Neuroprotective role of GLP-1 receptor agonists

GLP-1 受体激动剂的神经保护作用

• 批准号: 7963934
• 负责人: Nigel H. Greig
• 金额: $ 35.22万
• 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/7963934
• 关键词: Acute; Age; Aging; Agonist; Ally; Alzheimer' s Disease; Anabolism; Apoptosis; Appetite Regulation; Beta Cell; Binding; Biochemical; Biological; Brain; Caring; Cell Culture Techniques; Cell Proliferation; Cells; Chronic; Clinic; Clinical; Clinical Research; Clinical assessments; Collaborations; Degenerative Disorder; Dementia; Development; Diabetes Mellitus; Diet; Disease; Drug Design; Elderly; Endocrine; Epidemic; Epidemiologic Studies; Extramural Activities; Food; Functional disorder; GLP-I receptor; Genetic Predisposition to Disease; Genetic Transcription; Glucose; Goals; Huntington Disease; Insulin; Laboratories; Life; Link; Modeling; Morbidity - disease rate; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurologic; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Pancreas; Parkinson Disease; Peptides; Peripheral Nerves; Peripheral Nervous System Diseases; Plasma; Property; Reporting; Research; Risk Factors; Rodent; Role; Satiation; Scientist; Stroke; Structure of beta Cell of islet; Systemic disease; Testing; Tissues; Translating; Translational Research; United States National Institutes of Health; age related; analog; base; design; drug candidate; drug development; effective therapy; exenatide; glucagon-like peptide 1; in vivo; in vivo Model; insulin secretion; insulin signaling; interest; islet; mortality; neuroprotection; novel; pre-clinical; response; tool; treatment strategy; trend

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; 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. Current studies are focused on selecting agents for clinical assessment and defining mechanisms underpinning the neurotrophic/neuroprotective actions

2型糖尿病（T2DM）是老年人的一种常见疾病，目前的治疗方法不能令人满意。它是一种慢性、与年龄相关的退行性疾病，是老年人发病和死亡的主要原因，并已达到流行病的比例，全世界有超过171人患有这种疾病（Wild等人，Diabetes Care 27，104753，2004）。多种风险因素与T2DM的发展有关（Gtz等人，细胞分子生命科学66，1321 - 5，2009; Jin & Patti，Clin Sci（Lond）. 116，99 - 111，2009），包括遗传倾向、年龄、氧化应激、肥胖、饮食和身体活动不足。相比之下，这些相同因素中的几种似乎参与神经退行性疾病，例如阿尔茨海默病（AD），最常见的痴呆形式（Reddy et al.，J Alzheimers Dis.16，763 - 774，2009; Luchsinger & Gustafson，J Alzheimers Dis.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与其他疾病（包括帕金森病（PD）和中风）之间的联系，将T2DM鉴定为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 Alzheimers Dis. 16：687 - 91，2009; Craft. Curr Alzheimer Res.4，147 - 52，2007）。 胰腺和大脑都是高度胰岛素敏感的组织。 T2DM和AD，以及其他神经系统疾病。共有几个临床和生物化学特征，其中特别重要的是受损的胰岛素信号传导，表明重叠的致病机制。因此，一种疾病的有效治疗策略可能在另一种疾病中具有潜在价值。 T2DM中最近的有效治疗策略是使用基于内源性肽胰高血糖素样肽-I（GLP-1）的促胰岛素作用的基于肠降血糖素的疗法，利用长效类似物毒蜥外泌肽-4（Ex-4）（Lovshin & Drucker，Nat Rev Endocrinol. 5，262 - 9，2009）。GLP-1和受体（R）激动剂对β细胞的急性作用包括刺激葡萄糖依赖性胰岛素释放、增强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，它们一起促进β-细胞群的扩增和胰岛素信号传导的正常化（Drucker，Lancet. 372（9645），1240 - 50，2008，Lovshin & Drucker同上，2008）。据报道，Ex-4容易进入大脑（Kastin等人，Int J Obes Relat Metab Disord 27，313 - 8，2003），其中GLP-1R广泛表达（佩里和格雷格，趋势药理学科学（Trends Pharmacol Sci. 24，377 - 83，2003），并且其活化导致多种生物学应答。脑中的GLP-1R刺激与食欲和饱腹感的调节经典地相关（Lovshin & Drucker同上，2008）。然而，最近，它已与神经营养相关（佩里等人，J Pharmacol Exp Ther 300，95866，2002）和在急性和慢性神经变性病症的细胞和体内模型中的神经保护作用（佩里等人，药理学实验治疗学杂志302，881 - 8.，2002年;佩里等人，J Neurosci Res.72，603 - 12，2003），包括中风、AD、PD和亨廷顿病（HD）（Li等人，PNAS 106，1285 - 90，2009; Harkavyi等人，J Neuroinflam. 21，519，2008; Martin等人，Diabetes 58，318 - 328，2009; Bertilsson等人，J Neurosci Res 86，32638，2008）。 我们的药物设计目标是胰高血糖素样肽-1（GLP-1）受体（R）。GLP-1是一种有效的促分泌素，可与胰腺β细胞上的GLP-1R结合，诱导葡萄糖依赖性胰岛素分泌，从而控制血糖水平。我们正在开发长效GLP-1类似物（合作者：Drs.埃根，Mattson）。 这项研究有助于开发肽exendin-4（Ex-4）用于2型糖尿病的临床研究。还设计了联合收割机组合GLP-1和Ex-4的最佳特征的新型嵌合肽，并在多种模型中进行临床前评估（Wang et al.，《临床投资杂志》99：2883 - 9，1997，DeOre等人，老年人生物科学与医学杂志. 52：B245 - 9，1997; Greig等人，糖尿病学42：45 - 50，1999; Szayna等人，Endocrinol 141：1936 - 41，2000; Doyle等人，Endocrinol 142：4462 - 8，2001; Doyle等人，Regul Pept. 114：153 - 8，2003; Doyle等人，内分泌27：1 - 9，2005）。我们正在表征GLP-1R刺激在神经系统中的作用，因为它存在于大脑和外周神经中。我们的合作研究是第一个确定GLP-1类似物具有神经营养特性并保护神经元细胞免受各种致命损伤的研究。细胞培养中的神经保护作用转化为经典啮齿动物神经变性模型中的体内研究，包括AD、中风、PD、HD和周围神经病变。目前的研究集中在选择药物进行临床评估和确定神经营养/神经保护作用的机制