&nbsp;利拉鲁肽对百草枯诱导的小鼠帕金森病模型炎症及线粒体融合/分裂的影响

刘哲川; 李坤; 马帅男; 孟家琪; 王艳芹

doi:10.16098/j.issn.0529-1356.2023.06.008

PDF(1766 KB)

解剖学报 ›› 2023, Vol. 54 ›› Issue (6) : 676-681. DOI: 10.16098/j.issn.0529-1356.2023.06.008

神经生物学

利拉鲁肽对百草枯诱导的小鼠帕金森病模型炎症及线粒体融合/分裂的影响

刘哲川李坤马帅男孟家琪王艳芹*

作者信息 +

Effects of liraglutide on inflammation and mitochondrial fusion/division in Parkinson’s disease model of mice induced by paraquat

LIU Zhe-chuan LI Kun MA Shuai-nan MENG Jia-qi WANG Yan-qin*

Author information +

文章历史 +

摘要

目的探讨利拉鲁肽对百草枯（PQ）诱导的帕金森病（PD）小鼠模型保护作用以及作用机制。方法 24只昆明种小鼠随机分为对照组、PQ组、PQ +利拉鲁肽组，每组8只。通过连续5 d腹腔注射PQ (10 mg/kg)复制PD小鼠模型，连续7 d腹腔注射利拉鲁肽(50 nmol/kg)进行干预。采用行为学方法检测小鼠自主活动能力；免疫荧光观察酪氨酸羟化酶（TH）、离子钙接头蛋白分子1（Iba1）阳性细胞数；Western blotting检测TH、胶质纤维酸性蛋白（GFAP）、线粒体融合基因2（Mfn2）、线粒体动力相关蛋白1（Drp1）蛋白的表达。结果与对照组相比，PQ组站立次数极显著减少（P<0.01），活动次数显著减少（P<0.05），黑质TH阳性细胞数、TH蛋白表达极显著减少(P<0.01)，Iba1阳性细胞数、GFAP蛋白表达极显著增加(P<0.01)，Drp1蛋白表达显著增加(P<0.05)，Mfn2蛋白表达显著降低(P<0.05)。经利拉鲁肽干预后，与对照组相比，PQ +利拉鲁肽组TH阳性细胞数显著降低(P<0.05)；与PQ组相比，PQ +利拉鲁肽组小鼠站立次数、活动次数显著增加(P<0.05)，TH阳性细胞数、TH蛋白表达极显著增加(P<0.01)，Iba1阳性细胞数极显著减少(P<0.01)，GFAP蛋白表达显著减少(P<0.05)，Drp1蛋白表达极显著减少(P<0.01)，Mfn2蛋白表达极显著增加(P<0.01)。结论利拉鲁肽能减轻PQ诱导的PD模型小鼠黑质神经炎症，调节线粒体融合、分裂，减少多巴胺能神经元的丢失，具有神经保护作用。

Abstract

Objective To investigate the protective effect and mechanism of liraglutide on the paraquat (PQ)-induced Parkinson’s disease (PD) mouse model. Methods Totally 24 Kunming mice were randomly divided into control group, PQ group and PQ +liraglutide group, 8 mice in each group. PD model was established by intraperitoneal injection of PQ (10 mg/kg) for 5 consecutive days, and liraglutide (50 nmol/kg) was injected intraperitoneally for 7 consecutive days. The free-standing and locomotor activity of mice were measured by behavioral method. Immunofluorescence was used to observe the number of tyrosine hydroxylase (TH) and ionized calcium binding adaptor molecule 1 (Iba1) immunoreactive cells. Western blotting was used to detect the expression of protein TH, glial fibrillary acidic protein (GFAP), mitofusin-2 (Mfn2) and dynamin-related protein 1 (Drp1). Results The numbers of free-standing and locomotor activity numbers decreased significantly (P<0.01, P<0.05) in PQ group compared with the control group, and the number of TH immunoreactive cells and TH protein expression in substantia nigra decreased significantly (P<0.01, P<0.01) compared with the control group, while the number of Iba1 immunoreactive cells and GFAP protein expression increased significantly (P<0.01, P<0.01) compared with the control group; the expression of Drp1 protein in PQ group was significantly higher than that in control group (P<0.05), while the Mfn2 protein expression decreased significantly (P<0.05) compared with the control group. After treatment with liraglutide, the number of TH positive cells in PQ + liraglutide group was significantly lower than that in control group (P<0.05); the numbers of free-standing and locomotor activity increased significantly (P<0.05, P<0.05) in PQ + liraglutide group compared with the PQ group, and the number of TH positive cells and expression of TH protein in PQ + liraglutide group were significantly higher than that in PQ group (P<0.01, P<0.01); while the number of Iba1 positive cells and GFAP protein expression decreased significantly (P<0.01, P<0.05) compared with the PQ group; the Drp1 protein expression decreased significantly (P<0.01) compared with the PQ group, while the expression of Mfn2 protein in PQ + liraglutide group was significantly higher than that in PQ group (P<0.01). Conclusion Liraglutide has neuroprotective effect by reducing neuroinflammation in substantia nigra, regulating mitochondrial fusion and fission.

