Edaravone Dexborneol protects against blood-brain barrier disruption following cerebral ischemia/reperfusion by upregulating pericyte coverage via vitronectin-integrin and PDGFB/PDGFR-β signaling.

BACKGROUND

Recent advancements in brain cytoprotection therapies following cerebral ischemia-reperfusion (I/R) injury have become an emerging interest. Pericytes were vulnerable during the early stages of ischemia. This study aims to explore the protective effects of Edaravone dexborneol (Eda.B) on pericyte loss, as well as and the underlying mechanisms, given its potential in alleviating I/R injury.

METHODS

The rat transient middle cerebral artery occlusion (tMCAO) model was established. Rats were randomly divided into Sham group (Sham, n = 24), tMCAO group (tMCAO, n = 24), Edaravone group (Eda, n = 24), Dexborneol group (Dexborneol, n = 24), and Eda.B group (Eda.B, n = 24). Neurological function recovery, infarct volume, and blood-brain barrier (BBB) disruption were assessed using Zea-Longa scoring, TTC staining, and Evans Blue extravasation, respectively. Alterations in Basement membrane (BM) and pericyte coverage were assessed by transmission electron microscopy (TEM). The expression levels of pericyte marker NG2 and PDGFR-β in the ischemic region, as well as BBB transcellular transport-related proteins vitronectin (VTN), α5 and PDGFB were detected by western blotting. Furthermore, a specific inhibitor of PDGFB, MOR8457, was employed (Eda.B + MOR8457, n = 8) to explore the protective effects of Eda.B on pericyte injury via PDGFB/PDGFR-β.

RESULTS

Eda.B significantly reduced cerebral infarct volume and promoted neurological function recovery in comparison to the tMCAO, Eda and Dexborneol groups. Additionally, Eda.B significantly ameliorated BBB leakage, mitigated the decrease in pericyte coverage, and reduced vesicle density in endothelial cells and BM thickness following I/R. Mechanically, Eda.B inhibited the downregulation of NG2, PDGFB/PDGFR-β, VTN, while preventing upregulation of α5 protein expression in tMCAO rats. Blocking PDGFB with MOR8457 demonstrated that Eda.B improved pericyte loss and BBB permeability by activating PDGFB/PDGFR-β signaling.

CONCLUSIONS

We elucidated that vitronectin-integrin and PDGFB/PDGFR-β signaling contributed to Eda.B's protective effects against pericyte loss and BBB permeability following I/R injury, unraveling new insights into mechanisms of pericyte as a promising therapeutic target.