GuiZhou University Medical College, Guiyang, 550025, Guizhou Province, China.
Department of Neurosurgery, Guizhou Provincial People's Hospital, Guiyang, China.
J Neuroinflammation. 2024 May 17;21(1):131. doi: 10.1186/s12974-024-03111-w.
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.
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.
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.
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.
脓毒症相关性脑病（SAE）导致急性和长期认知缺陷。然而，关于脓毒症后认知功能障碍的预防和治疗的信息有限。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，从而在神经疾病中发挥保护作用。然而，OXA 在介导 SAE 的神经保护作用方面的作用尚未报道。
使用盲肠结扎穿孔（CLP）诱导 SAE 小鼠模型，并在手术后通过鼻腔内给予外源性 OXA 进行治疗。评估小鼠的存活率以及认知和焦虑行为。监测神经元变化、脑水肿、血脑屏障（BBB）通透性和脑超微结构。还测量了促炎因子（IL-1β、TNF-α）和小胶质细胞激活的水平。通过蛋白质组学分析和 Western blot 研究了潜在的分子机制。
鼻腔内 OXA 治疗可降低死亡率，改善认知和情绪障碍，并减轻脑水肿、BBB 破坏和脑超微结构损伤。此外，OXA 显著降低了促炎因子 IL-1β 和 TNF-α 的表达，并抑制了小胶质细胞激活。此外，OXA 下调了 Rras 和 RAS 蛋白的表达，并减少了 P-38 和 JNK 的磷酸化，从而抑制了 MAPK 通路的激活。JNJ-10,397,049（OXR2 阻断剂）逆转了 OXA 的作用，而 SB-334,867（OXR1 阻断剂）则没有。
这项研究表明，鼻腔内给予适量的 OXA 可保护 BBB 并抑制 OXR2/RAS/MAPK 通路的激活，从而减轻 SAE 的结局，表明 OXA 可能是治疗 SAE 的一种有前途的方法。
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