FDCA Attenuates Neuronal Ferroptosis and Reduces Hemorrhagic Transformation After Ischemic Stroke with High Glucose

Hemorrhagic transformation (HT) is a common complication of ischemic stroke that significantly increases the rates of disability and mortality, which could be promoted by hyperglycemia as a risk factor for HT after stroke. Neuronal ferroptosis was implicated as a key contributor to neuronal death during the development of HT which currently has few effective therapies in clinic. The compound fasudil dichloroacetate (FDCA), synthesized with ROCK inhibitor fasudil (F) and PDK inhibitor dichloroacetate (DCA) was previously reported to exhibit neuroprotective effects in ischemic stroke, but whether FDCA could ameliorate HT post-stroke remains unknown. In this study, FDCA was synthesized by combining the Rho kinase inhibitor F with the PDK inhibitor DCA. Rats with acute hyperglycemia and ischemic stroke were divided into the control group, 10 mg/kg FDCA treatment group, 7.875 mg/kg F + 3.6 mg/kg DCA combination treatment group, and other relevant control groups. Our findings demonstrate that FDCA treatment significantly reduced the area of cerebral HT, HT scores, and hemoglobin content in rat brains, improved neurological function, and decreased mortality. Mechanistically, FDCA inhibited neuronal ferroptosis in peri-hematomal region by downregulating the ACSL4 protein expression and the phosphorylation levels of MYPT1 and PDH, while upregulating the GPX4 protein expression. Additionally, FDCA attenuated RSL3-induced neuronal ferroptosis in SH-SY5Y cells in vitro. These results suggest that FDCA holds promise as a potential therapeutic agent for the clinical treatment of HT following ischemic stroke.