药学学报, 2021, 56(5): 1391-1399
引用本文:
胡子奇, 廖雁君, 刘玉民, 李淑坤, 仝萌, 汪晶, 舒娈. 葛根素对高脂诱导糖尿病小鼠抑郁症状的改善作用及机制研究[J]. 药学学报, 2021, 56(5): 1391-1399.
HU Zi-qi, LIAO Yan-jun, LIU Yu-min, LI Shu-kun, TONG Meng, WANG Jing, SHU Luan. Puerarin ameliorates depressive symptoms in diabetic mice induced by high-fat diet[J]. Acta Pharmaceutica Sinica, 2021, 56(5): 1391-1399.

葛根素对高脂诱导糖尿病小鼠抑郁症状的改善作用及机制研究
胡子奇1,2, 廖雁君1,2, 刘玉民1,2, 李淑坤1,2, 仝萌1,2, 汪晶1,2*, 舒娈1,2*
1. 南京中医药大学附属中西医结合医院, 江苏 南京 210028;
2. 江苏省中医药研究院, 江苏 南京 210028
摘要:
前期研究表明,中药葛根活性成分葛根素通过激活胰高血糖素样肽-1受体(glucagon-like peptide-1 receptor,GLP-1R)通路改善高脂(high-fat diet,HFD)诱导糖尿病小鼠糖代谢,本研究拟进一步评价葛根素对HFD小鼠抑郁症状的影响。采用高脂饲料长期喂养诱导小鼠产生2型糖尿病及并发抑郁样症状,动物福利和实验过程均遵循南京中医药大学附属中西医结合医院动物伦理委员会的规定(批准号:AEWC-025)。实验分为:对照组、模型组、模型/葛根素(150 mg·kg-1·day-1)组和模型/氟西汀(15 mg·kg-1·day-1)组。每日1次灌胃给药,连续给药6周后,进行小鼠口服葡萄糖耐量测试(oral glucose tolerance test,OGTT)及行为学测试分析。同时采用ELISA(enzyme-linked immunosorbent assay)法检测各组小鼠血清中白介素(interleukin,IL)-1β、IL-6、5-羟色胺(5-hydroxytryptamine,5-HT)和皮质酮(corticosterone,CORT)含量。Western blot法检测小鼠大脑海马体中神经可塑性以及抑郁症相关蛋白的激活与表达水平。同时采用小鼠海马神经元细胞系HT22细胞考察葛根素对细胞形态与生存的保护作用。结果显示葛根素能够有效保护在高糖与皮质酮环境下HT22细胞的生存。给予葛根素治疗后,糖尿病小鼠血糖调节能力改善,抑郁症状减轻,5-HT含量升高,CORT、IL-1β和IL-6含量降低。海马组织中GLP-1R/Wnt/mTOR(mammalian target of rapamycin)信号中相关蛋白上调,提示其对糖尿病小鼠抑郁症状的改善作用可能与激活GLP-1R/Wnt/mTOR信号通路相关。本研究表明,葛根素能够显著改善高脂诱导的糖尿病小鼠抑郁症状,其作用可能是通过激活GLP-1R/Wnt/mTOR信号通路,改善海马神经可塑性而实现。
关键词:    葛根素      糖尿病      抑郁症      海马      神经元可塑性      胰高血糖素样肽-1受体     
Puerarin ameliorates depressive symptoms in diabetic mice induced by high-fat diet
HU Zi-qi1,2, LIAO Yan-jun1,2, LIU Yu-min1,2, LI Shu-kun1,2, TONG Meng1,2, WANG Jing1,2*, SHU Luan1,2*
1. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China;
2. Jiangsu Academy of Traditional Chinese Medicine, Nanjing 210028, China
Abstract:
Our previous studies have shown that puerarin, an active component of the traditional Chinese medicine-Pueraria Lobata, can improve glycometabolism in high-fat diet (HFD) mice with diabetes by activating the glucagon-like peptide-1 receptor (GLP-1R) pathway. This study intends to further evaluate the effect of puerarin on depressive symptoms in HFD mice. Long-term HFD induces type 2 diabetes and depressive-like symptoms in mice. Animal welfare and experimental procedures follow the regulations of the Animal Ethics Committee of the Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Traditional Chinese Medicine (approval No. AEWC-025). The experiment was divided into:control group, model group, model/puerarin (150 mg·kg-1·day-1) group, and model/fluoxetine (15 mg·kg-1·day-1) group. The oral glucose tolerance test (OGTT) and behavioral experimental analysis were performed after 6 weeks of continuous administration. Afterwards, enzyme-linked immunosorbent assay (ELISA) was used to detect interleukin-1β (IL-1β), interleukin-6 (IL-6), 5-hydroxytryptamine (5-HT), and corticosterone (CORT) in serum of mice for each group. Western blot assays were used to detect the level of activation and expression of proteins related to neuroplasticity and depressive disorder in the hippocampus. Moreover, HT-22 cell line was used to investigate the protective effect of puerarin on cell morphology and survival. The results show that puerarin can effectively maintain the survival of HT22 in an environment with high glucose and corticosterone. Meantime, the glycemic regulation of diabetic mice was improved after treatment of puerarin, the depressive symptoms were alleviated, the 5-HT increased, and the corticosterone, IL-1β, and IL-6 decreased in the serum. The up-regulation of related proteins in GLP-1R/Wnt/mTOR (mammalian target of rapamycin) signaling in hippocampus suggests that its effect on ameliorating depression in diabetic mice may be related to the activation of GLP-1R/Wnt/mTOR signaling pathway. This study shows that puerarin can significantly ameliorate the depressive symptoms of HFD induced diabetic mice which might be achieved through activating the GLP-1R/Wnt/mTOR signaling pathway and improving hippocampal neuroplasticity.
