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Spinal cord injury (SCI), a devastating neurological impairment, usually imposes a long-term psychological stress and high socioeconomic burden for the sufferers and their family. Recent researchers have paid arousing attention to white matter injury and the underlying mechanism following SCI. Ferroptosis has been revealed to be associated with diverse diseases including stroke, cancer, and kidney degeneration. Ferrostatin-1, a potent inhibitor of ferroptosis, has been illustrated to curb ferroptosis in neurons, subsequently improving functional recovery after traumatic brain injury (TBI) and SCI. However, the role of ferroptosis in white matter injury and the therapeutic effect of ferrostatin-1 on SCI are still unknown. Here, our results indicated that ferroptosis played a pivotal role in the secondary white matter injury, and ferrostatin-1 could reduce iron and reactive oxygen species (ROS) accumulation and downregulate the ferroptosis-related genes and its products of IREB2 and PTGS2 to further inhibit ferroptosis in oligodendrocyte, finally reducing white matter injury and promoting functional recovery following SCI in rats. Meanwhile, the results demonstrated that ferrostatin-1 held the potential of inhibiting the activation of reactive astrocyte and microglia. Mechanically, the present study deciphers the potential mechanism of white matter damage, which enlarges the therapeutic effects of ferrostatin-1 on SCI and even in other central nervous system (CNS) diseases existing ferroptosis.

OBJECTIVETissue plasminogen activator (tPA) fibrinolysis did not improve functional outcomes of patients with intraventricular hemorrhage (IVH), largely because of the unsatisfactory clot clearance. The presence of neutrophil extracellular traps (NETs) within the clot has been confirmed to impair tPA fibrinolysis, but the mechanism has been unclear. The authors hypothesized that cell-free DNA (cfDNA), the main framework of NETs, might be the important reason for the fibrinolysis resistance, and they validated the hypothesis, hoping to provide a new target to promote intraventricular fibrinolysis.METHODSFirst, cfDNA was detected in IVH clots by immunofluorescence staining in a rat model of IVH. Second, after blood (with or without exogenous cfDNA) intraventricular injection, IVH rats were given intraventricular infusion of 2 μl of saline, tPA, or tPA + DNase1 randomly. Then, the ventricular volume, animal behavior, and reactive astrocyte proliferation were assessed. Third, the IVH clots were collected for fibrinolysis assay in vitro. Finally, the effects of exogenous cfDNA in IVH were evaluated.RESULTSThe presence of cfDNA in clots was observed as early as 1 hour after IVH. Compared with the whole-blood model, blood + cfDNA caused more severe ventricular dilation (day 7: blood 32.47 ± 2.096 mm3 vs blood + DNA 40.09 ± 2.787 mm3, p < 0.05), increased fibrinolysis resistance to tPA (day 7: tPA + DNA 26.04 ± 1.318 mm3 vs tPA 22.15 ± 1.706 mm3, p < 0.05), and further deteriorated the functional defects in rats (blood vs blood + DNA, p < 0.05). Degradation of cfDNA by DNase1 further enhanced the fibrinolysis effects on relieving the ventricular dilation (day 7: tPA + DNase1 11.67 ± 2.023 mm3 vs tPA, p < 0.05), improving the functional outcome (tPA vs tPA + DNase1, p < 0.05) and reducing periventricular astrocyte proliferation.CONCLUSIONScfDNA impaired tPA fibrinolysis for IVH, and degradation of cfDNA may be a new target to improve this condition.

Cattle encephalon glycoside and ignotin (CEGI) injection is known as a multi-target neuroprotective drug that contains numerous liposoluble molecules, such as polypeptides, monosialotetrahexosyl ganglioside (GM-1), free amino acids, hypoxanthine and carnosine. CEGI has been approved by the Chinese State Food and Drug Administration and widely used in the treatments of various diseases, such as stroke and Alzheimer's disease. However, the neuroprotective effects of CEGI beyond the time window of thrombolysis (within 4.5 hours) on acute ischemic stroke remain unclear. This study constructed a rat middle cerebral artery occlusion model by suture-occluded method to simulate ischemic stroke. The first daily dose was intraperitoneally injected at 8 hours post-surgery and the CEGI treatments continued for 14 days. Results of the modified five-point Bederson scale, beam balance test and rotameric test showed the neurological function of ischemic stroke rats treated with 4 mL/kg/d CEGI improved significantly, but the mortality within 14 days did not change significantly. Brain MRI and 2,3,5-triphenyltetrazolium chloride staining confirmed that the infarct size in the 4 mL/kg/d CEGI-treated rats was significantly reduced compared with ischemic insult only. The results of transmission electron microscopy and double immunofluorescence staining showed that the hippocampal neuronal necrosis in the ischemic penumbra decreased whereas the immunopositivity of new neuronal-specific protein doublecortin and the percentage of Ki67/doublecortin positive cells increased in CEGI-treated rats compared with untreated rats. Our results suggest that CEGI has an effective neuroprotective effect on ischemic stroke when administered after the time window of thrombolysis. The study was approved by the Animal Ethics Committee of The Third Military Medical University, China.

