GLP-1受体激动剂对新生儿缺氧缺血性脑损伤模型小鼠在突触可塑性方面的保护作用

Protective effect of GLP-1 receptor agonists on synaptic plasticity in neonatal hypoxic-ischemic brain injury model mice

摘要:

目的 探讨胰高血糖素样肽-1受体（glucagon-like peptide-1 receptor，GLP-1R）激动剂（agonist，NLY01）对新生儿缺氧缺血性脑损伤（hypoxia ischemia，HI）模型小鼠在突触可塑性方面的保护作用。方法 实验1，将P7小鼠分配到对照组（Con组）、HI组、NLY01组和HI+NLY01组，每组16只；实验2，将P7小鼠分配到HI组、HI+NLY01组、HI+Ex9-39组和HI+NLY01+Ex9-39组，每组8只。其中，Ex9-39用于阻断GLP-1R。进行行为测试以测量学习能力。高尔基染色用于测量齿状回突触的可塑性。通过蛋白质印迹和免疫荧光评估突触和神经炎症相关蛋白的表达。结果 NLY01对GLP-1R的激活防止了由HI引起的认知缺陷。NLY01阻止了HI诱导的GLP-1R水平降低。GLP-1R的激活显著改善了突触可塑性的损害，阻止了炎症因子的上调，并抑制了核因子-κB（nuclear factor-κB，NF-κB）磷酸化和小胶质细胞M1极化。在HI模型中，NLY01对HI诱导的新生小鼠急性脑损伤的保护作用被Ex9-39阻断。结论 GLP-1R可能是调节新生小鼠急性脑损伤炎症途径的功能靶点，支持GLP-1R激动剂在HI诱导新生小鼠脑损伤中的潜在治疗作用。

Abstract:

Objective To investigate the protective effect of glucagon-like peptide-1 receptor（GLP-1R） agonist（NLY01） on synaptic plasticity in neonatal hypoxia ischemia（HI） model mice.Methods In experiment 1，P7 mice were assigned to one of the following four groups，n=16/group：control group （Con group）， HI group， NLY01 group and HI+NLY01 group. In experiment 2， P7 mice were assigned to four groups（n=8/group）：HI group， HI+NLY01 group， HI+Ex9-39 group and HI+NLY01+Ex9-39 group. Among them， Ex9-39 was used to block GLP-1R. Behavioral tests were performed to measure learning ability. Golgi staining was used to measure dentate gyrus synaptic plasticity. Expression of synaptic and neuroinflammation-related proteins was assessed by Western blotting and immunofluorescence.Results Activation of GLP-1R by NLY01 prevented the emotional and cognitive deficits caused by HI. NLY01 prevented HI-induced reduction in GLP-1R levels. Activation of GLP-1R significantly ameliorated the impairment of synaptic plasticity，prevented the upregulation of inflammatory factors，and suppressed nuclear factor-κB（NF-κB） phosphorylation and microglial M1 polarization. In the HI model，the protective effect of NLY01 on HI-induced neonatal mice was blocked by Ex9-39.Conclusion GLP-1R may be a functional target regulating inflammatory pathways in acute brain injury in neonatal mice，supporting a potential therapeutic role of GLP-1R agonists in HI-induced neonatal mice.