Key words:    puerarin    diabetes mellitus    depressive disorder    hippocampus    neuronal plasticity    glucagon-like peptide-1 receptor   
收稿日期: 2020-12-28
DOI: 10.16438/j.0513-4870.2020-1971
基金项目: 国家自然科学基金资助项目(81102488,81370924,81803756);江苏省高校护理学优势学科建设工程资助项目(2019YSHL123).
通讯作者: 汪晶,Tel:13914718827,E-mail:wangjing3968@126.com;舒娈,E-mail:shuluan2006@hotmail.com
Email: wangjing3968@126.com;shuluan2006@hotmail.com
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参考文献:
[1] Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045:results from the International Diabetes Federation Diabetes Atlas, 9th edition[J]. Diabetes Res Clin Pract, 2019, 157:107843.
[2] Novak M, Mucsi I, Rhee CM, et al. Increased risk of incident chronic kidney disease, cardiovascular disease, and mortality in patients with diabetes with comorbid depression[J]. Diabetes Care, 2016, 39:1940-1947.
[3] Moulton CD, Pickup JC, Ismail K. The link between depression and diabetes:the search for shared mechanisms[J]. Lancet Diabetes Endocrinol, 2015, 3:461-471.
[4] Sartorius N. Depression and diabetes[J]. Dialogues Clin Neurosci, 2018, 20:47-52.
[5] Yao JH, Wang J, Hu ZQ, et al. Exendin-4 promotes the anti-diabetic effects of puerarin in high fat diet diabetic mice[J]. Acta Pharm Sin (药学学报), 2020, 55:1209-1213.
[6] Cork SC, Richards JE, Holt MK, et al. Distribution and characterisation of glucagon-like peptide-1 receptor expressing cells in the mouse brain[J]. Mol Metab, 2015, 4:718-731.
[7] Korol SV, Jin Z, Babateen O, et al. GLP-1 and exendin-4 transiently enhance GABAA receptor-mediated synaptic and tonic currents in rat hippocampal CA3 pyramidal neurons[J]. Diabetes, 2015, 64:79-89.
[8] Mansur RB, Lee Y, Subramaniapillai M, et al. Cognitive dysfunction and metabolic comorbidities in mood disorders:a repurposing opportunity for glucagon-like peptide 1 receptor agonists?[J]. Neuropharmacology, 2018, 136:335-342.
[9] Luo C, Ke Y, Yuan Y, et al. A novel herbal treatment reduces depressive-like behaviors and increases brain-derived neurotrophic factor levels in the brain of type 2 diabetic rats[J]. Neuropsychiatr Dis Treat, 2016, 12:3051-3059.
[10] Wang JQ, Mao L. The ERK pathway:molecular mechanisms and treatment of depression[J]. Mol Neurobiol, 2019, 56:6197-6205.
[11] Zanos P, Thompson SM, Duman RS, et al. Convergent mechanisms underlying rapid antidepressant action[J]. CNS Drugs, 2018, 32:197-227.
[12] Deng ZF, Zheng HL, Chen JG, et al. miR-214-3p targets β-catenin to regulate depressive-like behaviors induced by chronic social defeat stress in mice[J]. Cereb Cortex, 2019, 29:1509-1519.
[13] Huang SJ, WU W, Wang YY. Radix Puerariae in antidepressant research and application[J]. Liaoning J Tradit Chin Med (辽宁中医杂志), 2014, 41:1333-1336.
[14] Hassan AM, Mancano G, Kashofer K, et al. High-fat diet induces depression-like behaviour in mice associated with changes in microbiome, neuropeptide Y, and brain metabolome[J]. Nutr Neurosci, 2019, 22:877-893.
[15] Vagena E, Ryu JK, Baeza-Raja B, et al. A high-fat diet promotes depression-like behavior in mice by suppressing hypothalamic PKA signaling[J]. Transl Psychiatry, 2019, 9:141.
[16] Yang L, Yao D, Yang H, et al. Puerarin protects pancreatic β-cells in obese diabetic mice via activation of GLP-1R signaling[J]. Mol Endocrinol, 2016, 30:361-371.
[17] Lin J, Yang Q, Liu J, et al. Effects of zuogui jiangtang jieyu formula on hippocampus neuron apoptosis related proteins under diabetes mellitus with depression states[J]. Chin J Inf Tradit Chin Med (中国中医药信息杂志), 2017, 24:35-39.
