利西拉肽对阿尔茨海默病保护作用机制的研究进展
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摘要
近年来,越来越多的临床和实验数据表明2型糖尿病与阿尔茨海默病之间关系密切。2型糖尿病和阿尔茨海默病具有共同的病理生理特征:β淀粉样蛋白沉积、tau蛋白过磷酸化和葡萄糖合成酶3活性增加。研究发现2型糖尿病患者患阿尔茨海默病的风险与正常人比较有增加的趋势。对阿尔茨海默病动物模型脑组织进行研究,结果表明应用胰高血糖素样肽1类似物治疗后,脑内胰岛素抵抗得到改善,四羟壬烯酸、丙二醛等氧化应激指标显著减少,而其他病理特征有逆转的趋势,特别是新型的胰高血糖素样肽1受体激动剂利西拉肽作用更显著,且不良反应事件更少。最新文献证实利西拉肽具有神经保护作用,可用于阿尔茨海默病的治疗。文中就利西拉肽在阿尔茨海默病中的作用做一综述。
In recent years, more and more clinical and experimental evidence showed that type 2 diabetes mellitus(T2DM) is closely related to Alzheimer's disease(AD). T2 DM and AD have the common pathophysiological characteristics in the aspects of amyloid beta deposition, Tau protein phosphorylation and glucose synthase 3 activity increased. It was found that the risk of developing AD in patients with T2 DM was more likely to be increased compared with normal subjects. After animal model of AD brain tissue were studied, the results showed that the brain insulin resistance improved, MDA and 4-hydroxynonenal(4-HNE) indicators of oxidative stress significantly reduced and other pathological characteristics were reversed after the application of glucagon like peptide 1 analogues, especially the effect of lixisenatide more significantly. The results provide a theoretical basis for the GLP-1 analogues of AD potential therapeutic. The neuroprotective effect of lixisenatide in AD were reviewed.
In recent years, more and more clinical and experimental evidence showed that type 2 diabetes mellitus(T2DM) is closely related to Alzheimer's disease(AD). T2 DM and AD have the common pathophysiological characteristics in the aspects of amyloid beta deposition, Tau protein phosphorylation and glucose synthase 3 activity increased. It was found that the risk of developing AD in patients with T2 DM was more likely to be increased compared with normal subjects. After animal model of AD brain tissue were studied, the results showed that the brain insulin resistance improved, MDA and 4-hydroxynonenal(4-HNE) indicators of oxidative stress significantly reduced and other pathological characteristics were reversed after the application of glucagon like peptide 1 analogues, especially the effect of lixisenatide more significantly. The results provide a theoretical basis for the GLP-1 analogues of AD potential therapeutic. The neuroprotective effect of lixisenatide in AD were reviewed.
引文
[1]Cai HY,H?lscher C,Yue XH,et al.Lixisenatide rescues spatial memory and synaptic plasticity from amyloidβprotein-induced impairments in rats[J].Neuroscience,2014,26;277:6-13
[2]Lovshin JA,Drucker DJ.Incretin-based therapies for type 2 diabetes mellitus[J].Nat Rev Endocrinol,2009,5:262-269
[3]Impey S,Mark M,Villacres EC,et al.Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1of the hippocampus[J].Neuron,1996,16:973-982
[4]During MJ,Cao L,Zuzga DS,et al.Glucagon-like peptide-1 receptor is involved in learning and neuroprotection[J].Nat Med,2003,9:1173-1179
[5]Pappachan JM,Raveendran AV,Sriraman R.Incretin manipulation in diabetes management[J].World J Diabetes,2015,6:774-781
[6]Doyle ME,Egan JM.Mechanisms of action of glucagon-like peptide1 in the pancreas[J].Pharmacol Ther,2007,113:546-593
[7]Mu J,Woods J,Zhou YP,et al.Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreaticcell mass and function in a rodent model of type 2 diabetes[J].Diabetes,2006,55:1695-1704
[8]Farilla L,Bulotta A,Hirshberg B,et al.Glucagon-like peptide 1inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets[J].Endocrinology,2003,144:5149-5158
[9]Sokos GG,Nikolaidis LA,Mankad S,et al.Glucagon-like peptide-1infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure[J].J Card Fail,2006,12:694-699
