4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione rescues oligodendrocytes ferroptosis leading to myelin loss and ameliorates neuronal injury facilitating memory in neonatal hypoxic-ischemic brain damage.

Neonatal brain hypoxia-ischemia (HI) is proved to cause white matter injury (WMI), which resulted in behavioral disturbance. Myelin formed by oligodendrocytes vulnerable to hypoxia-ischemia (HI), regulating motor and cognitive function, is easily damaged by HI causing myelin loss. 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) has a potential rescue role in neuronal death post HI. Studies reported that neuronal ferroptosis could be induced by HI and linked to behavioral abnormalities. However, the effect of TDZD-8 on WMI and its involvement in memory recovery remains unclear. In this study, our HIBD model showed impaired memory function caused by neuronal injury and myelin loss. TDZD-8 effectively reversed this pathology. Underlying mechanistic exploration implied that TDZD-8 ameliorating myelin loss via ferroptosis pathway was involved in the process of TDZD-8 treating neonatal HIBD. In conclusion, our data demonstrated that combined effect of white matter repairment and neuronal protection achieved the therapeutic role of TDZD-8 in neonatal HIBD, and suggested that white matter repairment also could be a considerable clinical therapy for neonatal HIBD.