GuiZhou University Medical College, Guiyang, Guizhou, China.
Guizhou Medical University, Guiyang, China.
CNS Neurosci Ther. 2024 Nov;30(11):e70096. doi: 10.1111/cns.70096.
Oxidative stress-induced inflammation is a major pathogenic mechanism in sepsis-associated encephalopathy (SAE). We hypothesized that regulation of reactive oxygen species (ROS) by the neuropeptide orexin-A could prevent SAE-induced oxidative stress and inflammation. Therefore, the aim of this study was to investigate the effects of orexin-A on oxidative stress and inflammation in SAE in mice.
Adult male mice were treated with orexin-A (250 μg/kg, intranasal administration) to establish a cecal ligation perforation (CLP) model. We performed behavioral tests, observed neuronal damage in the hippocampal region, measured the levels of ROS, NOX2, and observed the structure of mitochondria by transmission electron microscopy. We then examined the inflammatory factors TNF-α and IL-1β, the activation of microglia and astrocytes, the expression of ERK/NF-κB, C3, and S100A10, and the presence of A1 type astrocytes and A2 type astrocytes.
Orexin-A treatment improved cognitive performance in CLP-induced SAE mice, attenuated neuronal apoptosis in the hippocampal region, ameliorated ROS levels and the extent of mitochondrial damage, and reduced protein expression of NOX2 in hippocampal tissue. In addition, orexin-A treatment significantly reduced microglia and astrocyte activation, inhibited the levels of P-ERK and NF-κB, and reduced the release of IL-1β and TNF-α, which were significantly increased after CLP. Finally, Orexin-A treatment significantly decreased the number of C3/glial fibrillary acidic protein (GFAP)-positive cells and increased the number of S100A10/GFAP-positive cells.
Our data suggest that orexin-A reduces ROS expression by inhibiting CLP-induced NOX2 production, thereby attenuating mitochondrial damage and neuronal apoptosis. Its inhibition of microglial and A1-type astrocyte activation and inflammation was associated with the ERK/NF-κB pathway. These suggest that orexin-A may reduce cognitive impairment in SAE by reducing oxidative stress-induced inflammation.
氧化应激诱导的炎症是脓毒症相关性脑病（SAE）的主要发病机制。我们假设神经肽食欲素 A 可以通过调节活性氧（ROS）来预防 SAE 诱导的氧化应激和炎症。因此，本研究旨在探讨食欲素 A 对小鼠 SAE 中氧化应激和炎症的影响。
成年雄性小鼠接受食欲素 A（250μg/kg，鼻腔给药）处理以建立盲肠结扎穿孔（CLP）模型。我们进行了行为测试，观察了海马区神经元损伤，测量了 ROS、NOX2 的水平，并通过透射电子显微镜观察了线粒体的结构。然后，我们检测了 TNF-α 和 IL-1β 等炎症因子、小胶质细胞和星形胶质细胞的激活、ERK/NF-κB 的表达、C3 和 S100A10 的表达以及 A1 型星形胶质细胞和 A2 型星形胶质细胞的存在。
食欲素 A 治疗改善了 CLP 诱导的 SAE 小鼠的认知表现，减轻了海马区神经元凋亡，改善了 ROS 水平和线粒体损伤程度，并降低了海马组织中 NOX2 的蛋白表达。此外，食欲素 A 治疗显著减少了小胶质细胞和星形胶质细胞的激活，抑制了 P-ERK 和 NF-κB 的水平，并降低了 CLP 后显著升高的 IL-1β 和 TNF-α 的释放。最后，食欲素 A 治疗显著减少了 C3/胶质纤维酸性蛋白（GFAP）阳性细胞的数量，并增加了 S100A10/GFAP 阳性细胞的数量。
我们的数据表明，食欲素 A 通过抑制 CLP 诱导的 NOX2 产生来减少 ROS 表达，从而减轻线粒体损伤和神经元凋亡。其对小胶质细胞和 A1 型星形胶质细胞激活和炎症的抑制与 ERK/NF-κB 途径有关。这些表明，食欲素 A 通过减少氧化应激诱导的炎症可能减轻 SAE 中的认知障碍。
