Deciphering the factors causing damage to white matter fiber bundles and exploring new strategies to alleviate white matter injury (WMI) is a promising treatment to improve neurological impairments after intracerebral hemorrhage (ICH). Ferroptosis usually occurs at perihematomal region and contributes to neuronal death due to reactive oxygen species (ROS) production. Dexpramipexole (DPX) easily crosses the blood brain barrier (BBB) and exerts antioxidative properties by reducing ROS production, while the role of DPX in ferroptosis after ICH remains elusive. Here, our results indicated that ferroptosis played a significant role in WMI resulting from iron and ROS accumulation around hematoma. Further evidence demonstrated that the administration of DPX decreased iron and ROS deposition to inhibit ferroptosis at perihematomal site. With the inhibition of ferroptosis, WMI was alleviated at perihematomal site, thereafter promoting locomotion and motor coordination recovery in mice after ICH. Subsequently, the results showcased that the expression of glutathione peroxidase 4 (GPX4) and ferroptosis suppressing protein 1 (FSP1) was upregulated with the administration of DPX. Collectively, the present study uncovers the underlying mechanism and elucidates the therapeutic effect of DPX on ICH, and even in other central nervous system (CNS) diseases with the presence of ferroptosis.

Neural stem cell (NSC) proliferation is the initial step for NSC participating in neurorehabilitation after central nervous system (CNS) injury. During this process, oxidative stress is always involved in restricting the regenerative ability of NSC. Tetrahydrofolate (THF) is susceptible to oxidative stress and exhibits a high antioxidant activity. While its effect on NSC proliferation under oxidative stress condition remains obscure. Here, NSC were isolated from embryonic mice and identified using immunofluorescent staining. Meanwhile, the results showed that THF (5 μM and 10 μM) attenuated oxidative stress induced by 50 μM hydrogen peroxide (H2O2) in NSC using mitochondrial hydroxyl radical detection and Western blotting assays. Afterward, administration of THF markedly alleviated the inhibitory effect of oxidative stress on NSC proliferation, which was evidenced by Cell Counting Kit-8 (CCK8), neurosphere formation, and immunofluorescence of Ki67 assays. Thereafter, the results revealed that PTEN/Akt/mTOR signaling pathway played a pivotal role in counteracting oxidative stress to rescue the inhibitory effect of oxidative stress on NSC proliferation using Western blotting assays and gene knockdown techniques. Collectively, these results demonstrate that THF mitigates the inhibitory effect of oxidative stress on NSC proliferation via PTEN/Akt/mTOR signaling pathway, which provides evidence for administrating THF to potentiate the neuro-reparative capacity of NSC in the treatment of CNS diseases with the presence of oxidative stress.