PDF(Pubmed)
Abstract：
BACKGROUND: Sepsis-associated encephalopathy (SAE) causes acute and long-term cognitive deficits. However, information on the prevention and treatment of cognitive dysfunction after sepsis is limited. The neuropeptide orexin-A (OXA) has been shown to play a protective role against neurological diseases by modulating the inflammatory response through the activation of OXR1 and OXR2 receptors. However, the role of OXA in mediating the neuroprotective effects of SAE has not yet been reported.
METHODS: A mouse model of SAE was induced using cecal ligation perforation (CLP) and treated via intranasal administration of exogenous OXA after surgery. Mouse survival, in addition to cognitive and anxiety behaviors, were assessed. Changes in neurons, cerebral edema, blood-brain barrier (BBB) permeability, and brain ultrastructure were monitored. Levels of pro-inflammatory factors (IL-1β, TNF-α) and microglial activation were also measured. The underlying molecular mechanisms were investigated by proteomics analysis and western blotting.
RESULTS: Intranasal OXA treatment reduced mortality, ameliorated cognitive and emotional deficits, and attenuated cerebral edema, BBB disruption, and ultrastructural brain damage in mice. In addition, OXA significantly reduced the expression of the pro-inflammatory factors IL-1β and TNF-α, and inhibited microglial activation. In addition, OXA downregulated the expression of the Rras and RAS proteins, and reduced the phosphorylation of P-38 and JNK, thus inhibiting activation of the MAPK pathway. JNJ-10,397,049 (an OXR2 blocker) reversed the effect of OXA, whereas SB-334,867 (an OXR1 blocker) did not.
CONCLUSIONS: This study demonstrated that the intranasal administration of moderate amounts of OXA protects the BBB and inhibits the activation of the OXR2/RAS/MAPK pathway to attenuate the outcome of SAE, suggesting that OXA may be a promising therapeutic approach for the management of SAE.
METHODS: A mouse model of SAE was induced using cecal ligation perforation (CLP) and treated via intranasal administration of exogenous OXA after surgery. Mouse survival, in addition to cognitive and anxiety behaviors, were assessed. Changes in neurons, cerebral edema, blood-brain barrier (BBB) permeability, and brain ultrastructure were monitored. Levels of pro-inflammatory factors (IL-1β, TNF-α) and microglial activation were also measured. The underlying molecular mechanisms were investigated by proteomics analysis and western blotting.
RESULTS: Intranasal OXA treatment reduced mortality, ameliorated cognitive and emotional deficits, and attenuated cerebral edema, BBB disruption, and ultrastructural brain damage in mice. In addition, OXA significantly reduced the expression of the pro-inflammatory factors IL-1β and TNF-α, and inhibited microglial activation. In addition, OXA downregulated the expression of the Rras and RAS proteins, and reduced the phosphorylation of P-38 and JNK, thus inhibiting activation of the MAPK pathway. JNJ-10,397,049 (an OXR2 blocker) reversed the effect of OXA, whereas SB-334,867 (an OXR1 blocker) did not.
CONCLUSIONS: This study demonstrated that the intranasal administration of moderate amounts of OXA protects the BBB and inhibits the activation of the OXR2/RAS/MAPK pathway to attenuate the outcome of SAE, suggesting that OXA may be a promising therapeutic approach for the management of SAE.
摘要：
背景：脓毒症相关性脑病（SAE）可引起急性和长期认知缺陷。然而,关于预防和治疗脓毒症后认知功能障碍的信息有限.神经肽食欲素A（OXA）已被证明通过激活OXR1和OXR2受体来调节炎症反应而对神经系统疾病起保护作用。然而,OXA在介导SAE的神经保护作用中的作用尚未见报道.
方法：使用盲肠结扎穿孔（CLP）诱导SAE小鼠模型，并在手术后通过鼻内给予外源性OXA进行治疗。老鼠的生存,除了认知和焦虑行为，被评估。神经元的变化，脑水肿,血脑屏障（BBB）通透性，监测脑超微结构。促炎因子水平（IL-1β，还测量了TNF-α）和小胶质细胞活化。通过蛋白质组学分析和蛋白质印迹研究了潜在的分子机制。
结果：鼻内OXA治疗降低了死亡率，改善认知和情感缺陷，减轻脑水肿，BBB中断,和小鼠的超微结构脑损伤。此外,OXA显著降低促炎因子IL-1β和TNF-α的表达,并抑制小胶质细胞的活化。此外,OXA下调Rras和RAS蛋白的表达，减少了P-38和JNK的磷酸化,从而抑制MAPK途径的激活。JNJ-10,397,049（一种OXR2阻断剂）逆转了OXA的作用，而SB-334,867（OXR1阻断剂）则没有。
结论：这项研究表明，鼻内给药适量的OXA可以保护BBB并抑制OXR2/RAS/MAPK通路的激活，从而减轻SAE的后果。提示OXA可能是一种有前途的SAE治疗方法。
方法：使用盲肠结扎穿孔（CLP）诱导SAE小鼠模型，并在手术后通过鼻内给予外源性OXA进行治疗。老鼠的生存,除了认知和焦虑行为，被评估。神经元的变化，脑水肿,血脑屏障（BBB）通透性，监测脑超微结构。促炎因子水平（IL-1β，还测量了TNF-α）和小胶质细胞活化。通过蛋白质组学分析和蛋白质印迹研究了潜在的分子机制。
结果：鼻内OXA治疗降低了死亡率，改善认知和情感缺陷，减轻脑水肿，BBB中断,和小鼠的超微结构脑损伤。此外,OXA显著降低促炎因子IL-1β和TNF-α的表达,并抑制小胶质细胞的活化。此外,OXA下调Rras和RAS蛋白的表达，减少了P-38和JNK的磷酸化,从而抑制MAPK途径的激活。JNJ-10,397,049（一种OXR2阻断剂）逆转了OXA的作用，而SB-334,867（OXR1阻断剂）则没有。
结论：这项研究表明，鼻内给药适量的OXA可以保护BBB并抑制OXR2/RAS/MAPK通路的激活，从而减轻SAE的后果。提示OXA可能是一种有前途的SAE治疗方法。
