TSG-6 alleviates cerebral ischemia/reperfusion injury and blood-brain barrier disruption by suppressing ER stress-mediated inflammation

Tumor necrosis factor-stimulated gene-6 (TSG-6) exhibits promising neuroprotective activity, but how it influences cerebral ischemia/reperfusion (CIR) injury remains to be established. Here, the impact of TSG-6 on the CIR-induced disturbance in the blood-brain barrier (BBB) and associated neurological degeneration was assessed, and the related molecular processes were explored. In this study, TSG-6 markedly reduced CIR-mediated increases in neurological deficit scores, decreased infarct volume, and protected against the apoptotic death of neurons in MCAO/R model rats. Similarly, TSG-6 pretreatment protected cultured neurons against OGD/R-associated neuronal death. TSG-6 also restored BBB integrity, suppressing PERK-eIF2α and IRE1α-TRAF2 pathway activation in CIR model systems, thereby inhibiting NF-κB, TNF-α, IL-1β, and IL-6. The further use of specific inhibitors of ER stress, 4-phenyl butyric acid (4-PBA), PERK (GSK2656157), and IRE1α (STF083010) demonstrated the ability of ER stress to drive inflammatory activity in the context of CIR injury i the PERK-eIF2α-NF-κB and IRE1α-TRAF2-NF-κB pathways. Consistently, the activation of ER stress using tunicamycin resulted in reversing the beneficial effects of TSG-6 on CIR-associated BBB disruption and neurological damage in vitro and in vivo. Treatment with TSG-6 can protect against CIR injury via the inhibition of ER stress-related inflammatory activity induced through the PERK-eIF2α-NF-κB and IRE1α-TRAF2-NF-κB pathways.