Neuroprotective role of GLP-1 receptor agonists

GLP-1 受体激动剂的神经保护作用

• 批准号: 8552374
• 负责人: Nigel H. Greig
• 金额: $ 63.41万
• 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/8552374
• 关键词: Acute; Age; Aging; Agonist; Ally; Alzheimer' s Disease; Anabolism; Animals; 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; Dipeptidyl Peptidases; Disease; Drug Design; Elderly; Endocrine; Enzymes; Epidemic; Epidemiologic Studies; Extramural Activities; Food; Functional disorder; Genetic Predisposition to Disease; Genetic Transcription; Glucose; Goals; Huntington Disease; Ingestion; Insulin; Laboratories; Life; Link; Metabolism; 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; Serine Protease; Stroke; Structure of beta Cell of islet; Systemic disease; Testing; Tissues; Translating; Translational Research; Translations; Traumatic Brain Injury; United States National Institutes of Health; age related; analog; base; design; drug candidate; drug development; effective therapy; exenatide; gastric inhibitory polypeptide receptor; glucagon-like peptide; in vivo; in vivo Model; inhibitor/antagonist; insulin secretion; insulin signaling; interest; islet; mortality; neuroprotection; novel; pre-clinical; receptor; 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; 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 that 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, ALS, traumatic brain injury 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, Li et al., PLoS One. ;7(2):e32008, 2012; Salcedo et al., Br J Pharmacol. 166:1586-99, 2012 ). 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). Additional research is focused on optimizing the translation of Ex-4 for the treatment of neurodegenerative disorders, and defining which specific disorders are most likely to have a clinical response. An alternate approach is to augment the levels of endogenous incretins available within the body by inhibiting their metabolism and, thereby, elevating their levels. In this regard, GLP-1 and the incretin, glucose-dependent insulinotropic polypeptide (GIP) are released following food ingestion and bind to their receptors on pancreatic beta cells to induce insulin secretion. Receptors for these endogenous peptides are found throughout the body, including the brain - which both GLP-1 and GIP can readily enter. The presence of the metabolizing serine protease enzyme, dipeptidyl peptidase-4 (DPP-4), results in the rapid clearance of both incretins. Current studies are assessing the utility of selective and well tolerated DPP-4 inhibitors in cellular and preclinical animal studies to elevate available GLP-1 and GIP levels in plasma and brain to a level at which they provide neurotrophic and neuroprotective actions for the treatment of neurodegenerative disorders.

2型糖尿病（T2DM）是老年人中的一种常见疾病，目前的治疗方法并不令人满意。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，并且已达到流行病的程度，全世界有超过 171 人患病（Wild 等人，Diabetes Care 27, 104753, 2004） 。 T2DM 的发展涉及多种危险因素（Gtz 等人，Cell Mol Life Sci. 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、饮食和缺乏身体活动。相比之下，这些相同的因素中的一些似乎与神经退行性疾病有关，例如阿尔茨海默病 (AD)，这是最常见的痴呆形式（Reddy 等人，J Alzheimers Dis. 16, 763-774, 2009；Luchsinger & Gustafson, J Albanys 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以及包括帕金森病 (PD) 和中风在内的其他疾病之间的联系，将 T2DM 确定为发生各种慢性和急性神经退行性疾病的危险因素（Toro 等人，J Alzheimers Dis. 16:687- 91, 2009; Curr 阿尔茨海默病研究 4, 147-52, 2007）。 AD 与其他神经系统疾病有一些共同的临床和生化特征，其中特别重要的是胰岛素信号传导受损，这表明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。 T2DM 最近的一种有效治疗策略是使用基于肠促胰岛素的疗法，该疗法基于内源性肽胰高血糖素样肽-1 (GLP-1) 的促胰岛素作用，并利用长效类似物 exendin-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，共同促进 β 细胞质量的扩张和胰岛素信号传导的正常化（德鲁克，柳叶刀。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），其中 GLP-1R 广泛表达（Perry & Greig, Trends Pharmacol Sci. 24） , 377-83, 2003）及其激活会导致多种生物反应。大脑中的 GLP-1R 刺激通常与食欲和饱腹感的调节有关（Lovshin & Drucker 同上，2008）。然而，最近，它在急性和慢性神经退行性疾病的细胞和体内模型中与神经营养作用（Perry 等人，J Pharmacol Exp Ther 300, 95866, 2002）和神经保护作用相关（Perry 等人，J） Pharmacol Exp Ther. 302, 881-8., 2002；Perry 等人，神经科学研究杂志 72， 603-12, 2003)，包括中风、AD、PD 和亨廷顿病 (HD)（Li 等人，PNAS 106, 1285-90, 2009；Li 等人，J Alz Dis. 19:1205-19, 2010 ；Harkavyi 等人，J Neuroinflam 21, 519, 2008；等人，糖尿病 58, 318-328, 2009；Bertilsson 等人，神经科学研究杂志 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剂，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，从而控制血浆葡萄糖水平。我们正在开发长效 GLP-1 类似物（合作者：Egan 博士、Mattson 博士）。 这项研究有助于将肽 exendin-4 (Ex-4) 开发到 2 型糖尿病的临床研究中。还设计了结合了 GLP-1 和 Ex-4 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 等人，J Clin Invest. 99:2883-9, 1997，DeOre 等人） ., J Gerontol A Biol Sci Med Sci. 52:B245-9, 1997；Diabetologia。 42：45-50，1999；Szayna 等，Endocrinol 141：1936-41，2000；Doyle 等，Endocrinol 142：4462-8，2001；Doyle 等，114：153-8。 2003；多伊尔等人，内分泌。 27:1-9, 2005）。我们正在描述 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定义了 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性损伤。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的体内研究，包括 AD、中风、PD、HD、ALS、创伤性脑损伤和周围神经病变（Perry 等人，Exp Neurol 203：293-301，2007；Li等人，PNAS 106, 1285-90, 2009；Li 等人，J Alz Dis。 19：1205-19，2010，Li 等人，PLoS One；7(2)：e32008，2012；Salcedo 等人，Br J Pharmacol 166：1586-99，2012。目前的研究重点是选择用于临床评估的药物和定义支持神经营养/神经保护作用的机制（Li 等人，J Neurochem 113：621-31，2010）。其他研究重点是优化 Ex-4 的翻译以治疗神经退行性疾病，并确定哪些特定疾病最有可能产生临床反应。 另一种方法是通过抑制新陈代谢来提高体内内源性肠促胰岛素的水平，从而提高其水平。在这方面，GLP-1 和肠促胰岛素、葡萄糖依赖性促胰岛素多肽 (GIP) 在食物摄入后释放，并与胰腺 β 细胞上的受体结合，诱导胰岛素分泌。这些内源性肽的受体遍布全身，包括大脑 - GLP-1 和 GIP 都可以轻松进入大脑。代谢丝氨酸蛋白酶二肽基肽酶 4 (DPP-4) 的存在导致两种肠降血糖素快速清除。目前的研究正在评估选择性且耐受性良好的 DPP-4 抑制剂在细胞和临床前动物研究中的效用，以将血浆和大脑中可用的 GLP-1 和 GIP 水平提高到为治疗神经退行性疾病提供神经营养和神经保护作用的水平失调。