利拉鲁肽通过p38 MAPK通路改善高同型半胱氨酸血症诱导的大鼠海马氧化应激及炎症损伤

目的:探讨胰高血糖素样肽1(GLP-1)类似物利拉鲁肽(Lir)对高同型半胱氨酸血症(Hhcy)大鼠海马损伤的保护作用及其机制。方法:40只SD大鼠随机分为对照(Ctrl)组、模型(Hhcy)组、Lir低剂量(12.5μg·kg~(-1)·h~(-1))组、Lir中剂量(25.0μg·kg~(-1)·h~(-1))组和Lir高剂量(37.5μg·kg~(-1)·h~(-1))组,采用Western blot法检测大鼠海马组织内丝裂原活化蛋白激酶(MAPK)信号通路中p38、JNK和ERK1/2的蛋白表达及活性依赖的磷酸化水平,同时采用Western blot和免疫组织化学法检测内质网应激标志蛋白免疫球蛋白重链结合蛋白(BIP)和C/EBP同源蛋白(CHOP)的表达水平;采用酶标法检测超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)活性及丙二醛(MDA)含量;酶联免疫吸附法检测炎症因子白细胞介素1β(IL-1β)、白细胞介素6(IL-6)和肿瘤坏死因子α(TNF-α)水平。结果:Hhcy可明显上调p-p38、BIP和CHOP的蛋白表达量,降低SOD和GSH的活性,升高MDA含量及IL-1β、IL-6和TNF-α水平;腹腔注射Lir可浓度依赖性地改善Hhcy引起的上述内质网应激和炎症反应,并伴有p38 MAPK通路的抑制。结论:Lir可改善Hhcy诱导的大鼠海马组织氧化应激和炎症损伤,其机制可能与抑制p38 MAPK信号通路的过度激活有关。

Liraglutide attenuates hyperhomocysteinemia-induced oxidative stress and inflammatory response in rat hippocampus via p38 MAPK signaling pathway

AIM: To investigate the protective effect of liraglutide (Lir), an analog of glucgon-like peptide-1 (GLP-1), on hyperhomocysteinemia (Hhcy)-induced hippocampal pathological injury and the underlying molecular mechanisms in rats. METHODS: Sprague-Dawley rats (n=40) were randomly divided into 5 groups:control (Ctrl) group, model (Hhcy) group, low-dose Lir treatment (Lir-L) group, medium-dose Lir treatment (Lir-M) group and high-dose Lir treatment (Lir-H) group. The protein levels of p-p38, p-ERK1/2, p-JNK, immunoglobulin heavy chain binding protein (BIP) and C/EBP homology protein (CHOP) were determined by Western blot and immunohistochemical staining. The activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH), and the content of malondialdehyde (MDA) were measured. The expression levels of interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) were examined by ELISA. RESULTS: Hhcy increased the levels of p-p38, BIP, CHOP, MDA, IL-1β, IL-6 and TNF-α,and reduced the activity of SOD and GSH, while simultaneous administration of Lir dose-dependently attenuated the Hhcy-induced oxidative stress and inflammatory responses, accompanied with the inhibition of p38 MAPK signaling pathway. CONCLUSION: Lir ameliorates Hhcy-induced oxidative stress and inflammatory injury in rat hippocampi with the mechanisms involving suppression of p38 MAPK pathway.