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

评估 BMY-14802 在 P 6-OHDA 大鼠模型中的抗运动障碍治疗作用

• 批准号: 7612809
• 负责人: Melanie A. Paquette
• 金额: $ 10.5万
• 依托单位: SKYBRIDGE PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2010-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612809
• 关键词: Adverse effects; Affect; Agonist; Amantadine; Animal Model; Animals; Brain; Buspirone; Catalepsy; Corpus striatum structure; Development; Dextromethorphan; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor; Dose; Dyskinetic syndrome; Elderly; Face; Future; Gold; Haloperidol; Individual; L-DOPA induced dyskinesia; Lesion; Levodopa; Limb structure; Mediating; Modeling; Molecular; Motor; Neurotoxins; Oxidopamine; Parkinson Disease; Patients; Pharmaceutical Preparations; Pharmacotherapy; Placebos; Population; Positioning Attribute; Property; Proteins; Quality of life; Rattus; Serotonin; Serotonin Receptor 5-HT1A; Side; Symptoms; Testing; Therapeutic; Work; abnormal involuntary movement; base; behavior test; brain surgery; brain tissue; cost; effective therapy; fiber cell; flesinoxan; prevent; prodynorphin; public health relevance; standard care

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.

描述（由申请人提供）：我们的目标是针对帕金森病患者出现的左旋多巴 (L-DOPA) 副作用开发新的药物治疗方法。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出现使人衰弱的副作用，即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。目前治疗运动障碍的药物治疗有缺点：它们可能在 8-12 个月后无效，可能具有成瘾性，可能导致精神病症状，或者可能加重帕金森病的症状。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。在使用公认的运动障碍动物模型进行的初步研究中，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，甚至更好，而且不会恶化帕金森症状。我们现在试图在更大的动物群体中证实这一发现，并确定大脑中的哪些蛋白质可能介导这些影响。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。每天用左旋多巴治疗大鼠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，我们将以不同剂量施用 BMY-14802，以确定 ED50，或根据 AIMS 运动障碍评级量表（特定目标 I）评估，将运动障碍抑制 50% 的剂量。老鼠还将接受一系列行为测试，以评估帕金森症状，并显示左旋多巴治疗后有所改善。这将使我们能够确定 BMY-14802 是否会阻止 L-DOPA 对帕金森症状的治疗（具体目标 II）。最后，动物将接受 BMY-14802（抑制运动障碍）、MK-801（不抑制运动障碍）或安慰剂治疗，然后接受 L-DOPA 或安慰剂治疗。将分析这些动物运动区域（纹状体）的脑组织中与运动障碍相关的蛋白质水平的变化，以确定哪些蛋白质特别受到 BMY-14802（具体目标 III）的影响。在另一组正常大鼠（没有 6-OHDA 损伤）中，我们将研究高剂量的 BMY-14802 是否对多巴胺 D2 受体有任何拮抗作用，因为这表明 BMY-14802 可能会加重帕金森氏症的症状。具体目标 IV)。 D2 受体的拮抗作用在行为上表现为僵直症，即摆脱尴尬姿势的缓慢状态。通过血清素 1A 受体的激动作用可以预防僵住症，并且已知 BMY-14802 具有血清素 1A 激动剂作用；因此，我们还将使用血清素 1A 激动剂来确定 BMY-14802 的其他作用机制是否包括 D2 拮抗作用。作为参考化合物，我们还将测试完全血清素 1A 激动剂、部分血清素 1A 激动剂和 D2 拮抗剂。公共卫生相关性 左旋多巴引起的运动障碍显着降低了 28-64% 帕金森病患者的生活质量（Friedman，1985；Schrag & Quinn，2000），LID 每增加一个单位，每位患者每年要花费 1328 美元评级量表（Pechevis 等，2005）。 6-羟基多巴胺大鼠是左旋多巴诱发的运动障碍模型，具有良好的预测有效性，该模型表明，抑制帕金森病患者运动障碍的药物（即金刚烷胺、右美沙芬和丁螺环酮）对大鼠也有效。不幸的是，这些治疗方法有严重的缺点，包括尚未证明长期疗效、滥用可能性、拟精神病作用或帕金森症状恶化；因此，当务之急是开发对这一弱势老年人群副作用较小的抗运动障碍药物疗法。