Oxidative stress plays an indispensable role in the pathogenesis of cerebral ischemia.Inhibiting oxidative stress has been considered as an effective approach for stroke treatment.Edaravone,a free radical scavenger,has been shown to prevent cerebral ischemic injury.However,the clinical efficacy of edaravone is limited because it has a low scavenging activity for superoxide anions(O_2^(·-)).Here,we report that 2-methyl-5 H-benzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine,a novel small-molecule compound structurally related to edaravone,showed a stronger inhibitory effect on oxidative stress in vitro.In vivo,2-methyl-5 H-benzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine reversed transient middle cerebral artery occlusion-induced dysfunctions of superoxide dismutases and malondialdehyde,two proteins crucial for oxidative stress,suggesting a strengthened antioxidant system.Moreover,2-methyl-5 H-benzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine decreased blood brain barrier permeability.Then,we found that 2-methyl-5 Hbenzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine had a stronger neuroprotective effect than edaravone.More importantly,2-methyl-5 H-benzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine decreased not only infarct size and neurological deficits in the acute phase but also modified neurological severity score and escape latency in Morris water maze task in the delayed period,indicating enhanced neuroprotection,sensorimotor function and spatial memory.Together,these findings suggest that 2-methyl-5 H-benzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine could be a preferable option for stroke treatment.
Phosphofructokinase-1(PFK-1),a major regulatory glycolytic enzyme,has been implicated in the functions of astrocytes and neurons.Here,we report that PFK-1 negatively regulates neurogenesis from neural stem cells(NSCs)by targeting pro-neural transcriptional factors.Using in vitro assays,we found that PFK-1 knockdown enhanced,and PFK-1 overexpression inhibited the neuronal differentiation of NSCs,which was consistent with the findings from NSCs subjected to 5 h of hypoxia.Meanwhile,the neurogenesis induced by PFK-1 knockdown was attributed to the increased proliferation of neural progenitors and the commitment of NSCs to the neuronal lineage.Similarly,in vivo knockdown of PFK-1 also increased neurogenesis in the dentate gyrus of the hippocampus.Finally,we demonstrated that the neurogenesis mediated by PFK-1 was likely achieved by targeting mammalian achaete-scute homologue-1(Mash 1),neuronal differentiation factor(NeuroD),and sex-determining region Y(SRY)-related HMG box 2(Sox2).All together,our results reveal PFK-1 as an important regulator of neurogenesis.
Stroke is one of the leading causes of disability and death globally.It occurs when a major artery is occluded in the brain and leads to death of cells within the injured tissue.(+)-Borneol,a simple bicyclic monoterpene extracted from traditional Chinese medicine,is widely used in various types of diseases.However,no study has proved the effects of(+)-borneol on functional recovery from permanent ischemic stroke and the mechanism is still unknown.Here,we report that in the rat model of permanent cerebral ischemia,we found that(+)-borneol(1.0 mg/kg) significantly ameliorated infarct size and neurological scores via reducing the expression of inducible nitric oxide synthase(iNOS)and tumor necrosis factor-alpha(TNF-α) in a dose dependent manner.Notably,(+)-borneol showed long-term effects on the improvement of sensorimotor functions in the photothrombotic model of stroke,which decreased the number of foot faults in the grid-walking task and forelimb asymmetry scores in the cylinder task,at least in part through reducing loss of dendritic spines in the length,brunch number and density.These findings suggest that(+)-borneol could serve as a therapeutic target for ischemic stroke.
Lei ChangChun-Yu YinHai-Yin WuBin-Bin TianYan ZhuChun-Xia LuoDong-Ya Zhu
目的 :探讨雌二醇(E2)对慢性温和性应激(chronic mild stress,CMS)引起的卵巢摘除(ovariectomized,OVX)抑郁模型雌鼠认知功能障碍的改善作用及其机制。方法:采用CMS制备抑郁症动物模型,检测正常及抑郁症模型小鼠的血浆皮质酮水平。造模2周后开始给予OVX小鼠E2,同时继续造模1周。末次给药后采用Morris水迷宫测试其空间学习记忆能力。检测血浆E2以及海马神经元型一氧化氮合酶(n NOS)m RNA和蛋白表达水平,并标记海马齿状回n NOS阳性细胞数。体外采用雌性胎鼠海马神经元原代培养,给予皮质酮(CORT)及CORT合并E2后24 h,检测n NOS m RNA及蛋白表达水平。此外,体外给予E2后24 h,检测胞外调节激酶(ERK)磷酸化水平。结果 :CMS造模后小鼠血浆皮质酮水平均显著上升。外源性补充E2可逆转CMS诱导的OVX雌鼠血浆E2水平的降低、CMS及体外CORT诱导的海马n NOS m RNA及蛋白表达水平的降低,并恢复OVX雌鼠空间学习记忆功能。此外,E2可显著升高雌性胎鼠海马神经元的ERK磷酸化水平。结论:E2逆转了由CMS诱导的OVX抑郁模型雌鼠海马n NOS的异常表达,并改善了其空间学习记忆缺陷,其作用可能是通过ERK磷酸化介导的。
