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Exendin-4 and linagliptin attenuate neuroinflammation in a mouse model of Parkinson's disease

Neural Regeneration Research 2023年第8期18卷 1818-1826页

作者： Hai-Yang Yu Tong Sun Zhen Wang Hong Li Duo Xu Jing An Lu-Lu Wen Jia-Yi Li Wen Li Juan Feng Department of Neurology Shengjing Hospital of China Medical UniversityShenyangLiaoning ProvinceChina Department of Pediatrics Shengjing Hospital of China Medical UniversityShenyangLiaoning ProvinceChina Laboratory of Research in Parkinson’s Disease and Related Disorders Health Sciences InstituteChina Medical UniversityShenyangLiaoning ProvinceChina Neural Plasticity and Repair Unit Department of Experimental Medical ScienceLund UniversityLundSweden

Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson's disease in patients with diabetes ***,using these two treatments may help treat Parkinson's *** further investigate the mechanisms of action of these two compounds,we established a model of Parkinson's disease by treating mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then subcutaneously injected them with the glucagon-like peptide-1 receptor agonist exendin-4 or the dipeptidyl peptidase 4 inhibitor *** found that both exendin-4 and linagliptin reversed motor dysfunction,glial activation,and dopaminergic neuronal death in this *** addition,both exendin-4 and linagliptin induced microglial polarization to the anti-inflammatory M2 phenotype and reduced pro-inflammatory cytokine ***,in vitro experiments showed that treatment with exendin-4 and linagliptin inhibited activation of the nucleotide-binding oligomerization domain-and leucine-rich-repeat-and pyrin-domaincontaining 3/caspase-1/interleukin-1βpathway and subsequent pyroptosis by decreasing the production of reactive oxygen *** findings suggest that exendin-4 and linagliptin exert neuroprotective effects by attenuating neuroinflammation through regulation of microglial polarization and the nucleotidebinding oligomerization domain-and leucine-rich-repeat-and pyrin-domain-containing 3/caspase-1/interleukin-1βpathway in a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,***,these two drugs may serve as novel anti-inflammatory treatments for Parkinson's disease.

关键词： diabetes mellitus dipeptidyl peptidase 4 inhibitor exendin-4 glucagon-like peptide-1 receptor agonist 1-methyl-4-phenyl-1 2 3 6-tetrahydropyridine linagliptin microglia neuroinflammation NLRP3 inflammasome Parkinson's disease pyroptosis

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Comparison of gliclazide vs linagliptin on hypoglycemia and cardiovascular events in type 2 diabetes mellitus: A systematic review

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World Journal of Diabetes 2022年第12期13卷 1168-1183页

作者： Viswanathan Mohan Subhash Wangnoo Sambit Das Rajnish Dhediya Kumar Gaurav Department of Diabetes Madras Diabetes Research Foundation&Dr Mohan’s Diabetes Specialties CentreChennai 600086Tamil NaduIndia Department of Diabetes Apollo Hospital Education and Research FoundationNew Delhi 110001India Department of Endocrinology Endeavour ClinicsBhubaneswar 750017India Medical Affairs Dr.Reddy’s Laboratories LtdHyderabad 500016India

BACKGROUND Cardiovascular outcome trials have demonstrated cardiovascular safety of glimepiride(a sulfonylureas) against dipeptidyl peptidase-4 inhibitor ***(another newer sulfonylureas) has shown similar glycemic efficacy and 50% decreased risk of hypoglycemia compared to *** Considering the absence of cardiovascular outcome trials for gliclazide, we decided to conduct a systematic review of the literature to assess the cardiovascular(CV) safety by assessing the risk for major adverse CV events and hypoglycemia risk of gliclazide vs linagliptin in patients with type 2 diabetes(T2D).METHODS This systematic review followed the current Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to analyze all the clinical studies published from 2008 that compared the two drugs in patients with T2D with no risk of CV disease(CVD). We included only evidence designated high quality by the Oxford Center for Evidence-based Medicine-Levels of *** Eight clinical studies were included in the narrative descriptive analysis(gliclazide: 5 and linagliptin: 3). The CV safety of gliclazide in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation trial and of linagliptin in the Cardiovascular and Renal Microvascular Outcome Study With linagliptin(CARMELINA) and CARdiovascular Outcome study of linagliptin vs glimepiride in patients with T2D(CAROLINA)trials were excluded from the comparative analysis as these trials demonstrated CV and hypoglycemia benefits in patients at high risk of CVD. However, since these are landmark trials,they were discussed in brief to show the CV benefits and low hypoglycemia risk of gliclazide and linagliptin. We did not find any study comparing gliclazide with linagliptin. Hence, direct comparison of their major adverse CV events and hypoglycemia risk could not be carried ***, the literature meeting the inclusion criteria showed that b

