Polydatin alleviates traumatic brain injury: Role of inhibiting ferroptosis

Abstract

Secondary injury is the main cause of high mortality and poor prognosis of TBI, which has recently been suggested to be related to ferroptosis. Polydatin, a monocrystalline compound extracted from the rhizome of Polygonum, has been shown to exert potential neuroprotective effects. However, its role and mechanism in the secondary injury of TBI has not been elucidated. In this study, the inhibition of Polydatin on ferroptosis was observed both in the hemoglobin treated Neuro2A cells in vitro and in TBI mouse model in vivo, characterized by reversion of accumulation or deposition of free Fe²⁺, increased content of MDA, decreased activity of key REDOX enzyme GPx4, cell death and tissues loss. Although Polydatin corrected the increased mRNA levels of ferroptosis signaling molecules GPX4, SLC7A11, PTGS2, and ATP5G3 after TBI, TBI and Polydatin treatment had no significant effect on their protein expression. Notably, Polydatin could completely reverse the decrease of GPx4 activity after TBI in vivo and in vitro, and the effect was stronger than that of the classical ferroptosis inhibitor FER-1 in vitro. Further, Polydatin has been shown to reduce the severity of acute neurological impairment and significantly improve subacute motor dysfunction in TBI mice. Our findings provided translational insight into neuroprotection with Polydatin in TBI by inhibiting ferroptosis mainly depending on the maintenance of GPx4 activity.

Keywords: Ferroptosis; GPx4; Polydatin; TBI.