Abstract

Cerebral thrombosis, a major cause of ischemic stroke, involves complex cellular and molecular mechanisms, including the response of glial cells to pro-thrombotic factors like thrombin. $\beta$-Arrestin-2 (Arrb2) is a critical scaffolding protein known to regulate G protein-coupled receptor (GPCR) signaling, particularly the Protease-Activated Receptor 1 (PAR-1) which is activated by thrombin. This study investigates the role of Arrb2 in mediating the cellular response to thrombin-induced toxicity in the central nervous system. We utilized Arrb2 gene knockout mice to assess the survival of cultured primary astrocytes exposed to thrombin *in vitro* and to evaluate the neurological and histological aftereffects following an induced cerebral thrombosis *in vivo*. Our *in vitro* findings demonstrate that Arrb2 deficiency significantly exacerbates thrombin-induced astrocyte death, suggesting a crucial protective role for Arrb2 in glial cell survival. Correspondingly, *in vivo* experiments revealed that Arrb2 knockout mice exhibited a more severe neurological deficit and larger infarct volumes compared to wild-type controls following the thrombotic event. These results establish $\beta$-Arrestin-2 as a key component in the cytoprotective signaling pathways activated by thrombin in astrocytes, highlighting its potential as a therapeutic target for mitigating secondary brain injury and improving outcomes after cerebral thrombosis.