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）是老年人的普遍疾病，目前治疗不令人满意。这是一种长期与年龄相关的退行性疾病，是老年人发病率和死亡率的主要原因，并且已经达到了流行比例，在全球范围内超过171人（Wild等人，糖尿病等，27，104753，2004）。各种危险因素与T2DM的发展有关（GTZ等人，细胞摩尔生命科学66，1321-5，2009; Jin＆Patti，Clin Sci（Lond）。116，99-111，2009），包括遗传易感性，年龄，年龄，氧化应激，氧化应激，氧化应激，氧化性，饮食，饮食，饮食，饮食，饮食，物理性和物理性。相比之下，这些相同的因素中的几个似乎与神经退行性疾病有关，例如阿尔茨海默氏病（AD），这是痴呆症的最常见形式（Reddy等，J Alzheimers Dis。16，763-774，2009; Luchsinger＆Gustafsingson; Luchsinger＆Gustafson，j alzheimers normel never in norker norly never in。流行病学研究已经与包括帕金森氏病（PD）和中风在内的其他两种疾病之间建立了联系，将T2DM识别为发展各种慢性和急性神经退行性疾病的危险因素（Toro等人，J Alzheimers，J AlzheimersDis。16：687-91-91，2009年，2009年； Currs.2007胰腺和大脑都是高度胰岛素敏感的组织，以及其他神经疾病的临床和生化特征。 T2DM中最新的有效治疗策略是基于内源性肽，胰高血糖素样肽-1（GLP-1）的胰岛素疗法的使用，利用长效类似物Exendin-4（ex-4）（ex-4）（ex-4）（lovshin＆drucker＆drucker，lovshin＆drucker，nat Rev Endocrinol。 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，胰岛素生物合成的增强和胰岛素基因转录的刺激。慢性作用包括刺激β细胞增殖，胰岛新生成的诱导和抑制β细胞凋亡的抑制作用，共同促进了β细胞质量的扩展以及胰岛素信号的归一化（Drucker，Lancet。372（9645）（9645），1240-50-50-50-50-50-50-50，2008年，Lovshin＆Druckshin＆Drucker＆Drucker ibid，2008）。据报道，EX-4很容易进入大脑（Kastin等，Int J obes Relat Metab疾病27，313-8，2003），其中GLP-1R被广泛表达（Perry＆Greig，Perry＆Greig，Phartry＆Greig，Phorts Pharmacol Sci。24，377-83，2003）及其激活导致多种生物学反应。大脑中的GLP-1R刺激与食欲和饱腹感的调节相关（Lovshin＆Drucker Ibid，2008）。然而，最近，它与神经营养性有关（Perry等，J Pharmacol Exp Ther 300，95866，2002）和神经保护作用在细胞和体内急性和慢性神经退行性条件的模型中都相关。 603-12，2003），包括中风，AD，PD和Huntingtons病（HD）（Li.等，PNAS 106，1285-90，2009; Harkavyi等，J Neuroinflam。21，519，519，2008; Martin等人，Martin等，Diabetes 58，318，318，318-328，2009，2009，2009; bertils; bertils; bertils; bertil; bertil; 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是从肠道中分泌的，是对食物的响应，是一种有效的促分泌物，它与胰腺β细胞上的GLP-1R结合，以诱导葡萄糖依赖性胰岛素分泌，从而控制血浆葡萄糖水平。我们正在开发长效的GLP-1类似物（合作者：Egan博士，马特森）。 这项研究有助于将肽Exendin-4（EX-4）开发到2型糖尿病中的临床研究中。结合了GLP-1和EX-4最佳特征的新型嵌合肽也已经设计并在临床前评估（Wang et al。，J ClinInvest。99：2883-9，1997，Deore等，J Gerontol a Biol Sci MedSci。52：B245-9，1997，1997; GREIG; GREIG; GREIG 52：45：45：45：45：45：45：45：45。 Szayna等人，内分泌141：1936-41，2000;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周围神经中。我们的协作研究是第一个定义GLP-1类似物具有神经营养特性并保护神经元细胞免受多种致命损伤的研究。细胞培养中的神经保护转化为经典啮齿动物神经变性模型中的体内研究，其中包括AD，中风，PD，HD，HD和周围神经病。当前的研究集中于选择临床评估和定义机制的药物，为神经营养/神经保护作用提供了