导出引用

刘哲川李坤马帅男孟家琪王艳芹.

利拉鲁肽对百草枯诱导的小鼠帕金森病模型炎症及线粒体融合/分裂的影响

[J]. 解剖学报. 2023, 54(6): 676-681 https://doi.org/10.16098/j.issn.0529-1356.2023.06.008

LIU Zhe-chuan LI Kun MA Shuai-nan MENG Jia-qi WANG Yan-qin. Effects of liraglutide on inflammation and mitochondrial fusion/division in Parkinson’s disease model of mice induced by paraquat[J]. Acta Anatomica Sinica. 2023, 54(6): 676-681 https://doi.org/10.16098/j.issn.0529-1356.2023.06.008

中图分类号： R742. 5

参考文献

［1］Tysnes OB, Storstein A. Epidemiology of Parkinson’s disease ［J］. J Neural Transm (Vienna), 2017,124(8):901-905.

［2］Beitz JM. Parkinson’ disease: a review［J］. Front Biosci (Schol Ed), 2014, (1):65-74.

［3］Sun X, Liang JQ, He JCh, et al. Research progress of animal models of Parkinson’s disease induced by neurotoxin［J］. Journal of Medical Research, 2020, 49(12):21-24.（in Chinese）

孙雪, 梁建庆, 何建成, 等. 神经毒素诱导帕金森病动物模型的研究进展［J］. 医学研究杂志, 2020, 49(12):21-24.

［4］Wang TT, Chen ZhCh, Ye X, et al. Effect of allopregnenolone on the dopaminergic neurons in the substantia nigra of Parkinson’s disease mice［J］. Acta Anatomisica Sinica, 2020, 51(4):473-482.（in Chinese）

王彤彤, 陈治池, 叶鑫, 等. 别孕烯醇酮对帕金森病模型小鼠黑质多巴胺能神经元的影响及可能的分子机制［J］. 解剖学报, 2020, 51(4):473-482.

［5］Marogianni C, Sokratous M, Dardiotis E, et al. Neurodegeneration and inflammation-an interesting interplay in Parkinson’s disease［J］. Int J Mol Sci, 2020,21(22):8427.

［6］Bose A, Beal MF. Mitochondrial dysfunction in Parkinson’s disease［J］. J Neurochem, 2016,139(1):216-231.

［7］Zhang L, Zhang L, Li Y, et al. The novel dual GLP-1/GIP receptor agonist DA-CH5 is superior to single GLP-1 receptor agonists in the MPTP model of Parkinson’s disease［J］. J Parkinsons Dis, 2020,10(2):523-542.

［8］Lin TK, Lin KJ, Lin HY, et al. Glucagon-like peptide-1 receptor agonist ameliorates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity through enhancing mitophagy flux and reducing α-synuclein and oxidative stress［J］. Front Mol Neurosci, 2021,14:697440.

［9］Jalewa J, Sharma MK, Hlscher C. Novel incretin analogues improve autophagy and protect from mitochondrial stress induced by rotenone in SH-SY5Y cells［J］. J Neurochem, 2016,139(1):55-67.

