Novel mechanistic insight on the neuroprotective effect of berberine: The role of PPAR8 for antioxidant action

Cerebral ischemic stroke ranks the second leading cause of death and the third leading cause of disability in lifetime all around the world, urgently necessitating effective therapeutic interventions. Reactive oxygen species (ROS) have been implicated in stroke pathogenesis and peroxisome proliferator-activated receptors (PPARs) are prominent targets for ROS management. Although recent research has shown antioxidant effect of berberine (BBR), little is known regarding its effect upon ROS-PPARs signaling in stroke. The aim of this study is to explore whether BBR could target on ROS-PPARs pathway to ameliorate middle cerebral artery occlusion (MCAO)-induced stroke. Herein, we report that BBR is able to scavenge ROS in oxidation-damaged C17.2 neural stem cells and stroked mice. PPAR8, rather than PPAR alpha or PPAR gamma, is involved in the anti-ROS effect of BBR, as evidenced by the siRNA transfection and specific antagonist treatment data. Further, we have found BBR could upregulate NF-E2 related factor-1/2 (NRF1/2) and NAD(P)H:quinone oxidoreductase 1 (NQO1) following a PPAR8-dependent manner. Mechanistic study has revealed that BBR acts as a potent ligand (Kd = 290 +/- 92 nM) to activate PPAR8 and initiates the transcriptional regulation functions, thus promoting the expression of PPAR8, NRF1, NRF2 and NQO1. Collectively, our results indicate that BBR confers neuroprotective effects by activating PPAR8 to scav-enge ROS, providing a novel mechanistic insight for the antioxidant action of BBR.

Automated summary

Cerebral ischemic stroke is a major cause of death and disability worldwide, and effective therapeutic interventions are urgently needed. This study demonstrates that berberine (BBR) can alleviate stroke by scavenging ROS and activating PPAR8, leading to the upregulation of NRF1/2 and NQO1.