[18] Mahar I, Bambico FR, Mechawar N, et al. Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects[J]. Neurosci Biobehav Rev, 2014, 38:173-192.
[19] van Donkelaar EL, Vaessen KRD, Pawluski JL, et al. Long-term corticosterone exposure decreases insulin sensitivity and induces depressive-like behaviour in the C57BL/6NCrl mouse[J]. PLoS One, 2014, 9:e106960.
[20] Shukla V, Shakya AK, Perez-Pinzon MA, et al. Cerebral ischemic damage in diabetes:an inflammatory perspective[J]. J Neuroinflamm, 2017, 14:21.
[21] Del Giudice M, Gangestad SW. Rethinking IL-6 and CRP:why they are more than inflammatory biomarkers, and why it matters[J]. Brain Behav Immun, 2018, 70:61-75.
[22] Timper K, Denson JL, Steculorum SM, et al. IL-6 improves energy and glucose homeostasis in obesity via enhanced central IL-6 trans-signaling[J]. Cell Rep, 2017, 19:267-280.
[23] Stieglitz J, Trumble BC, Thompson ME, et al. Depression as sickness behavior? A test of the host defense hypothesis in a high pathogen population[J]. Brain Behav Immun, 2015, 49:130-139.
[24] Meresman GF, Götte M, Laschke MW. Plants as source of new therapies for endometriosis:a review of preclinical and clinical studies[J]. Hum Reprod Update, 2020. DOI:10.1093/humupd/dmaa039.
[25] Wang X, Yan J, Xu X, et al. Puerarin prevents LPS-induced acute lung injury via inhibiting inflammatory response[J]. Microb Pathog, 2018, 118:170-176.
[26] Deng HF, Wang S, Wang XL, et al. Puerarin protects against LPS-induced vascular endothelial cell hyperpermeability via preventing downregulation of endothelial cadherin[J]. Inflammation, 2019, 42:1504-1510.
[27] Gao L, Li SL, Li YK. Liraglutide promotes the osteogenic differentiation in MC3T3-E1 cells via regulating the expression of Smad2/3 through PI3K/Akt and Wnt/β-catenin pathways[J]. DNA Cell Biol, 2018, 37:1031-1043.
[28] Xie J, El Sayed NM, Qi C, et al. Exendin-4 stimulates islet cell replication via the IGF1 receptor activation of mTORC1/S6K1[J]. J Mol Endocrinol, 2014, 53:105-115.
[29] Fanne RA, Nassar T, Heyman SN, et al. Insulin and glucagon share the same mechanism of neuroprotection in diabetic rats:role of glutamate[J]. Am J Physiol Regul Integr Comp Physiol, 2011, 70:R668-R673.
[30] Rehni A, Nautiyal N, Perez-Pinzon M, et al. Hyperglycemia/hypoglycemia-induced mitochondrial dysfunction and cerebral ischemic damage in diabetics[J]. Metab Brain Dis, 2015, 30:437-447.
[31] Abbas G, Al-Harrasi AS, Hussain H, et al. Antiglycation therapy:discovery of promising antiglycation agents for the management of diabetic complications[J]. Pharm Biol, 2016, 54:198-206.
[32] Pugazhenthi S, Qin L, Reddy PH. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer's disease[J]. Biochim Biophys Acta Mol Basis Dis, 2017, 1863:1037-1045.
[33] Zhu SW, Gao XX, Tian JS, et al. Research progress of traditional Chinese antidepressant herb-pair[J]. Acta Pharm Sin (药学学报), 2019, 54:235-244.
[34] Tu YM, Gong CX, Ding L, et al. A high concentration of fatty acids induces TNF-α as well as NO release mediated by the P2X4 receptor, and the protective effects of puerarin in RAW264.7 cells[J]. Food Funct, 2017, 8:4336-4346.
[35] Yokoyama K, Yamada T, Mitani H, et al. Relationship between hypothalamic-pituitary-adrenal axis dysregulation and insulin resistance in elderly patients with depression[J]. Psychiatry Res, 2015, 226:494-498.
[36] Grieco M, Giorgi A, Gentile MC, et al. Glucagon-like peptide-1:a focus on neurodegenerative diseases[J]. Front Neurosci, 2019, 13:1112.
[37] Weina H, Yuhu N, Christian H, et al. Liraglutide attenuates the depressive- and anxiety-like behaviour in the corticosterone induced depression model via improving hippocampal neural plasticity[J]. Brain Res, 2018, 1694:55-62.
[38] Licznerski P, Jonas EA. BDNF signaling:harnessing stress to battle mood disorder[J]. Proc Natl Acad Sci U S A, 2018, 115:3742-3744.
[39] Teo CH, Soga T, Parhar IS. Brain beta-catenin signalling during stress and depression[J]. Neurosignals, 2018, 26:31-42.
[40] Bockaert J, Marin P. mTOR in brain physiology and pathologies[J]. Physiol Rev, 2015, 95:1157-1187.
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