ABSTRACT NUMBER: ESOC2026LB183 TARGETING HRI KINASE TO PROMOTE NEUROPROTECTION FOLLOWING CEREBRAL ISCHEMIA

Abstract Background and aims Currently, there are no current reliable treatments promoting neuroprotection and functional recovery following stroke. Here, we aimed to assess the potential of the HRI kinase and downstream pathways as a main neuroprotective hub following cerebral ischemia. Methods We used two different animal models of cerebral ischemia: the transient occlusion of the middle cerebral artery (tMCAO) model, where mice underwent tMCAO followed by intraperitoneal (IP) injections of 10 mg/kg BTdCPU at 1h and 24h post-injury; and the thromboembolic model, where mice received a single injection of 10 mg/kg BTdCPU with or without rtPA at 1h post-injury. We carried out several behavioral tests: open field, corridor test, and the grip test. A proteomic analysis of human samples were performed using OLINK technology. Results We found that 10 mg/kg dose of BTdCPU acutely reduced lesion and edema volumes and improved behavioral recovery at 24h in both animal models. Moreover, in the thromboembolic model, the BTdCPU treatment reduced the rate of hemorrhagic transformation. Importantly, the combination of rtPA with BTdCPU showed the best outcomes in lesion volume, behavior and hemorrhagic transformation. When looking at human samples, we found that higher levels of ATF4 were correlated with lower ΔNIHSS (6h vs 24h), in agreement with animal model results. Conclusions Pharmacological manipulation of the HRI kinase has beneficial effects in two different preclinical models of ischemic stroke. BTdCPU is a promising candidate to be used in clinics along with rtPA in order to achieve better patient outcomes. Conflict of interest