[10]Uccellatore A,Genovese S,Dicembrini I,et al.Comparison Review of Short-Acting and Long-Acting Glucagon-like Peptide-1 Receptor Agonists[J].Diabetes Ther,2015,6:239-256
[11]Lennox R,Flatt PR,Gault VA,et al.Lixisenatide improves recognition memory and exerts neuroprotective actions in high-fat fed mice[J].Peptides,2014,61:38-47
[12]Correia SC,Santos RX,Carvalho C,et al.Insulin signaling,glucose metabolism and mitochondria:major players in Alzheimer’s disease and diabetes interrelation[J].Brain Res,2012,1441:64-78
[13]Moreira PI.Alzheimer’s disease and diabetes:an integrative view of the role of mitochondria,oxidative stress,and insulin[J].J Alzheimers Dis,2012,30:S199-S215
[14]Li L,Holscher C.Common pathological processes in Alzheimer disease and type 2 diabetes:a review[J].Brain Res Rev,2007,56:384-402
[15]Bomfim TR,Forny-Germano L,Sathler LB,et al.An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease-associated Abeta oligomers[J].J Clin Invest,2012,122:1339-1353
[16]Lester-Coll N,Rivera EJ,Soscia SJ,et al.Intracerebral streptozotocin model of type 3 diabetes:relevance to sporadic Alzheimer’s disease[J].J Alzheimers Dis,2006,9:13-33
[17]Steen E,Terry BM,Rivera EJ,et al.Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease-is this type 3 diabetes?[J].J Alzheimers Dis,2005,7:63-68
[18]Cole AR,Astell A,Green C,et al.Molecular connexions between dementia and diabetes[J].Neurosci Biobehav Rev,2007,31:1046-1063
[19]de la Monte SM.Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer's disease[J].Drugs,2012,72:49-66
[20]Egefjord L,Gejl M,M?ller A,et al.Effects of liraglutide on neurodegeneration,blood flow and cognition in Alzheimer’s disease protocol for a controlled,randomized double-blinded trial[J].Dan Med J,2012,59:A4519-A4519
[21]唐晶,董齐,伊然.胰高血糖素样肽1及其类似物治疗阿尔茨海默病作用机制研究进展[J].中国临床神经科学,2015,23:95-101
[22]Mc Clean PL,Parthsarathy V,Faivre E,et al.The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease[J].J Neurosci,2011,31:6587-6594
[23]Gault VA,Porter WD,Flatt PR,et al.Actions of exendin-4 therapy on cognitive function and hippocampal synaptic plasticity in mice fed a high-fat diet[J].Int J Obes(Lond),2010,34:1341-1344
[24]Porter DW,Kerr BD,Flatt PR,et al.Four weeks administration of Liraglutide improves memory and learning as well as glycaemic control in mice with high fat dietary-induced obesity and insulin resistance[J].Diabetes Obes Metab,2010,12:891-899
[25]During MJ,Cao L,Zuzga DS,et al.Glucagon-like peptide-1 receptor is involved in learning and neuroprotection[J].Nat Med,2003,9:1173-1179
[26]Abbas T,Faivre E,H?lscher C.Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice:Interaction between type 2 diabetes and Alzheimer’s disease[J].Behav Brain Res,2009,205:265-271
[27]H?lscher C.Drugs developed for treatment of diabetes show protective effects in Alzheimer’s and Parkinson’s diseases[J].Sheng Li Xue Bao,2014,66:497-510
[28]Li L.Is Glucagon-like peptide-1,an agent treating diabetes,a new hope for Alzheimer’s disease?[J].Neurosci Bull,2007,23:58-65
[29]Cai Z,Chen G,He W,et al.Activation of m TOR:a culprit of Alzheimer’s disease?[J].Neuropsychiatr Dis Treat,2015,11:1015-1030
[30]Asnaghi L,Bruno P,Priulla M,et al.m TOR:a protein kinase switching between life and death[J].Pharmacol Res,2004,50:545-549
[31]Balasubramanian S,Johnston RK,Moschella PC,et al.m TOR in growth and protection of hypertrophying myocardium[J].Cardiovasc Hematol Agents Med Chem,2009,7:52-63
[32]Spilman P,Podlutskaya N,Hart MJ,et al.Inhibition of m TORby rapamycin abolishes cognitive deficits and reduces amyloidbeta levels in a mouse model of Alzheimer’s disease[J].PLo SOne,2010,5:e99799-e9979..
