Abstract Body: Introduction
Recent advances in brain cytoprotection therapies following cerebral ischemia-reperfusion (I/R) injury have become an emerging interest. Our previous study has shown the great potency of Edaravone Dexborneol (Eda.B), the latest generation multitarget cytoprotective agent, in alleviating I/R injury, while the mechanism warrants further investigation. Pericytes play important roles in protecting blood-brain barrier (BBB) integrity and regulating haemodynamics. This study aims to explore of Eda.B's protective effect on pericyte injury after I/R and its underlying mechanisms.
Methods
The rat transient middle artery occlusion (t-MCAO) 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, BBB disruption was assessed using Zea-Longa scoring, TTC staining, and Evans Blue extravasation, respectively. Basement membrane (BM) edema and pericyte coverage were assessed by transmission electron microscopy (TEM). The expression levels of pericyte marker proteins NG2 and PDGFR-β in the ischemic zone, BBB transcellular transport-related proteins VTN, α5, PDGFB were detected by western blot. Furthermore, a high-affinity monoclonal antibody against PDGFB, MOR8457, was used to explore Eda. B’s protectiveness on pericytes injury via PDGFB/PDGFR-β (Eda.B+MOR8457, n=8).
Results
Eda.B significantly reduced cerebral infarct volume and promoted neurological function recovery, and showed more significant promotion compared to tMCAO group, Eda group and Dexbornrol group. Additionally, Eda.B significantly reduced the BBB leakage, decreased pericyte coverage, the number of endotheliocytes (EC) vesicles, and the extent of BM edema than the other groups. Furthermore, Eda.B inhibited the downregulation of NG2, PDGFB/PDGFR-β, VTN, and the upregulation of α5 protein expression, which were induced after I/R. Blocking PDGFB with MOR8457 after receiving Eda.B indicated that, Eda.B improved pericyte loss and BBB permeability by activating PDGFB/PDGFR-β signaling.
Conclusions
This study unravels new insights into mechanisms of pericyte as a promising therapeutic target and Eda.B’s protectiveness against pericytes loss and BBB permeability after I/R injury.