Spinal cord injury (SCI), a devastating neurological impairment, ubiquitously imposes a long-term psychological stress and high socioeconomic burden for the suffers and their family. To date, recent researchers have paid arousing attention to white matter injury and uncovering the underlying mechanism post-SCI. Ferroptosis, to our knowledge, has been revealed to be associated with diverse diseases including stroke, cancer, and kidney degeneration. However, its role in white matter damage after SCI remains unclear. Ferrostatin-1, a potent inhibitor of ferroptosis, has been illustrated to curb ferroptosis in neurons, subsequently improve functional recovery after traumatic brain injury (TBI). But whether it inhibits white matter injury post-SCI is still unknown. Here, our results indicated that ferroptosis played an important role in the secondary white matter injury following SCI and ferrostatin-1 could reduce iron and reactive oxygen species (ROS) accumulation, downregulate the ferroptosis-related genes and its products of IREB2 and PTGS2 to further inhibit ferroptosis in oligodendrocyte progenitor cells (OPCs), nally reducing white matter injury and promoting functional recovery following SCI in rats, which enlarges the therapeutic scope for ferrostatin-1 and deciphers the potential mechanism of white matter damage after SCI.

Stroke is one of the leading causes of death worldwide that also result in long-term disability. Endogenous neural stem/progenitor cells (NSPCs) within subventricular (SVZ) and dentate gyrus (DG) zone, stimulated by cerebral infarction, can promote neural function recovery. However, the proliferation of eNSPCs triggered by ischemia is not enough to induce neural repair, which may contribute to the permanent disability in stroke patients. In this study, our results showed that following the treatment with artesunate (ART, 150 mg/kg), the functional recovery was significantly improved, the infarct volume was notably reduced, and the expression of Nestin, a proliferation marker of NSPCs in the infarcted cortex, was also increased. Additionally, the proliferative activity of NSPCs with or without oxygen-glucose deprivation/reperfusion was significantly promoted by ART treatment, and the therapeutic concentration was 0.8 μmol/L (without OGD/R) or 0.4 μmol/L (with OGD/R) in the in vitro model. Furthermore, the effects of ART can be abolished by the treatment of PI3K inhibitor wortmannin. The expression levels of related molecules in PI3K/Akt/FOXO-3a/p27 kip1 signaling pathway (p-AKT, p-FOXO-3a, p27 kip1) were examined using western blotting. The results suggested ART could inhibit the transcriptional function of FOXO-3a by inducing its phosphorylation, subsequently downregulating p27 kip1 and enhancing neural stem cell proliferation in the infarcted cortex via PI3K/AKT signaling, further alleviating ischemia-reperfusion injury after ischemic stroke.

Ischemic stroke is one of the most leading diseases causing death/long-term disability worldwide. Activating endogenous neural stem/progenitors cells (NSPCs), lining in the subventricular zone (SVZ) and dentate gyrus, facilitates injured brain tissue recovery in both short and long-term experimental settings. While, only a few proliferated NSPCs migrate toward the lesions to enhance endogenous repair after ischemia. Here, the results indicated that the functional recovery was evidently improved and the infarct volume was significantly reduced with ascorbic acid (AA) treatment in a dose-dependent manner from 125 to 500 mg/Kg, and the suitable therapeutic concentration was 250 mg/Kg. The possible mechanism might be due to activating sodium-vitamin C cotransporter 2 (SVCT2), which was down-regulated in SVZ after ischemia. Furthermore, immunostaining images depicted the number of migrated NSPCs from SVZ were significantly increased with 250 mg/Kg AA treatment or SVCT2 overexpression under the physiological and pathological condition in vivo. Besides, the data also represented that 250 mg/Kg AA or SVCT2 overexpression facilitated NSPCs migration via promoting F-actin assembling in the manner of up-regulating CDC42 expression using oxygen-glucose deprivation in vitro. Collectively, the present study indicates that SVCT2 promotes NSPCs migration through CDC42 activation to facilitate F-actin assembling, which enlarges the therapeutic scope of AA and the role of SVCT2 in NSPCs migration after brain injury.