[33]Cai Z,Zhao B,Li K,et al.Mammalian target of rapamycin:a valid therapeutic target through the autophagy pathway for Alzheimer’s disease?[J].J Neurosci Res,2012,90:1105-1118
[34]Pozueta J,Lefort R,Shelanski ML.Synaptic changes in Alzheimer’s disease and its models[J].Neuroscience,2013,251:51-65
[35]Lafay-Chebassier C,Paccalin M,Page G,et al.m TOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1transgenic models and in patients with Alzheimer’s disease[J].JNeurochem,2005,94:215-225
[36]Caccamo A,MagrìA,Medina DX,et al.m TOR regulates tau phosphorylation and degradation:implications for Alzheimer’s disease and other tauopathies[J].Aging Cell,2013,12:370-380
[37]Paccalin M,Pain-Barc S,Pluchon C,et al.Activated m TOR and PKRkinases in lymphocytes correlate with memory and cognitive decline in Alzheimer’s disease[J].Dement Geriatr Cogn Disord,2006,22:320-326
[38]O’Neill C.PI3-kinase/Akt/m TOR signaling:impaired on/off switches in aging,cognitive decline and Alzheimer’s disease[J].Exp Gerontol,2013,48:647-653
[39]Sui L,Wang J,Li BM.Role of the phosphoinositide 3-kinase-Aktmammalian target of the rapamycin signaling pathway in longterm potentiation and trace fear conditioning memory in rat medial prefrontal cortex[J].Learn Mem,2008,15:762-776
[40]Hunter K,H?lscher C.Drugs developed to treat diabetes,liraglutide and lixisenatide,cross the blood brain barrier and enhance neurogenesis[J].BMC Neurosci,2012,23:13-33
[41]H?lscher C.Central effects of GLP-1:new opportunities for treatments of neurodegenerative diseases[J].J Endocrinol,2014,221:T31-T41
[42]Harman D.The aging process[J].Proc Natl Acad Sci U S A,1981,78:7124-7128
[43]Su B,Wang X,Nunomura A,et al.Oxidative stress signaling in Alzheimer’s disease[J].Curr Alzheimer Res,2008,5,525-532
[44]Agrawal R,Zhuang Y,Cummings BP,et al.Deterioration of plasticity and metabolic homeostasis in the brain of the UCD-T2DM rat model of naturally occurring type-2 diabetes[J].Biochim Biophys Acta,2014,1842:1313-1323
[45]Buldak L,Labuzek K,Buldak RJ,et al.Exenatide(a GLP-1 agonist)improves the antioxidative potential of in vitro cultured human monocytes/macrophages[J].Naunyn Schmiedebergs Arch Pharmacol,2015,388:905-919
[46]Yu J,Morimoto K,Bao W,et al.Glucagon like peptide 1 prevented abdominal aortic aneurysm development in rats[J].Surg Today,2015Dec 13.[Epub ahead of print]
[47]Nauck MA,Petrie JR,Sesti G,et al.A Phase 2,Randomized,DoseFinding Study of the Novel Once-Weekly Human GLP-1Analog,Semaglutide,Compared With Placebo and Open-Label Liraglutide in Patients With Type 2 Diabetes[J].Diabetes Care,2016,39:231-241
[48]Miyagawa J,Odawara M,Takamura T,et al.Once-weekly glucagonlike peptide-1 receptor agonist dulaglutide is non-inferior to oncedaily liraglutide and superior to placebo in Japanese patients with type2 diabetes:a 26-week randomized phase III study[J].Diabetes Obes Metab,2015,17:974-983
[49]Nauck MA,Stewart MW,Perkins C,et al.Efficacy and safety of onceweekly GLP-1 receptor agonist albiglutide(HARMONY 2):52 week primary endpoint results from a randomised,placebo-controlled trial in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise[J].Diabetologia,2016,59:266-274
[50]Tella SH,Rendell MS.Glucagon-like polypeptide agonists in type2 diabetes mellitus:efficacy and tolerability,a balance[J].Ther Adv Endocrinol Metab,2015,6:109-134
[2]Lovshin JA,Drucker DJ.Incretin-based therapies for type 2 diabetes mellitus[J].Nat Rev Endocrinol,2009,5:262-269
[3]Impey S,Mark M,Villacres EC,et al.Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1of the hippocampus[J].Neuron,1996,16:973-982
[4]During MJ,Cao L,Zuzga DS,et al.Glucagon-like peptide-1 receptor is involved in learning and neuroprotection[J].Nat Med,2003,9:1173-1179
[5]Pappachan JM,Raveendran AV,Sriraman R.Incretin manipulation in diabetes management[J].World J Diabetes,2015,6:774-781
[6]Doyle ME,Egan JM.Mechanisms of action of glucagon-like peptide1 in the pancreas[J].Pharmacol Ther,2007,113:546-593