关键词： linagliptin Gliclazide Hypoglycemia Major cardiovascular adverse events Type 2 diabetes

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DPP-4 Inhibitor linagliptin is Neuroprotective in Hyperglycemic Mice with Stroke via the AKT/mTOR Pathway and Anti-apoptotic Effects

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Neuroscience Bulletin 2020年第4期36卷 407-418页

作者： Gang Zhang Samuel Kim Xiaohuan Gu Shan Ping Yu Ling Wei Department of Anesthesiology Emory University School of MedicineAtlantaGA 30322USA Department of Neurology Children's Hospital of Nanjing Medical UniversityNanjing 210000China Department of Neurology Emory University School of MedicineAtlantaGA 30322USA

Dipeptidyl peptidase 4 (DPP-4) inhibitors have been shown to have neuroprotective effects in diabetic patients suffering from stroke, but less research has focused on patients with mild hyperglycemia below the threshold for a diagnosis of diabetes. In this investigation, a hyperglycemic mouse model was generated by intraperitoneal injection of streptozotocin and then subjected to focal cerebral ischemia. We demonstrated that the DPP-4 inhibitor linagliptin significantly decreased the infarct volume, reduced neuronal cell death, decreased inflammation, and improved neurological deficit compared with control mice. linagliptin up-regulated the expression of p-Akt and p-m TOR and regulated the apoptosis factors Bcl-2, Bax, and caspase 9. Taken together, these results suggest that linagliptin exerts a neuroprotective action likely through activation of the Akt/m TOR pathway along with anti-apoptotic and anti-inflammatory ***, linagliptin may be considered as a therapeutic treatment for stroke patients with mild hyperglycemia.

关键词： Cerebral ischemia Hyperglycemia DPP-4 inhibitor linagliptin Neuroprotection

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Efficacy of anagliptin as compared to linagliptin on metabolic parameters over 2 years of drug consumption: A retrospective cohort study

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World Journal of Diabetes 2018年第10期9卷 165-171页

作者： Hidetaka Hamasaki Yasuteru Hamasaki Endocrinology and Metabolism Internal Medicine Hamasaki Clinic Diabetes Hamasaki Clinic

AIM To evaluate the comparative effectiveness of anagliptin and linagliptin on the clinical parameters in patients with type 2 diabetes mellitus(T2 DM). METHODS A 2-year retrospective cohort study was conducted in patients with T2 DM who received anagliptin and linagliptin. We enrolled 234 patients(anagliptin group, 117 patients; linagliptin group, 117 patients). RESULTS The glycemic control considerably improved 3, 6, 12, and 24 mo after the administration of both dipeptidyl peptidase-4(DPP-4) inhibitors. Following the administration of anagliptin, the diastolic blood pressure and serum total cholesterol levels decreased. However, serum high-density lipoprotein cholesterol levels increased and urinary albumin-creatinine ratio decreased following linagliptin administration. Furthermore, the liver function improved after the administration of *** These findings suggest that that the efficacy of DPP-4 inhibitors on the blood pressure, lipid profile, and liver function differs between anagliptin and linagliptin.

关键词： Type 2 diabetes mellitus Dipeptidyl peptidase-4 inhibitor Anagliptin linagliptin Cholesterol

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Cardioprotective effect of linagliptin on diabetic Wistar rats

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Journal of Chinese Pharmaceutical Sciences 2021年第4期30卷 334-346页

作者： Rong Li Lihua Song Jie Liu Yang Bai Yuming Du Chunhua Lin Xiuyuan Su Zongxue Yu Jilin People’s Hospital Changchun 130000JilinChina Qingdao Third People’s Hospital Qingdao 266000ShandongChina First Hospital of Jilin University Changchun 130000JilinChina

Diabetic cardiomyopathy(DCM)is an important cardiovascular complication of diabetes mellitus,while the pathogenesis of DCM has not been fully *** the present study,we aimed to investigate the effect of linagliptin on cardiomyocytes of diabetic rats and its *** function was evaluated by two-dimensional ultrasound at different time points for each *** staining was used to evaluate myocardial injury and inflammatory ***-red staining was used to observe the degree of myocardial fibrosis under optical *** staining was used to investigate the degree of cardiomyocyte apoptosis in four *** expressions of m RNAs in relevant cells,including Bcl-2,Bax,TNF-α,PAI-1,CTGF and TGF-β1,were measured by reverse transcription polymerase chain reaction(RT-PCR)and Western blotting analysis in different *** expression and transcriptional function of Nrf2 in myocardium activated by Lingliptin were determined using RT-PCR,Western blotting analysis and *** results showed that the left ventricular volume(LV),left ventricular thickness(LT),fasting blood glucose(FBG)and heart weight/body weight(HW/BW)in diabetes and linagliptin CO treatment group were significantly lower compared with diabetic group(Plinagliptin made the arrangement of myocardial fibers more regular,and the striation of myocardial cells became *** Sirus-red staining showed that there was significant accumulation of collagen in the diabetic group rats,indicating that the rats in diabetic group had cardiac *** phenomenon in diabetes and linagliptin CO treatment group was *** staining showed that at time point of 4 weeks,the degree of cardiomyocyte apoptosis in diabetes and linagliptin CO treatment group was lower compared with diabetic group(P<0.01).The expressions of cleaved-caspase-3,TNF-α,PAI-

