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

帕金森氏病（PD）是一种进行性的不可治愈的神经系统疾病，在世界范围内影响1-2百万人。 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变性 在黑质的腹侧部然而，患有PD的患者患有许多症状， 如嗅觉减退、睡眠障碍、抑郁、张力减退和便秘，这些都不能仅仅是由于 黑质多巴胺能神经元变性。胞浆内（路易体）和神经内（路易神经突） 含有α-突触核蛋白的内含物是PD的病理学标志。α-突触核蛋白发挥着关键作用 在PD病因学中的作用。除了大脑，路易体和神经突病变出现在外周 自主神经系统在疾病过程中的早期。帕金森病的全身性变性始于 在中枢神经系统内，从尾侧到喙侧，向中心发展。 我们的假设是，垂体腺苷酸环化酶激活多肽（PACAP）在发病后， 运动功能障碍会阻止或减缓PD的进展。PACAP是一种多效性肽， 抗炎和有效的细胞保护特性。PACAP可明显减轻黑质细胞的变性， 多巴胺能神经元由1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）或6- 羟多巴胺然而，这两种神经毒素都会在数小时内引起PD样症状，而PD通常 几十年才会出现症状神经系统对大脑的反应是极不可能的。 对于极其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，对于动物模型存在巨大的未满足的需求， 更好地模仿人类的生活条件。α-突触核蛋白过表达转基因（A53 T）小鼠似乎 满足这些期望。第一次自主神经功能障碍的泌尿道和肠道出现在4个月 而运动功能障碍出现在10-11月龄。缓慢的进展和 A53 T小鼠中症状的器官选择性外观与患有PD的人类中的那些相似。 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 血流短，因此其用于慢性疾病是不实际的。因此，我们将评估 专利的、代谢稳定的PACAP类似物在PD的A53 T小鼠模型中用于神经保护。 具体目标1：提供证据证明运动功能障碍发作后给予PACAP将停止或 减缓PD样症状的进展。具体目标2：提供代谢稳定和 如具体目标1中所述施用的受体亚型特异性PACAP类似物也将停止或减缓 PD样症状的进展。运动功能障碍（圆筒测试，爪印分析和握力）将 在治疗前和治疗期间每两周检测一次，然后处理小鼠的大脑以进行PD 病理学（α-突触核蛋白、路易体、酪氨酸羟化酶和凋亡和炎症标志物）。

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).