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

帕金森氏病(PD)是一种进行性不可治愈的神经系统疾病，在美国有100-200万人受到影响 美国帕金森病的主要运动症状被认为是由于多巴胺能神经元的退化 在黑质致密部。然而，帕金森病患者会出现一些症状 如营养不良、睡眠障碍、抑郁、低眼压和便秘，这些都不能仅仅是由于 黑质多巴胺能神经元变性。胞浆内(路易小体)和内质(路易突起) 含有α-突触核蛋白的包裹体是帕金森病的病理特征。α-突触核蛋白发挥着关键作用 在帕金森病病因学中的作用。除了大脑，路易体和轴突病理也出现在外周。 自主神经系统在疾病过程的早期。帕金森病中发生的全身性退行性变始于 外周神经系统在中枢神经系统内向心性发展，然后向尾端向嘴方向发展。 我们的假设是在发病后给予垂体腺苷酸环化酶激活多肽(PACAP) 运动功能障碍会阻止或减缓帕金森病的进展。PACAP是一种多效肽，具有两种效力 具有抗炎和强大的细胞保护作用。PACAP显著减轻黑质退行性变 1-甲基-4-苯基-1，2，3，6-四氢吡啶或6-甲基-4-苯基-1，2，3，6-四氢吡啶引起的多巴胺能神经元 羟基多巴胺。然而，这两种神经毒素都会在数小时内引起帕金森病样症状，而帕金森病通常 症状需要几十年的时间才能发展。神经系统不太可能在 对极快速和缓慢进展的疾病也是如此。这些急性模型的预测价值 进行性慢性疾病是值得怀疑的。因此，有一个巨大的未得到满足的动物模型的需求 更好地模拟了人类的状况。过表达α-突触核蛋白的转基因(A53T)小鼠似乎 满足这些期望。首发自主神经功能障碍出现在4个月大的时候。 这些小鼠的年龄较大，而运动功能障碍出现在10-11个月大的时候。缓慢的进展和 A53T小鼠的症状在器官上的选择性表现与人类帕金森病患者相似。 尽管PACAP具有显著的细胞保护和抗炎特性，但其在体内的半衰期 血液很短，因此，将其用于慢性病是不切实际的。因此，我们将评估我们的 专有的，代谢稳定的PACAP类似物，用于帕金森病A53T小鼠模型的神经保护。 具体目标1：提供证据表明，在运动功能障碍开始后使用PACAP将停止或 延缓帕金森病样症状的发展。具体目标2：提供证据证明新陈代谢稳定和 受体亚型特异性PACAP类似物按特定目的1所述给药也将停止或减缓 帕金森病样症状的进展。运动功能障碍(圆柱体测试、爪印分析和握力)将 在治疗前和治疗期间每两周进行一次测试，然后对小鼠的大脑进行PD处理 病理学(α-突触核蛋白、路易小体、酪氨酸羟基酶、细胞凋亡和炎症标记物)。

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).