GFH312 Reduces Neuronal Death by Inhibiting RIPK1‐Mediated Apoptosis and Necroptosis After Ischemic Stroke

Abstract

ABSTRACT Aims To investigate the role of the RIPK1 inhibitor GFH312 in ischemic stroke and identify its potential mechanisms. Methods GFH312 was administered to adult mice in an ischemic stroke model. To ascertain the effectiveness of treatment, neurobehavioral tests and assessments of brain damage were carried out. Brain tissues were examined using immunofluorescence as well as western blot and real‐time quantitative PCR at various intervals following ischemia to evaluate inflammatory gene expression and signaling pathways linked to apoptosis and necroptosis. Results Temporal analysis revealed that necroptosis and apoptosis were rapidly activated following ischemia, peaking at 1–3 days. GFH312 significantly improved neurological function and reduced brain injury in stroke mice. Mechanistically, GFH312 markedly inhibited apoptosis and necroptosis via suppression of the RIPK1‐related signaling pathway (RIPK1‐RIPK3‐MLKL). In addition, GFH312 greatly decreased inflammatory gene expression in the brain. Conclusion Apoptosis and necrotic apoptosis occur primarily during the acute poststroke phase. GFH312 exerts neuroprotective effects after ischemic stroke, which are associated with suppression of RIPK1‐related apoptosis, necroptosis, and neuroinflammation.