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/p27kip1 signaling pathway (p-AKT, p-FOXO-3a, p27kip1) were examined using western blotting. The results suggested ART could inhibit the transcriptional function of FOXO-3a by inducing its phosphorylation, subsequently downregulating p27kip1 and enhancing neural stem cell proliferation in the infarcted cortex via PI3K/AKT signaling, further alleviating ischemia-reperfusion injury after ischemic stroke.

Iron-mediated toxicity is a key factor causing brain injury after intracerebral hemorrhage (ICH). This study was performed to investigate the noninvasive neuroimaging method for quantifying brain iron content using a minipig ICH model and assess the effects of minocycline treatment on ICH-induced iron overload and brain injury. The minipig ICH model was established by injecting 2 ml of autologous blood into the right basal ganglia, which were then subjected to the treatments of minocycline and vehicle. Furthermore, the quantitative susceptibility mapping (QSM) was used to quantify iron content, and diffusion tensor imaging (DTI) was performed to evaluate white matter tract. Additionally, we also performed immunohistochemistry, Western blot, iron assay, Perl's staining, brain water content, and neurological score to evaluate the iron overload and brain injury. Interestingly, we found that the ICH-induced iron overload could be accurately quantified by the QSM. Moreover, the minocycline was quite beneficial for protecting brain injury by reducing the lesion volume and brain edema, preventing brain iron accumulation, downsizing ventricle enlargement, and alleviating white matter injury and neurological deficits. In summary, we suggest that the QSM be an accurate and noninvasive method for quantifying brain iron level, and the minocycline may be a promising therapeutic agent for patients with ICH.

Background and purpose The blood–brain barrier (BBB) disruption and the following development of brain edema, is the most life-threatening secondary injury after intracerebral hemorrhage (ICH). This study is to investigate a potential role and mechanism of JWH133, a selected cannabinoid receptor type2 (CB2R) agonist, on protecting blood–brain barrier integrity after ICH. Methods 192 adult male Sprague-Dawley (SD) rats were randomly divided into Sham; ICH + Vehicle; ICH + JWH 1.0 mg/kg, ICH + JWH 1.5 mg/kg and ICH + JWH 2.0 mg/kg; ICH + SR + JWH respectively. Animals were euthanized at 24 h following western blots and immunofluorescence staining, we also examined the effect of JWH133 on the brain water contents, neurobehavioral deficits and blood brain barrier (BBB) permeability, meanwhile reassessed the inflammatory cytokines concentrations around the hematoma by enzyme-linked immunosorbent assay (ELISA) in each group. Results JWH133 (1.5 mg/kg) administration ameliorated brain edema, neurological deficits and blood–brain barrier damage, as well as microglia activation. The expression of pro-inflammatory mediators interleukin 1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and matrix metallopeptidase-2/9 (MMP2/9) were attenuated, but not monocyte chemoattractant protein-1 (MCP-1). Additionally, decreases in zonula occludens-1 (ZO-1) and claudin-5 expression were partially recovered by JWH133. Furthermore, JWH133 upregulated the expression level of MKP-1, which leads to the inhibition of MAPKs signaling pathway activation, especially for ERK and P38. However, these effects were reversed by pretreatment with a selective CB2R antagonist, SR144528. Conclusions CB2R agonist alleviated neuroinflammation and protected blood–brain barrier permeability in a rat ICH model. Further molecular mechanisms revealed which is probably mediated by enhancing the expression of MKP-1, then inhibited MAPKs signal transduction.