关键词： Diabetic cardiomyopathy linagliptin Nrf2 Oxidative stress

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Effects of linagliptin on inflammatory factors and arteriosclerosis in patients with newly diagnosed type 2 diabetes mellitus

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Journal of Chinese Pharmaceutical Sciences 2021年第8期30卷 692-698页

作者： Rui Li Yanru Kong Department of Emergency The Second HospitalCheeloo College of MedicineShandong UniversityJinan 250033ShandongChina Department of Echocardiography The Second HospitalCheeloo College of MedicineShandong UniversityJinan 250033ShandongChina

In the present study,we aimed to investigate the effects of linagliptin on inflammatory factors and carotid intima-media thickness(CIMT)in newly diagnosed type 2 diabetes mellitus(T2 DM)patients with carotid atherosclerotic disease(CAD).A total of 326 patients with newly diagnosed T2 DM complicated with CAD were randomly divided into two *** were 163 patients in the control group,who were treated with metformin *** were 163 patients in the experimental group,who were treated with metformin in combination with *** CIMT before and after treatment was measured by color Doppler ultrasound,and the contents of IL-6 and IL-1βbefore and after treatment were detected by *** levels of inflammatory factors and CIMT before and after treatment were compared between the two groups,and the correlation between IL-6,IL-1βand CIMT was *** 24 weeks of treatment,the levels of inflammatory factors and CIMT in the experimental group were significantly lower compared with the control group(Plinagliptin could improve the levels of inflammatory factors and CIMT in newly diagnosed T2 DM patients with CAD,and IL-6 and IL-1βmight participate in the occurrence and development of CAD by influencing CIMT.

关键词： linagliptin Type 2 diabetes mellitus Carotid atherosclerosis disease Inflammatory factors Carotid intima-media thickness

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linagliptin alleviates fatty liver disease in diabetic db/db mice

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World Journal of Diabetes 2016年第19期7卷 534-546页

作者： Svetlana V Michurina Irina Ju Ishenko Vadim V Klimontov Sergey A Archipov Natalia E Myakina Marina A Cherepanova Eugenii L Zavjalov Galina V Koncevaya Vladimir I Konenkov Laboratory of Functional Morphology Scientific Institute of Clinical and Experimental Lymphology Laboratory of Endocrinology Scientific Institute of Clinical and Experimental Lymphology SPF-vivarium Institute of Cytology and Genetics of Siberian Branch of Russian Academy of Sciences Laboratory of Clinical Immunogenetics Scientific Institute of Clinical and Experimental Lymphology

AIM To study the effects of linagliptin on the structural signs of non-alcoholic fatty liver disease(NAFLD) in db/db mice. METHODS Male diabetic db /db mice(***-Dock7m+/+Leprdb/J) aged 10 wk received the dipeptidyl peptidase 4(DPP4) inhibitor linagliptin(10 mg/kg) or saline as a placebo once per day by gavage for 8 wk. Intact db/db mice served as controls. Structural changes in the liver were analyzed from light and electron microscopic images of sections from intact, placebo-treated and linagliptin-treated animals. We estimated the changes in hepatocytes, sinusoidal cells, liver microvasculature and lymphatic roots. Hepatic staining for lymphatic vessel endothelial hyaluronan receptor-1(LYVE-1) was assessed by immunohistochemistry. RESULTS In 18-wk-old diabetic mice, liver steatosis(predominantly microvesicular and mediovesicular steatosis) was accompanied by dilation of the roots of the lymphatic system, interlobular blood vessels and bile canaliculi. Compared to saline-treated mice, linagliptin-treated mice exhibited a reduction in the mean numeral densities of hepatocytes with lipid droplets(92.4% ± 1.7% vs 64.9% ± 5.8% per field of view, P = 0.0002) and a lower proportion of hepatocytes with a high density of lipid droplets(20.7% ± 3.6% vs 50.4% ± 3.1%, P = 0.0007). We observed heterogeneous hepatocytes and relatively preserved cell structures in the linagliptin group. Dilation of blood and lymphatic vessels, as well as ultrastructural changes in the hepatocyte endoplasmic reticulum and mitochondria, were alleviated by linagliptin treatment. In intact and placebo-treated mice, immunohistochemical staining for LYVE-1 was observed in the endothelial cells of interlobular lymphatic vessels and on the membranes of some endothelial sinusoidal cells. We observed an enlarged LYVE-1 reaction area in linagliptin-treated mice compared to intact and placebo-treated mice. The improvement in the structural parameters of the liver in linagliptin-treated mice was independe

