背景:左西孟旦(Levo)是一种常用于治疗心力衰竭的药物。最近的研究表明,Levo可能具有神经保护作用,但它到底是如何导致缺氧引起的脑损伤还不清楚。因此,本研究的目的是研究Levo如何影响缺氧诱导的脑损伤,并阐明任何可能的潜在机制.
方法:一组大鼠(Levo组)通过口服力喂养用Levo预处理4周。另一组(Ferrostatin-1(Fer-1)组)用Fer-1腹膜内注射预处理4周。通过在封闭的缺氧室中用13%O2处理大鼠14天,建立慢性缺氧的大鼠模型。对于每个组(对照,型号,Levo,Fer-1),我们评估了大鼠脑组织中的学习记忆能力以及神经元的形态和结构。其他测量包括肿瘤坏死因子-α(TNF-α),白细胞介素-1β(IL-1β),和白细胞介素-6(IL-6);丙二醛(MDA),超氧化物歧化酶(SOD),和谷胱甘肽过氧化物酶(GSH-Px);Fe2;凋亡;裂解的caspase-3,caspase-3;磷酸酶和张力蛋白同源物(PTEN),蛋白激酶B(Akt),磷酸化Akt(p-Akt);和铁凋亡相关蛋白核因子红细胞2相关因子2(Nrf2),谷胱甘肽过氧化物酶4(GPX4),和溶质载体家族7成员11(SLC7A11)。
结果:模型组大鼠的神经元数量明显少于对照组,细胞排列松散,学习和记忆能力明显受损(p<0.05)。模型组脑组织氧化损伤和炎症反应明显加剧,伴随着神经元凋亡的大量增加(p<0.05)。PTEN蛋白,Fe2+浓度,切割的caspase-3表达均显著上调,而p-Akt,Nrf2、GPX4和SLC7A11蛋白显著下调(p<0.05)。与模型组相比,Levo和Fer-1组显示出明显更多的神经元和排列紧密的细胞。学习和记忆能力显着提高(p<0.05)。Levo和Fer-1组脑组织的氧化损伤和炎症反应明显减轻,神经元凋亡受到抑制(p<0.05)。p-Akt,Nrf2、GPX4和SLC7A11蛋白显著上调,而裂解的caspase-3,PTEN蛋白的表达,Fe2+含量显著下调(p<0.05)。
结论:Levo能有效减轻慢性缺氧大鼠的脑损伤,可能通过PTEN/Akt信号通路调节铁凋亡。
BACKGROUND: Levosimendan (Levo) is a drug commonly used to treat heart failure. Recent studies have suggested that Levo may have neuroprotective effects, but it is still unknown how exactly it contributes to hypoxia-induced brain damage. Thus, the aim of this study was to investigate how Levo affects hypoxia-induced brain damage and to clarify any possible underlying mechanisms.
METHODS: One group of rats (Levo group) was pretreated with Levo via oral force-feeding for four weeks. Another group (Ferrostatin-1 (Fer-1) group) was pretreated with intraperitoneal injections of Fer-1 for four weeks. A rat model of chronic hypoxia was created by treating rats with 13% O2 for 14 days in a closed hypoxia chamber. For each group (Control, Model, Levo, Fer-1), we evaluated learning and memory capacity and the morphology and structure of neurons in the rats\' brain tissue. Other measurements included tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6); malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px); Fe2+; apoptosis; cleaved caspase-3, caspase-3; phosphatase and tensin homolog (PTEN), protein kinase B (Akt), phosphorylated Akt (p-Akt); and ferroptosis-related proteins Nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11).
RESULTS: The Model group rats had considerably fewer neurons than the Control group, with loosely arranged cells, and markedly impaired learning and memory abilities (p < 0.05). Oxidative damage and inflammation in brain tissues of the Model group were significantly intensified, accompanied by a substantial increase in neuronal apoptosis (p < 0.05). PTEN protein, Fe2+ concentration, and cleaved caspase-3 expression were all significantly upregulated, whereas p-Akt, Nrf2, GPX4, and SLC7A11 proteins were dramatically downregulated (p < 0.05). Both the Levo and Fer-1 groups demonstrated significantly more neurons and closely arranged cells than the Model group, along with a notable improvement in learning and memory abilities (p < 0.05). Oxidative damage and inflammation in brain tissues of the Levo and Fer-1 groups were markedly alleviated, and neuronal apoptosis was suppressed (p < 0.05). p-Akt, Nrf2, GPX4, and SLC7A11 proteins were dramatically upregulated, whereas the expression of cleaved caspase-3, PTEN protein, and Fe2+ content was considerably downregulated (p < 0.05).
CONCLUSIONS: Levo effectively mitigates brain injury in rats with chronic hypoxia, likely by regulating ferroptosis via the PTEN/Akt signaling pathway.