A novel ferroptosis inhibitor phenothiazine derivative reduces cell death and alleviates neurological impairments after cerebral hemorrhage

Abstract

The precise etiology of brain injury induced by intracerebral hemorrhage (ICH) remains unclear. Currently, there are no effective therapeutic options available to slow down or prevent the progression of the disease. An increasing body of evidence suggests that ferroptosis plays a significant role in the development of injury related to ICH. Furthermore, pharmacological inhibition of ferroptosis has been identified as a promising therapeutic target for ICH injury. The compound 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine (compound-51), a derivative of promethazine, has been demonstrated to exhibit anti-ferroptosis and antioxidant properties. The aim of this study is to investigate the role and mechanism of action of compound-51 in a rat model of ICH. The in vivo experiments demonstrated that compound-51 significantly alleviated neurological impairments, reduced brain edema, and decreased hematoma volume. At the cellular level, compound-51 was observed to significantly enhance cellular survival and inhibit ferroptosis. Furthermore, compound-51 demonstrated a more pronounced therapeutic effect than Fer-1, without causing any injury to the heart, kidney, or liver. In vitro experiments demonstrated that compound-51 significantly increased cell viability and intracellular GPX4 levels, while reducing lipid peroxidation and oxidized glutathione levels. Collectively, these findings indicate that compound-51 exhibits a pronounced anti-ferroptosis function and alleviates neurological impairments in an ICH model, suggesting its potential as a new therapeutic agent for the treatment of ICH.