Angelicin Alleviates Maternal Isoflurane Exposure-Induced Offspring Cognitive Defects Through the Carbonic Anhydrase 4/Aquaporin-4 Pathway.

An increasing number of studies reveal the deleterious effects of isoflurane (Iso) exposure during pregnancy on offspring cognition. However, no effective therapeutic strategy for Iso-induced deleterious effects has been well developed. Angelicin exerts an anti-inflammatory effect on neurons and glial cells. This study investigated the roles and mechanism of action of angelicin in Iso-induced neurotoxicity in vitro and in vivo. After exposing C57BL/6 J mice on embryonic day 15 (E15) to Iso for 3 and 6 h, respectively, neonatal mice on embryonic day 18 (E18) displayed obvious anesthetic neurotoxicity, which was revealed by the elevation of cerebral inflammatory factors and blood-brain barrier (BBB) permeability and cognitive dysfunction in mice. Angelicin treatment could not only significantly reduce the Iso-induced embryonic inflammation and BBB disruption but also improve the cognitive dysfunction of offspring mice. Iso exposure resulted in an increase of carbonic anhydrase (CA) 4 and aquaporin-4 (AQP4) expression at both mRNA and protein levels in vascular endothelial cells and mouse brain tissue collected from neonatal mice on E18. Remarkably, the Iso-induced upregulation of CA4 and AQP4 expression could be partially reversed by angelicin treatment. Moreover, GSK1016790A, an AQP4 agonist, was used to confirm the role of AQP4 in the protective effect of angelicin. Results showed that GSK1016790A abolished the therapeutic effect of angelicin on Iso-induced inflammation and BBB disruption in the embryonic brain and on the cognitive function of offspring mice. In conclusion, angelicin may serve as a potential therapeutic for Iso-induced neurotoxicity in neonatal mice by regulating the CA4/AQP4 pathway.