Hydroxysafflor Yellow A Together with Blood–Brain Barrier Regulator Lexiscan for Cerebral Ischemia Reperfusion Injury Treatment

[Image: see text] Pharmacodynamic and biodistribution effects are two important factors in drug research. As a clinical drug, the neuroprotective effects and mechanisms of hydroxysafflor yellow A (HSYA) have been widely reported but have still not been described in enough detail. In this study, we first aimed to improve the pharmacology of HSYA in nerve injury treatments. The down-regulative expression of cytokines, including NLRP3, ASC, Caspase-1, GSDMD, IL-1β, IL-18, LDH, NF-κB, and p-p56, suggested that HSYA could both suppress pyroptosis and apoptosis pathway activation during the nerve injury. Additionally, HSYA improved the cellular viability in an oxidative stress damage cell model. Second, to further improve the therapeutic effect of the HSYA, we tried to enhance the concentration of HSYA in a lesion. The FDA-approved adenosine receptor agonist Lexiscan (Lex) could inhibit the expression of P-glycoprotein on the endothelial cell surface to transiently increase the permeability of the blood–brain barrier (BBB) without any sustained damage, which was used to assist HSYA in passing through the BBB to increase the accumulation in the brain. Furthermore, living image and distribution detection in vivo showed that the accumulation of HSYA in the brain could be significantly increased with the addition of Lex. Lastly, HSYA together with Lex (Lex-HSYA) could significantly reduce the volume of cerebral infarction, improve the histopathological morphology, and recruit brain-derived neurotrophic factors to alleviate the cerebral ischemia reperfusion injury. In conclusion, the pyroptosis pathway could act as a novel therapeutic target of HSYA in nerve injury treatment, and Lex-HSYA could be a promising candidate for nerve injury treatments.