Neuroprotective role of GLP-1 receptor agonists

GLP-1 受体激动剂的神经保护作用

• 批准号: 8148224
• 负责人: Nigel H. Greig
• 金额: $ 30.39万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8148224
• 关键词: Agonist; GLP-I receptor; Role

Type 2 diabetes mellitus (T2DM) is a prevalent disease in the elderly for which current treatments are unsatisfactory. It is a chronic, age-related degenerative disorder that is a leading cause of morbidity and mortality in the elderly, and has attained epidemic proportion, with in excess of 171 afflicted worldwide (Wild et al., Diabetes Care 27, 104753, 2004). A variety of risk factors have been implicated in the development of T2DM (Gtz et al., Cell Mol Life Sci. 66, 1321-5, 2009; Jin & Patti, Clin Sci (Lond). 116, 99-111, 2009), including a genetic predisposition, age, oxidative stress, obesity, diet, and physical inactivity. By comparison, several of these same factors appear to be involved in neurodegenerative disorders, such as Alzheimer's disease (AD), the most common form of dementia (Reddy et al., J Alzheimers Dis. 16, 763-774, 2009; Luchsinger & Gustafson, J Alzheimers Dis. 16, 693-704, 2009. Interestingly, a number of well-designed epidemiological studies have established a link between these two diseases, together with others, including Parkinson's disease (PD) and stroke, identifying T2DM as a risk factor for developing various chronic and acute neurodegenerative disorders (Toro et al., J Alzheimers Dis. 16:687-91, 2009; Craft. Curr Alzheimer Res. 4, 147-52, 2007). The pancreas and brain are both highly insulin sensitive tissues. T2DM and AD, together with other neurological conditions. share several clinical and biochemical features, particularly important amongst these is an impaired insulin signaling, suggesting overlapping pathogenic mechanisms. Hence, an effective treatment strategy in one disease could have potential value in the other. A recent effective treatment strategy in T2DM is the use of incretin-based therapies based on the insulinotropic actions of the endogenous peptide, glucagon-like peptide-1 (GLP-1), utilizing the long-acting analog exendin-4 (Ex-4) (Lovshin & Drucker, Nat Rev Endocrinol. 5, 262-9, 2009). The acute actions of GLP-1 and receptor (R) agonists on beta-cells include stimulation of glucose-dependent insulin release, augmentation of insulin biosynthesis and stimulation of insulin gene transcription. Chronic actions include stimulation of beta-cell proliferation, induction of islet neogenesis and inhibition of beta-cell apoptosis that, together, promote expansion of beta-cell mass and the normalization of insulin signaling (Drucker, Lancet. 372(9645), 1240-50, 2008, Lovshin & Drucker ibid, 2008). Ex-4 has been reported to readily enter the brain (Kastin et al., Int J Obes Relat Metab Disord 27, 313-8, 2003), where the GLP-1R is expressed widely (Perry & Greig, Trends Pharmacol Sci. 24, 377-83, 2003) and its activation results in multiple biological responses. GLP-1R stimulation in brain is classically allied to regulation of appetite and satiety (Lovshin & Drucker ibid, 2008). More recently, however, it has been associated with neurotrophic (Perry et al., J Pharmacol Exp Ther 300, 95866, 2002) and neuroprotective actions in both cellular and in vivo models of acute and chronic neurodegenerative conditions (Perry et al., J Pharmacol Exp Ther. 302, 881-8., 2002; Perry et al., J Neurosci Res. 72, 603-12, 2003), including stroke, AD, PD and Huntingtons disease (HD) (Li et al., PNAS 106, 1285-90, 2009; Li et al., J Alz Dis. 19:1205-19, 2010; Harkavyi et al., J Neuroinflam. 21, 519, 2008; Martin et al., Diabetes 58, 318-328, 2009; Bertilsson et al., J Neurosci Res 86, 32638, 2008). Our target for drug design is the glucagon-like peptide-1 (GLP-1) receptor (R). GLP-1 is secreted from the gut in response to food and is a potent secretagogue it binds to the GLP-1R on pancreatic beta-cells to induce glucose-dependent insulin secretion, thereby controling plasma glucose levels. We are developing long-acting GLP-1 analogues (collaborators: Drs. Egan, Mattson). This research aided in the development of the peptide exendin-4 (Ex-4) into clinical studies in type 2 diabetes. Novel chimeric peptides that combine the best features of GLP-1 and Ex-4 have also been designed and are under preclinical assessment in a variety models (Wang et al., J Clin Invest. 99:2883-9, 1997, DeOre et al., J Gerontol A Biol Sci Med Sci. 52:B245-9, 1997; Greig et al., Diabetologia. 42:45-50, 1999; Szayna et al., Endocrinol 141:1936-41, 2000; Doyle et al., Endocrinol 142:4462-8, 2001; Doyle et al., Regul Pept. 114:153-8, 2003; Doyle et al., Endocrine. 27:1-9, 2005). We are characterizing the role of the GLP-1R stimulation in the nervous system, as it is found present in brain and peripheral nerve. Our collaborative studies were the first to define that GLP-1 analogues possess neurotrophic properties and protect neuronal cells from a wide variety of lethal insults. Neuroprotection in cell culture translated to in vivo studies in classical rodent neurodegeneration models, which include AD, stroke, PD, HD and peripheral neuropathy (Perry et al., Exp Neurol 203: 293-301, 2007; Li et al., PNAS 106, 1285-90, 2009; Li et al., J Alz Dis. 19:1205-19, 2010). Current studies are focused on selecting agents for clinical assessment and defining mechanisms underpinning the neurotrophic/neuroprotective actions (Li et al., J Neurochem 113: 621-31, 2010).

