-reperfusion injury by mediating neuroinflammation and oxidative stress through PPAR-γ/NF-κB pathway

Inflammation and oxidative stress are associated with the pathogenesis of cerebral ischemia-reperfusion (I/R) injury. Fraxin, one of the primary active ingredients of Cortex Fraxini, may have potent anti-inflammatory activity. This study intended to investigate the function and mechanism of fraxin in a middle cerebral artery occlusion (MCAO) model. A middle cerebral artery occlusion (MCAO) rat model was engineered. Both in-vivo and in-vitro models were dealt with Fraxin. The profiles of inflammation-concerned cytokines, proteins and oxidative stress factors were determined by RT-PCR, western blot, and enzyme-linked immunosorbent assay (ELISA), and neuronal apoptosis and reactive oxygen species (ROS) levels were measured. The neurological functions of rats were evaluated by Morris water maze and modified neurological severity scores (mNSS). The data revealed that fraxin abated the OGD/R-mediated release of inflammatory and oxidative stress mediators, enhanced “M2″-like BV2 microglia polarization, and mitigated HT22 cell apoptosis. Mechanistically, fraxin boosted PPAR-γ expression, activated the Nrf2/HO-1 pathway, and suppressed NF-κB, IKK-β，p38 MAPK, ERK1/2 and Keap1 in a dose-dependent manner. Furthermore, attenuating PPAR-γ through pharmacological treatment with GW9662 (a PPAR-γ antagonist) mainly weakened the neuroprotective and anti-inflammatory functions of fraxin. Fraxin could considerably ameliorate cerebral I/R damage by repressing oxidative stress, inflammatory response, and cell apoptosis through abrogating the PPARγ/ NF-κB pathway.