[7]Mu J,Woods J,Zhou YP,et al.Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreaticcell mass and function in a rodent model of type 2 diabetes[J].Diabetes,2006,55:1695-1704
[8]Farilla L,Bulotta A,Hirshberg B,et al.Glucagon-like peptide 1inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets[J].Endocrinology,2003,144:5149-5158
[9]Sokos GG,Nikolaidis LA,Mankad S,et al.Glucagon-like peptide-1infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure[J].J Card Fail,2006,12:694-699
[10]Uccellatore A,Genovese S,Dicembrini I,et al.Comparison Review of Short-Acting and Long-Acting Glucagon-like Peptide-1 Receptor Agonists[J].Diabetes Ther,2015,6:239-256
[11]Lennox R,Flatt PR,Gault VA,et al.Lixisenatide improves recognition memory and exerts neuroprotective actions in high-fat fed mice[J].Peptides,2014,61:38-47
[12]Correia SC,Santos RX,Carvalho C,et al.Insulin signaling,glucose metabolism and mitochondria:major players in Alzheimer’s disease and diabetes interrelation[J].Brain Res,2012,1441:64-78
[13]Moreira PI.Alzheimer’s disease and diabetes:an integrative view of the role of mitochondria,oxidative stress,and insulin[J].J Alzheimers Dis,2012,30:S199-S215
[14]Li L,Holscher C.Common pathological processes in Alzheimer disease and type 2 diabetes:a review[J].Brain Res Rev,2007,56:384-402
[15]Bomfim TR,Forny-Germano L,Sathler LB,et al.An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease-associated Abeta oligomers[J].J Clin Invest,2012,122:1339-1353
[16]Lester-Coll N,Rivera EJ,Soscia SJ,et al.Intracerebral streptozotocin model of type 3 diabetes:relevance to sporadic Alzheimer’s disease[J].J Alzheimers Dis,2006,9:13-33
[17]Steen E,Terry BM,Rivera EJ,et al.Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease-is this type 3 diabetes?[J].J Alzheimers Dis,2005,7:63-68
[18]Cole AR,Astell A,Green C,et al.Molecular connexions between dementia and diabetes[J].Neurosci Biobehav Rev,2007,31:1046-1063
[19]de la Monte SM.Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer's disease[J].Drugs,2012,72:49-66
[20]Egefjord L,Gejl M,M?ller A,et al.Effects of liraglutide on neurodegeneration,blood flow and cognition in Alzheimer’s disease protocol for a controlled,randomized double-blinded trial[J].Dan Med J,2012,59:A4519-A4519
[21]唐晶,董齐,伊然.胰高血糖素样肽1及其类似物治疗阿尔茨海默病作用机制研究进展[J].中国临床神经科学,2015,23:95-101
[22]Mc Clean PL,Parthsarathy V,Faivre E,et al.The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease[J].J Neurosci,2011,31:6587-6594
[23]Gault VA,Porter WD,Flatt PR,et al.Actions of exendin-4 therapy on cognitive function and hippocampal synaptic plasticity in mice fed a high-fat diet[J].Int J Obes(Lond),2010,34:1341-1344
[24]Porter DW,Kerr BD,Flatt PR,et al.Four weeks administration of Liraglutide improves memory and learning as well as glycaemic control in mice with high fat dietary-induced obesity and insulin resistance[J].Diabetes Obes Metab,2010,12:891-899
[25]During MJ,Cao L,Zuzga DS,et al.Glucagon-like peptide-1 receptor is involved in learning and neuroprotection[J].Nat Med,2003,9:1173-1179
[26]Abbas T,Faivre E,H?lscher C.Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice:Interaction between type 2 diabetes and Alzheimer’s disease[J].Behav Brain Res,2009,205:265-271
[27]H?lscher C.Drugs developed for treatment of diabetes show protective effects in Alzheimer’s and Parkinson’s diseases[J].Sheng Li Xue Bao,2014,66:497-510
[28]Li L.Is Glucagon-like peptide-1,an agent treating diabetes,a new hope for Alzheimer’s disease?[J].Neurosci Bull,2007,23:58-65
[29]Cai Z,Chen G,He W,et al.Activation of m TOR:a culprit of Alzheimer’s disease?[J].Neuropsychiatr Dis Treat,2015,11:1015-1030
[30]Asnaghi L,Bruno P,Priulla M,et al.m TOR:a protein kinase switching between life and death[J].Pharmacol Res,2004,50:545-549
[31]Balasubramanian S,Johnston RK,Moschella PC,et al.m TOR in growth and protection of hypertrophying myocardium[J].Cardiovasc Hematol Agents Med Chem,2009,7:52-63
[32]Spilman P,Podlutskaya N,Hart MJ,et al.Inhibition of m TORby rapamycin abolishes cognitive deficits and reduces amyloidbeta levels in a mouse model of Alzheimer’s disease[J].PLo SOne,2010,5:e99799-e9979..