关键词： Diabetes Obesity Non-alcoholic fatty liver disease Dipeptidyl peptidase 4 linagliptin

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抗糖尿病新药linagliptin的临床研究进展

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中国药房 2012年第22期23卷 2086-2090页

作者：余志清湖北秭归县人民医院湖北秭归443600

目的:介绍抗糖尿病新药linagliptin的临床研究进展。方法:根据文献,综述该药的理化性质及临床研究进展。结果与结论:linagliptin是一种口服有效的具有高选择性的DPP-4抑制剂,单用或与其他经典抗糖尿病药合用,均可有效降低糖化血红蛋白(H... 详细信息

目的:介绍抗糖尿病新药linagliptin的临床研究进展。方法:根据文献,综述该药的理化性质及临床研究进展。结果与结论:linagliptin是一种口服有效的具有高选择性的DPP-4抑制剂,单用或与其他经典抗糖尿病药合用,均可有效降低糖化血红蛋白(HbA1c)水平;同时也可有效控制空腹血糖浓度和餐后2h血糖浓度,且肝功能下降和肾功能不全的2型糖尿病患者的给药剂量无需调整。在安全性、有效性及耐受性等方面具有独特的优点。

关键词： linagliptin 糖尿病临床研究进展

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抗2型糖尿病药linagliptin

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药学进展 2010年第9期34卷 429-429页

作者：范鸣

linagliptin是由勃林格殷格翰(BI)公司开发的gliptins类二肽基肽酶-4(DPP-4)抑制剂,该类药物,包括默克公司于2006年获准上市的首个gliptins类药物sitagliptin(Januvia)、百时美施贵宝公司在欧美上市的saxagliptin(Onglyza)、诺华公司仅在欧盟上市的vildagliptin(Galvus)以及武田公司已在日本获准、并正在美国申请上市的alogliptin(Nesina),具有大致相似的功效,但linagliptin的主要优势在于其与其他DPP-4抑制剂不同,主要经粪便排泄,其经口给药后,经肾排泄的量仅为用药量的约5%,即使静脉注射给药,也只有30.8%经肾排泄,因此其使用者无需定期检查肾功能和相应调整用药剂量,所有用药者可统一固定剂量,更便于开处方.

关键词： linagliptin DPP-4抑制剂 2型糖尿病 HbA1c

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Dipeptidyl peptidase-4: A key player in chronic liver disease

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World Journal of Gastroenterology 2013年第15期19卷 2298-2306页

作者： Minoru Itou Takumi Kawaguchi Eitaro Taniguchi Michio Sata Division of Gastroenterology Department of MedicineKurume University School of MedicineKurume 830-0011Japan Division of Gastroenterology Department of Medicine and Department of Digestive Disease Information and ResearchKurume University School of MedicineKurume 830-0011Japan

Dipeptidyl peptidase-4 (DPP-4) is a membrane-associated peptidase, also known as CD26. DPP-4 has widespread organ distribution throughout the body and exerts pleiotropic effects via its peptidase activity. A representative target peptide is glucagon-like peptide-1, and inactivation of glucagon-like peptide-1 results in the development of glucose intolerance/diabetes mellitus and hepatic steatosis. In addition to its peptidase activity, DPP-4 is known to be associated with immune stimulation, binding to and degradation of extracellular matrix, resistance to anti-cancer agents, and lipid accumulation. The liver expresses DPP-4 to a high degree, and recent accumulating data suggest that DPP-4 is involved in the development of various chronic liver diseases such as hepatitis C virus infection, non-alcoholic fatty liver disease, and hepatocellular carcinoma. Furthermore, DPP-4 occurs in hepatic stem cells and plays a crucial role in hepatic regeneration. In this review, we described the tissue distribution and various biological effects of DPP-4. Then, we discussed the impact of DPP-4 in chronic liver disease and the possible therapeutic effects of a DPP-4 inhibitor.

关键词： Incretin Viral hepatitis Insulin resistance Steatohepatitis Cancer Sitagliptin Vildagliptin Alogliptin Teneligliptin linagliptin

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