2型糖尿病(T2 DM)是一种在老年人中流行的疾病，目前的治疗方法并不令人满意。它是一种与年龄相关的慢性退行性疾病，是老年人发病率和死亡率的主要原因，并且已经达到流行比例，全世界有超过171000人患有糖尿病(Wild等人，糖尿病护理27,104753,2004年)。多种风险因素与T2 DM的发生有关(Gtz等人，细胞分子生命科学。66,1321-5,2009；金和帕蒂，临床科学(隆德)。116、99-111、2009)，包括遗传倾向、年龄、氧化应激、肥胖、饮食和缺乏运动。相比之下，这些相同的因素中有几个似乎与神经退行性疾病有关，例如阿尔茨海默病(AD)，这是最常见的痴呆症形式(Reddy等人，J阿尔茨海默斯Dis。16,763-774,2009；Luchinger&Gustafson，J阿尔茨海默氏病。16,693-704,2009。有趣的是，许多精心设计的流行病学研究已经建立了这两种疾病以及包括帕金森氏病(PD)和中风在内的其他疾病之间的联系，确定T2 DM是发展各种慢性和急性神经退行性疾病的风险因素(Toro等人，J阿尔茨海默氏病)。16：687-91,2009；Craft。Curr阿尔茨海默病研究报告4,147-52,2007)。胰腺和大脑都是对胰岛素高度敏感的组织。2型糖尿病、阿尔茨海默病合并其他神经系统疾病。有几个共同的临床和生化特征，其中特别重要的是胰岛素信号受损，提示发病机制重叠。因此，一种疾病的有效治疗策略可能对另一种疾病具有潜在的价值。 最近治疗T2 DM的一个有效策略是使用基于内源性多肽-胰升糖素样肽-1(GLP-1)的胰岛素调节作用的基于胰岛素的治疗，利用长效类似物Exendin-4(Exendin-4)(Lovshin&Drucker，NAT Rev Endocrinol)。5,262-9,2009)。GLP-1和R受体激动剂对胰岛β细胞的急性作用包括刺激葡萄糖依赖的胰岛素释放、促进胰岛素生物合成和刺激胰岛素基因转录。慢性作用包括刺激β细胞增殖、诱导胰岛新生和抑制β细胞凋亡，这些共同促进了β细胞团的扩张和胰岛素信号的正常化(Drucker，Lancet)。372(9645)，1240-50,2008，Lovshin&Drucker，同上，2008)。据报道，EX-4很容易进入大脑(Kastin等人，Int J OBEs relat Metab Disord 27,313-8,2003)，在那里GLP-1R广泛表达(Perry&Greig，Trends Pharmacol Sci)。24,377-83,2003)，并且其激活导致多种生物反应。大脑中的GLP-1R刺激与食欲和饱腹感的调节经典地结合在一起(Lovshin&Drucker，同上，2008)。然而，最近，在急性和慢性神经退行性疾病的细胞和体内模型中，它与神经营养(Perry等人，J Pharmacol Exp Ther 300,95866,2002年)和神经保护作用(Perry等人，J Pharmacol Exp Ther)有关。302,881-8,2002；Perry等，J Neurosci Res.72,603-12,2003)，包括中风、AD、PD和亨廷顿病(HD)(Li等，PNAS 106,1285-90,2009；Li等，J Alz Dis.19：1205-19,2010；Harkavyi等人，J Neuroifam。21,519,2008年；Martin等人，糖尿病58,318-328,2009年；Bertilsson等人，J Neurosci Res 86,32638,2008年)。 我们的药物设计目标是胰升糖素样肽-1(GLP-1)受体(R)。GLP-1是肠道对食物的反应，是一种强有力的促分泌剂，它与胰岛β细胞上的GLP-1R结合，诱导葡萄糖依赖的胰岛素分泌，从而控制血糖水平。我们正在开发长效GLP-1类似物(合作者：伊根、马特森博士)。这项研究帮助将Exendin-4(Ex-4)多肽发展成为治疗2型糖尿病的临床研究。结合GLP-1和Ex-4的最佳特征的新型嵌合肽也已被设计出来，并在各种模型中进行临床前评估(Wang等人，J Clin Invest)。99：2883-9,1997，Deore等人，J Gerontol A Biol Sci Med Sci.52：B245-9,1997；Greig等人，Diabetologia。42：45-50,1999；Szayna等人，Endocrinol 141：1936-41,2000；Doyle等人，Endocrinol 142：4462-8,2001；Doyle等人，Regul Pt.114：153-8,2003；Doyle等人，内分泌。27：1-9,2005)。我们正在研究GLP-1R刺激在神经系统中的作用，因为它存在于大脑和周围神经中。我们的合作研究首次确定GLP-1类似物具有神经营养特性，并保护神经细胞免受各种致命伤害。细胞培养中的神经保护转化为经典啮齿动物神经退化模型的体内研究，这些模型包括AD、中风、PD、HD和周围神经病变(Perry等，Exp Neurol 203：293-301,2007；Li等，PNAS 106,1285-90,2009；Li等，J Alz Dis。2010年19：1205-19)。目前的研究集中于临床评估药物的选择和确定神经营养/神经保护作用的机制(Li等人，《神经化学杂志》113：621-31,2010)。