[33]Cai Z,Zhao B,Li K,et al.Mammalian target of rapamycin:a valid therapeutic target through the autophagy pathway for Alzheimer’s disease?[J].J Neurosci Res,2012,90:1105-1118
[34]Pozueta J,Lefort R,Shelanski ML.Synaptic changes in Alzheimer’s disease and its models[J].Neuroscience,2013,251:51-65
[35]Lafay-Chebassier C,Paccalin M,Page G,et al.m TOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1transgenic models and in patients with Alzheimer’s disease[J].JNeurochem,2005,94:215-225
[36]Caccamo A,MagrìA,Medina DX,et al.m TOR regulates tau phosphorylation and degradation:implications for Alzheimer’s disease and other tauopathies[J].Aging Cell,2013,12:370-380
[37]Paccalin M,Pain-Barc S,Pluchon C,et al.Activated m TOR and PKRkinases in lymphocytes correlate with memory and cognitive decline in Alzheimer’s disease[J].Dement Geriatr Cogn Disord,2006,22:320-326
[38]O’Neill C.PI3-kinase/Akt/m TOR signaling:impaired on/off switches in aging,cognitive decline and Alzheimer’s disease[J].Exp Gerontol,2013,48:647-653
[39]Sui L,Wang J,Li BM.Role of the phosphoinositide 3-kinase-Aktmammalian target of the rapamycin signaling pathway in longterm potentiation and trace fear conditioning memory in rat medial prefrontal cortex[J].Learn Mem,2008,15:762-776
[40]Hunter K,H?lscher C.Drugs developed to treat diabetes,liraglutide and lixisenatide,cross the blood brain barrier and enhance neurogenesis[J].BMC Neurosci,2012,23:13-33
[41]H?lscher C.Central effects of GLP-1:new opportunities for treatments of neurodegenerative diseases[J].J Endocrinol,2014,221:T31-T41
[42]Harman D.The aging process[J].Proc Natl Acad Sci U S A,1981,78:7124-7128
[43]Su B,Wang X,Nunomura A,et al.Oxidative stress signaling in Alzheimer’s disease[J].Curr Alzheimer Res,2008,5,525-532
[44]Agrawal R,Zhuang Y,Cummings BP,et al.Deterioration of plasticity and metabolic homeostasis in the brain of the UCD-T2DM rat model of naturally occurring type-2 diabetes[J].Biochim Biophys Acta,2014,1842:1313-1323
[45]Buldak L,Labuzek K,Buldak RJ,et al.Exenatide(a GLP-1 agonist)improves the antioxidative potential of in vitro cultured human monocytes/macrophages[J].Naunyn Schmiedebergs Arch Pharmacol,2015,388:905-919
[46]Yu J,Morimoto K,Bao W,et al.Glucagon like peptide 1 prevented abdominal aortic aneurysm development in rats[J].Surg Today,2015Dec 13.[Epub ahead of print]
[47]Nauck MA,Petrie JR,Sesti G,et al.A Phase 2,Randomized,DoseFinding Study of the Novel Once-Weekly Human GLP-1Analog,Semaglutide,Compared With Placebo and Open-Label Liraglutide in Patients With Type 2 Diabetes[J].Diabetes Care,2016,39:231-241
[48]Miyagawa J,Odawara M,Takamura T,et al.Once-weekly glucagonlike peptide-1 receptor agonist dulaglutide is non-inferior to oncedaily liraglutide and superior to placebo in Japanese patients with type2 diabetes:a 26-week randomized phase III study[J].Diabetes Obes Metab,2015,17:974-983
[49]Nauck MA,Stewart MW,Perkins C,et al.Efficacy and safety of onceweekly GLP-1 receptor agonist albiglutide(HARMONY 2):52 week primary endpoint results from a randomised,placebo-controlled trial in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise[J].Diabetologia,2016,59:266-274
[50]Tella SH,Rendell MS.Glucagon-like polypeptide agonists in type2 diabetes mellitus:efficacy and tolerability,a balance[J].Ther Adv Endocrinol Metab,2015,6:109-134