Flavonoids from Polypodium hastatum as neuroprotective agents attenuate cerebral ischemia/reperfusion injury in vitro and in vivo via activating Nrf2

Objectives: Cerebral ischemic stroke is a leading cause of death worldwide. Though timely reperfusion reduces the infarction size, it exacerbates neuronal Apoptosis due to oxidative stress. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor regulating the expression of antioxidant Enzymes. Activating Nrf2 gives a therapeutic approach to ischemic stroke.

Methods: Herein we explored Flavonoids identified from Polypodium hastatum as Nrf2 activators and their protective effects on PC12 cells injured by oxygen and glucose deprivation/restoration (OGD/R) as well as middle cerebral artery occlusion (MCAO) mice.

Results: The results showed among these Flavonoids, AAKR significantly improved the survival of PC12 cells induced by OGD/R and activated Nrf2 in a Keap1-dependent manner. Further investigations have disclosed AAKR attenuated oxidative stress, mitochondrial dysfunction and following Apoptosis resulting from OGD/R. Meanwhile, activation of Nrf2 by AAKR was involved in the protective effects. Finally, it was found that AAKR could protect MCAO mice brains against ischemia/reperfusion injury via activating Nrf2.

Discussion: This investigation could provide lead compounds for the discovery of novel Nrf2 activators targeting ischemia/reperfusion injury.

Flavonoids; MCAO mice; Nrf2; PC12 cells; apoptosis; ischemia/reperfusion injury; oxidative stress; ‌Polypodium hastatum.