［10］Williams GP, Schonhoff AM, Jurkuvenaite A, et al. CD4 T cells mediate brain inflammation and neurodegeneration in a mouse model of Parkinson’s disease［J］. Brain, 2021,144(7):2047-2059.

［11］Hickman S, Izzy S, Sen P, et al. Microglia in neurodegeneration［J］. Nat Neurosci, 2018,21(10):1359-1369.

［12］Siracusa R, Fusco R, Cuzzocrea S. Astrocytes: role and functions in brain pathologies［J］. Front Pharmacol, 2019,10:1114.

［13］Diao X, Wang F, Becerra-Calixto A, et al. Induced pluripotent stem cell-derived dopaminergic neurons from familial Parkinson’s disease patients display α-synuclein pathology and abnormal mitochondrial morphology［J］. Cells, 2021,10(9):2402.

［14］Cao B, Zhang Y, Chen J, et al. Neuroprotective effects of liraglutide against inflammation through the AMPK/NF-κB pathway in a mouse model of Parkinson’s disease［J］. Metab Brain Dis, 2022,37(2):451-462.

［15］Monzio Compagnoni G, Di Fonzo A, Corti S, et al. The role of mitochondria in neurodegenerative diseases: the lesson from Alzheimer’s disease and Parkinson’s disease［J］. Mol Neurobiol, 2020,57(7):2959-2980.

［16］Richter V, Singh AP, Kvansakul M, et al. Splitting up the powerhouse: structural insights into the mechanism of mitochondrial fission［J］. Cell Mol Life Sci, 2015,72(19):3695-3707.

［17］Feng ST, Wang ZZ, Yuan YH, et al. Dynaminrelated protein 1: a protein critical for mitochondrial fission, mitophagy, and neuronal death in Parkinson’s disease［J］. Pharmacol Res, 2020,151:104553.

［18］Lee JY, Nagano Y, Taylor JP, et al. Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy［J］. J Cell Biol, 2010,189(4):671-679.

［19］Pham AH, Meng S, Chu QN, et al. Loss of Mfn2 results in progressive, retrograde degeneration of dopaminergic neurons in the nigrostriatal circuit［J］. Hum Mol Genet, 2012,21(22):4817-4826.

［20］Zhao F, Wang W, Wang C, et al. Mfn2 protects dopaminergic neurons exposed to paraquat both in vitro and in vivo: implications for idiopathic Parkinson’s disease［J］. Biochim Biophys Acta Mol Basis Dis, 2017,1863(6):1359-1370.

［21］Hu Z, Mao C, Wang H, et al. CHIP protects against MPP(+)/MPTP-induced damage by regulating Drp1 in two models of Parkinson’s disease［J］. Aging (Albany NY), 2021,13(1):1458-1472.

［22］Wu P, Dong Y, Chen J, et al. Liraglutide regulates mitochondrial quality control system through PGC-1α in a mouse model of Parkinson’s disease［J］. Neurotox Res, 2022,40(1):286-297.

［23］Jassim AH, Inman DM, Mitchell CH. Crosstalk between dysfunctional mitochondria and inflammation in glaucomatous neurodegeneration［J］. Front Pharmacol, 2021,12:699623.

［24］Voloboueva LA, Emery JF, Sun X, et al. Inflammatory response of microglial BV-2 cells includes a glycolytic shift and is modulated by mitochondrial glucose-regulated protein 75/mortalin［J］. FEBS Lett, 2013,587(6):756-762.

［25］Misawa T, Takahama M, Kozaki T, et al. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome［J］. Nat Immunol, 2013,14(5):454-460.

［26］Ongnok B, Maneechote C, Chunchai T, et al. Modulation of mitochondrial dynamics rescues cognitive function in rats with ’doxorubicin-induced chemobrain via ’ mitigation of mitochondrial dysfunction and neuroinflammation［J］. FEBS J, 2022,289(20):6435-6455.

［27］Stavropoulos F, Sargiannidou I, Potamiti L, et al. Aberrant mitochondrial dynamics and exacerbated response to neuroinflammation in a novel mouse model of CMT2A［J］. Int J Mol Sci, 2021,22(21):11569.