Objective To elucidate the relationship between the risk factors and hematoma expansion(HE)shapes. Patients and methods From February 2013 to November 2018, 60 patients diagnosed as basal ganglia ICH were divided into the filled type hematoma expansion group (FTE group) and the expanded type hematoma expansion group (ETE group). we performed follow-up CT and three-dimensional reconstruction for the patients and compared the hematoma before and after the expansion of size and extent. Results The regression analysis showed that the irregular sign (odds ratio, 3.64; 95 % CI, 1.46–9.12), black hole sign (odds ratio, 3.85; 95 % CI, 1.40–10.60), blend sign (odds ratio, 2.86; 95 % CI, 1.03–7.95), and early use of dehydration (odds ratio, 4.59; 95 % CI, 1.59–13.19) were possible risk factors for the ETE group, while the high systolic blood pressure (odds ratio, 1.51; 95 % CI, 1.04–2.30), early use of dehydration (odds ratio, 3.27; 95 % CI, 1.10–9.69) and low density low-density band (odds ratio, 4.52; 95 % CI, 1.54–13.28) were possible risk factors for the FTE group. Conclusions The irregular sign, black hole sign, blend sign and early use of dehydration may be the main risk factors for ETE, whereas early use of dehydration, high systolic blood pressure, and low density low-density band may be the main risk factors for FTE.

Background With little information available on axonal and myelin damage surrounding the contusion, the study of spinal cord injury (SCI) so far has focused on neuronal death. In this study, we investigated the role of iron overload in long-term oligodendroglia death and progressive white matter damage to rats after SCI using the iron chelator, deferoxamine (DFX). Methods Female Sprague-Dawley rats received either a contusion at T10 or sham-surgery. The rats were treated with DFX or vehicle. All rats were evaluated in behavioral assessments and then euthanized at different time points. Spinal cords were analyzed by diaminobenzidine-enhanced Perls' staining, non-heme iron measurements, Western blotting, immunohistochemistry, and transmission electron microscopy. Results Iron accumulation after SCI resulted in the upregulation of transferrin receptor and divalent metal transporter 1, which exacerbated the intracellular iron overload. DFX treatment reduced iron overload–induced delayed oligodendrocyte death (e.g., 21 days: 47.12 ± 10.5 vs. 20.02 ± 9.4 x 103/mm2 in the vehicle-treated group, n = 4, P Conclusions Iron overload plays an important role in progressive white matter damage after SCI. DFX may be an effective treatment for white matter damage after SCI.

Urokinase-type plasminogen activator (uPA) was demonstrated to alleviate kaolin-induced communicating hydrocephalus via inhibiting subarachnoid space fibrosis, but the exact mechanism remains elusive. Thus, this study was designed to investigate if hepatocyte growth factor (HGF), which plays a vital role in uPA-triggered inhibiting of fibrosis in multiple systems, is involved in this process in hydrocephalus. There were 2 parts in this study. First, hydrocephalus was induced in rats by basal cistern injection of kaolin. Then rats were treated with saline or uPA and brain tissue and CSF were collected for Western blot and enzyme-linked immuno sorbent assay (ELISA) four days later. Second, kaolin-induced hydrocephalus rats were treated with saline, uPA, uPA + PHA665752 (antagonist of HGF) or PHA665752. Some animals received MRI four weeks later and brains were used for immunofluorescence. The others were euthanized four days later for ELISA. Both levels of total and activated HGF in the CSF was increased after uPA injections, but related mRNA expression of HGF showed no statistical significance when compared with the control group. Further, the effects of uPA that alleviating ventricular enlargement, subarachnoid fibrosis and reactive astrocytosis were partially reversed by PHA665752. Moreover, PHA665752 partially abolished uPA-induced reduction of transforming growth factor- β1(TGF- β1) level in CSF. Our data suggest that uPA effectively inhibited subarachnoid fibrosis and restricted the development of communicating hydrocephalus in rats in part by promoting HGF release and activation, which may further regulate the TGF-β1 expression in CSF.

Glioma‑initiating cells are a small population of cells that have the ability to undergo self‑renewal and initiate tumorigenesis. In the present study, the potential role of salinomycin, a polyether antibiotic, on the suppression of glioma cell growth was investigated. GL261 glioma cells were maintained in a stem‑cell‑like status [GL261 neurospheres (GL261‑NS)] or induced for differentiation [GL261 adherent cells (GL261‑AC)]. It was demonstrated that salinomycin significantly reduced the cell viability of GL261‑NS and GL261‑AC cells in a dose‑dependent manner, with a more substantial inhibition of GL261‑NS proliferation (P