Effect of PACAP on the progression of Parkinson's disease in chronic mouse model

PACAP对慢性小鼠帕金森病进展的影响

• 批准号: 9317792
• 负责人: ISTVAN Jozsef MERCHENTHALER
• 金额: $ 20.07万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317792
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Acute; Adverse effects; Affect; Age-Months; Anatomy; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Appearance; Autonomic Dysfunction; Autonomic nervous system; Behavior; Binding; Blood - brain barrier anatomy; Blood Circulation; Brain; CASP3 gene; Cell Nucleus; Central Nervous System Diseases; Chronic; Chronic Disease; Clinical Trials; Constipation; Cytoprotection; Disease; Dose; Drug Targeting; Etiology; European Union; Exposure to; Future; G-Protein-Coupled Receptors; Goals; Half-Life; Hand Strength; Hour; Human; Human Volunteers; Hydroxydopamines; In Situ Nick-End Labeling; Incidence; Intestines; Investigational New Drug Application; Laboratories; Lead; Lewy Bodies; Maps; Mental Depression; Messenger RNA; Metabolic; Midbrain structure; Modeling; Motor; Multiple Myeloma; Mus; Muscle hypotonia; Nerve Degeneration; Nervous system structure; Neuraxis; Neurites; Neurons; Neurotoxins; Neurotransmitters; Organ; Orthostatic Hypotension; PACAP38; PACAPR-1 protein; Parkinson Disease; Pathologic; Pathology; Patients; Pattern; Penetration; Peptides; Peripheral; Peripheral Nervous System; Pesticides; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase I Clinical Trials; Phase III Clinical Trials; Play; Predictive Value; Process; Production; Progressive Disease; Property; Proteolysis; Regulation; Research Proposals; Resistance; Role; Rotation; Secretin; Series; Serum; Sleep disturbances; Substantia nigra structure; Symptoms; System; Testing; Transgenic Organisms; Translational Research; Treatment Protocols; Triptorelin; Tyrosine 3-Monooxygenase; United States Food and Drug Administration; Universities; alpha synuclein; analog; candidate selection; cytokine; dopaminergic neuron; drug development; expectation; experimental study; hyposmia; inflammatory marker; motor disorder; motor symptom; mouse model; nervous system disorder; neuron loss; neuroprotection; novel therapeutics; pars compacta; pituitary adenylate cyclase activating polypeptide; prevent; receptor; urinary; vasoactive intestinal peptide 2 receptor; vasoactive intestinal peptide receptor 1

Parkinson's disease (PD) is a progressive incurable neurological disease that affects 1-2 million people in the U.S. The cardinal motor symptoms of PD are believed to be due to the degeneration of dopaminergic neurons in the pars compacta of the substantia nigra. However, patients with PD suffer from a number of symptoms such as hyposmia, sleep disturbances, depression, hypotonia, and constipation that cannot be due only to the degeneration of nigral dopaminergic neurons. Intracytoplasmic (Lewy bodies) and intraneuritic (Lewy neurites) inclusions that contain alpha-synuclein are the pathological hallmarks of PD. alpha-Synuclein plays a critical role in the etiology of PD. In addition to the brain, Lewy body and neurite pathologies appear in the peripheral autonomic nervous system early in the disease process. The systemic degenerations that occur in PD start in peripheral neuronal systems and progress centripetally and then caudal to rostral within the CNS. Our hypothesis is that pituitary adenylate cyclase-activating polypeptide (PACAP) administered after the onset of motor dysfunction will halt or slow the progression of PD. PACAP is a pleiotropic peptide with both potent anti-inflammatory and potent cytoprotective properties. PACAP significantly reduces the degeneration of nigral dopaminergic neurons caused by either 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6- hydroxydopamine. However, both of these neurotoxins cause PD-like symptoms in hours while PD usually takes decades for symptoms to develop. It is exceedingly unlikely that the nervous system responds in the same way to extremely rapid and slowly progressive diseases. The predictive value of these acute models for a progressive chronic disease is questionable. Therefore, there is a huge unmet need for an animal model that better mimics the human conditions. The alpha-synuclein over-expressing transgenic (A53T) mice seem to meet these expectations. The first autonomic dysfunctions in the urinary and intestinal tracts appear at 4 month of age in these mice while the motor dysfunction appears at 10-11 months of age. The slow progression and the organ-selective appearance of the symptoms in the A53T mice are similar to those in humans with PD. Although PACAP has remarkable cytoprotective and anti-inflammatory properties, its half-life in the bloodstream is short and, therefore, its use for chronic diseases is not practical. Therefore, we will evaluate our proprietary, metabolically stable PACAP analogs for neuroprotection in the A53T mouse model of PD. Specific Aim 1: Provide evidence that PACAP administered after the onset of motor dysfunction will halt or slow the progression of PD-like symptoms. Specific Aim 2: Provide evidence that the metabolically stable and receptor subtype-specific PACAP analogs administered as described in Specific Aim 1 will also halt or slow the progression of PD-like symptoms. Motor dysfunction (cylinder test, paw-print analysis, and grip strength) will be tested biweekly before and during treatment, and then the brains of the mice will be processed for PD pathology (alpha-synuclein, Lewy bodies, tyrosine hydroxylase, and apoptotic and inflammatory markers).

