Evaluating BMY-14802 as an anti-dyskinesia treatment in the 6-OHDA rat model of P

描述（由申请人提供）：我们的目标是开发新的药物治疗左旋多巴（左旋多巴）的副作用发生在帕金森氏病的人。左旋多巴是治疗帕金森氏症的黄金标准，但不幸的是，大多数服用左旋多巴的人最终会产生使人衰弱的副作用，称为运动障碍的异常不自主运动，这可能会影响四肢，身体和/或面部。目前用于运动障碍的药物治疗具有缺点：它们可能在8-12个月后无效，可能具有成瘾性，可能引起精神病症状，或可能使帕金森病的症状恶化。其他治疗需要脑部手术。因此，非常需要开发新的抗运动障碍药物。在使用广泛接受的运动障碍动物模型的初步研究中，我们发现药物BMY-14802抑制运动障碍的效果与目前有效的治疗方法一样好或更好，而不会恶化帕金森氏症的症状。我们现在试图在更大的动物群体中证实这一发现，并确定大脑中哪些蛋白质可能介导这些效应。具体来说，我们计划使用6-羟基多巴胺（6-OHDA）损伤的帕金森病大鼠模型，其中神经毒素6-OHDA被注射到大脑一侧的多巴胺细胞纤维中。每天用L-DOPA处理大鼠21天以诱导运动障碍，然后每周两次以维持运动障碍。一旦运动障碍稳定，我们将给予不同剂量的BMY-14802，以确定ED 50，或抑制运动障碍50%的剂量，如通过AIMS运动障碍评级量表（特定目标I）评估的。大鼠还将接受一系列行为测试，评估帕金森氏症的症状，并显示L-DOPA治疗后的改善。这将使我们能够确定BMY- 14802是否阻止L-DOPA（特定目标II）治疗帕金森症状。最后，动物将用BMY-14802（其抑制运动障碍）、MK-801（其不抑制运动障碍）或安慰剂处理，随后用L-DOPA或安慰剂处理。将分析这些动物运动区（纹状体）的脑组织中与运动障碍相关的蛋白质水平的变化，以确定哪些蛋白质受到BMY-14802（特定目标III）的特异性影响。在另一组正常大鼠（无6-OHDA损伤）中，我们将研究高剂量的BMY-14802是否对多巴胺D2受体具有任何拮抗剂作用，因为这将表明BMY-14802可能使帕金森症状恶化（特定目的IV）。D2受体的拮抗作用在行为上被观察到为僵住症，从尴尬的位置移动缓慢。通过激动5-羟色胺1A受体来预防僵住症，已知BMY-14802具有5-羟色胺1A激动剂作用;因此，我们还将给予5-羟色胺1A激动剂以确定BMY-14802的其他作用机制是否包括D2拮抗作用。作为参比化合物，我们还将测试完全5-羟色胺1A激动剂、部分5-羟色胺1A激动剂和D2拮抗剂。L-DOPA诱导的运动障碍显著降低了28-64%的帕金森病患者的生活质量（Friedman，1985; Schrag & Quinn，2000），对于LID等级量表上的每单位增加，每名患者每年花费1328美元（Pechevis等人，2005年）。具有优异预测有效性的L-DOPA诱导的运动障碍的模型是6-羟基多巴胺大鼠，其已经显示抑制帕金森病患者中的运动障碍的相同药物在大鼠中起作用（即，金刚烷胺、美沙芬和丁螺环酮）。不幸的是，这些治疗有严重的缺点，包括没有证明的长期疗效，滥用的可能性，拟精神病的影响，或帕金森氏症的症状加重;因此，必须开发抗运动障碍药物治疗，在这个脆弱的老年人群中具有较少的副作用。

DESCRIPTION (provided by applicant): Our objective is to develop new drug treatments for the side effects of levodopa (L-DOPA) that occur in people with Parkinson's Disease. L-DOPA is the gold standard of treatment for Parkinson's, but unfortunately, the majority of people who take L-DOPA eventually develop debilitating side effects, abnormal involuntary movements called dyskinesias, which may affect the limbs, body, and or face. Current drug treatments for dyskinesia have drawbacks: they may not be effective after 8-12 months, may have addictive properties, may cause psychotic symptoms, or may worsen symptoms of Parkinson's Disease. Other treatments require brain surgery. Thus, there is a great need to develop new anti-dyskinesia medications. In preliminary studies using a well-accepted animal model for dyskinesias, we have found that the drug BMY-14802 suppresses dyskinesias as well or better than currently effective treatments without worsening Parkinson's symptoms. We now seek to confirm this finding in a larger group of animals and to determine what proteins in the brain may be mediating these effects. Specifically, we plan to use the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's Disease, in which the neurotoxin 6-OHDA is injected into the dopamine cell fibers on one side of the brain. Rats will be treated with L-DOPA daily for 21 days to induce dyskinesias, then twice/week to maintain dyskinesias. Once dyskinesias are stable, we will administer BMY-14802 at different doses to determine the ED50, or dose that suppresses dyskinesias by 50%, as assessed by the AIMS dyskinesia rating scale (Specific Aim I). Rats will also be subjected to a battery of behavioral tests that assess Parkinson's symptoms and that show improvement after L-DOPA treatment. This will allow us to determine whether BMY- 14802 prevents treatment of Parkinson's symptoms by L-DOPA (Specific Aim II). Finally, animals will be treated with BMY-14802 (which suppresses dyskinesias), MK-801 (which does not suppress dyskinesias), or placebo, followed by L-DOPA or placebo. Brain tissue from a motor region (the striatum) of these animals will be analyzed for changes in levels of proteins that have been associated with dyskinesias to determine what proteins are specifically affected by BMY-14802 (Specific Aim III). In a separate group of normal rats (without the 6-OHDA lesion), we will investigate whether a high dose of BMY-14802 has any antagonist effects at the dopamine D2 receptor, as this would indicate that BMY-14802 might worsen Parkinson's symptoms (Specific Aim IV). Antagonism of the D2 receptor is observed behaviorally as catalepsy, a slowness to move out of awkward positions. Catalepsy is prevented by agonism at the serotonin 1A receptor, and BMY-14802 is known to have serotonin 1A agonist effects; therefore, we will also administer a serotonin 1A agonist to determine whether BMY-14802's other mechanisms of action include D2 antagonism. As reference compounds, we will also test a full serotonin 1A agonist, a partial serotonin 1A agonist, and a D2 antagonist. PUBLIC HEALTH RELEVANCE L-DOPA-induced dyskinesia significantly reduces the quality of life of 28-64% of individuals with Parkinson's Disease (Friedman, 1985; Schrag & Quinn, 2000), costing $1328 per patient annually for each unit of increase on the LID rating scale (Pechevis et al., 2005). A model of L-DOPA-induced dyskinesia with excellent predictive validity is the 6-hydroxydopamine rat, which has shown that the same drugs that suppress dyskinesia in Parkinson's patients work in the rat (i.e., amantadine, dextromethorphan, and buspirone). Unfotunately, these treatments have serious drawbacks, including no proven long-term efficacy, abuse potential, psychotomimetic effects, or exacerbation of Parkinson's symptoms; therefore, it is imperative to develop anti-dyskinesia pharmacotherapies with less adverse effects in this vulnerable geriatric population.