帕金森氏病（PD）是一种渐进性无法治愈的神经系统疾病，影响1-200万人 美国，PD的主要运动症状被认为是由于多巴胺能神经元的变性 在尼格拉山的pars compacta中。但是，PD患者患有多种症状 例如低血症，睡眠障碍，抑郁，低调和便秘，不能仅仅是由于 果膜多巴胺能神经元的变性。胞质内（路易体）和尿布内（路易神经突） 包含α-核蛋白的夹杂物是PD的病理标志。 α-突触核蛋白起着关键 在PD病因中的作用。除了大脑外，Lewy身体和神经突的病理出现在周围 疾病过程的早期自主神经系统。 PD中发生的全身性变性开始 周围神经元系统，并以中心为中心，然后在中枢神经系统内进行尾骨。 我们的假设是垂体腺苷酸环化酶激活多肽（PACAP）发作后进行 电动功能障碍会停止或减慢PD的进展。 PACAP是一种多效肽，两者都有效 抗炎和有效的细胞保护特性。 PACAP显着降低了nigral的变性 由1-甲基-4-苯基1,2,3,6-四氢吡啶（MPTP）或6-引起的多巴胺能神经元或6- 羟基多巴胺。但是，这两种神经毒素都会在小时内引起PD样症状，而PD通常 症状需要数十年的时间。神经系统在 相同的快速和缓慢进行性疾病的方式。这些急性模型的预测价值 进行性慢性病是值得怀疑的。因此，对动物模型有巨大的未满足的需求 更好地模仿人类状况。 α-突触核蛋白过表达的转基因（A53T）小鼠似乎 满足这些期望。尿和肠道中的第一个自主功能障碍出现在4个月 这些小鼠的年龄在运动功能障碍时出现在10-11个月大。缓慢的进展和 A53T小鼠中症状的器官选择性外观与PD人类的器官选择性相似。 尽管PACAP具有显着的细胞保护和抗炎特性，但其半衰期在 血液很短，因此，它用于慢性疾病是不切实际的。因此，我们将评估我们的 在PD的A53T小鼠模型中，用于神经保护的专有，代谢稳定的PACAP类似物。 具体目的1：提供证据表明，电动机功能障碍发作后施用的PACAP将停止或 减慢PD样症状的进展。特定目的2：提供代谢稳定和的证据 如特定AIM 1所述给予的受体亚型特异性PACAP类似物也会停止或减慢 PD样症状的进展。运动功能障碍（气缸测试，爪形分析和握力）将会 在治疗前和期间每两周进行一次测试，然后将小鼠的大脑用于PD 病理学（α-突触核蛋白，刘易体，酪氨酸羟化酶以及凋亡和炎症标志物）。