DEVELOPMENT OF MODEL OF MILD & ADVANCED PARKINSONISM IN NON HUMAN PRIMATES

轻度模型的开发

• 批准号: 6591303
• 负责人: MARTIN GOULET
• 金额: $ 11.11万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6591303
• 关键词: Mammalia; aging; behavioral /social science research tag; drug adverse effect; nervous system; pharmacology; psychology; technology /technique; Mammalia; aging; behavioral /social science research tag; drug adverse effect; nervous system; pharmacology; psychology; technology /technique

Parkinson's disease is a progressive neurodegenerative disease characterized primarily by degeneration of dopamine-containing neurons in the pars compacta of the substantia nigra The early symptoms of Parkinson's disease are bradykinesia, rigidity, tremor but with disease progression, postural instability, immobility and confinement to a wheel-chair are commonly observed The effectiveness of the most widely used treatment L-Dopa, which is converted to dopamine, wanes with disease progression Alternatives to L-Dopa therapy include direct agonists that activate the targets of dopamine, D1 and D2 dopamine receptors Several dopamine agonists have been tried as monotherapies at the onset of therapy (Hoehn and Yahr stage I-III), as substitutes for L-Dopa in patients with advanced Parkinson's disease (Hoehn and Yahr stage III-V) and as adjuncts to L-Dopa The antiparkinsonian activity of D2-like agonists (bromocriptine, lisuride, pergolide) are effective in early Parki nson 's disease and newer D2-like agonists (pramipexole, ropinirole and cabergoline) are efficacious when used as monotherapy for symptomatic treatment of early as well as advanced stages of Parkinson's disease The therapeutic efficacy of D1 agonists at different stages of the disease are not known To investigate whether D1 agonists will produce different therapeutic relief at different stages of Parkinson's disease, we developed a model of mild and advanced parkinsonism in monkeys with two dosing regimens of the neurotoxin1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) To create a model of mild Parkinsonism, 2 doses of 0 6 mg/kg MPTP were administered i v 1 month apart Advanced Parkinsonism was developed by administering 3 doses of 0 6 mg/kg MPTP within 10 days, i v Motor function was evaluated using a rating scale of general activity, locomotor activity, bradykinesia, rigidity, posture, imbalance, tremor frequency, body freeze, and feeding ability The majority of behaviors w ere measured on a normal (0), slight (1) and absent (2) scale The effects of the two dosing regimens led to a mild and an advanced form of Parkinsonism that were distinguishable statistically from each other and from normal animals Prominent differences were the higher incidence of body freeze, feeding ability, rigidity, and general activity in advanced parkinsonism Tremor frequency was more pronounced in the mild than in the advanced Parkinsonism The scale also permitted rating of dyskinesia and imbalance The two models were used to effectively evaluate the therapeutic and undesirable side effects of the two full D1 agonists and two very selective D2 agonists These data demonstrate that 1 mild and severe parkinsonism can be produced by two different dosing regimens of MPTP 2 The motor dysfunction engendered by the two dosing regimens can be distinguished from one another by a rating scale and these differences are statistically significant 3 The two models of Parkinsoni sm are distinguishable from normal animals 3 The therapeutic effectiveness of D1 and D2 agonists depends on the degree of parkinsonism This model is useful for the evaluation of anti-parkinsonian medications at different degrees of motor impairment

帕金森氏病是一种进行性神经退行性疾病 主要由含多巴胺神经元退化的特征 在黑质的pars compacta中 帕金森氏病是Bradykinesia，僵化，震颤，但 疾病进展，姿势不稳定，固定和拘留 通常观察到轮椅的有效性最大 广泛使用的治疗l-dopa，转化为多巴胺，减弱 疾病进展的替代方法是L-DOPA疗法的直接 激活多巴胺，D1和D2多巴胺靶的激动剂 受体几种多巴胺激动剂已被尝试作为单疗法 在治疗开始时（Hoehn和Yahr阶段I-III），替代 对于晚期帕金森氏病（Hoehn and Hoehn和 yahr级III-V），作为l-dopa的辅助 D2样激动剂的活性（溴封然，lisuride，pergolide）是 在早期帕基·恩森（Parki Nson）的疾病和较新的类似D2的激动剂中有效 （Pramipexole，Ropinirole和Cabergoline）当用作用作 对早期和晚期治疗的有症状治疗的单一疗法 帕金森氏病的阶段D1激动剂的治疗功效 在疾病的不同阶段，尚不清楚调查 D1激动剂是否会在 帕金森氏病的不同阶段，我们开发了一种温和的模型 和猴子的高级帕金森氏症，有两种给药方案 神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）至 创建一个温和的帕金森主义模型，2剂0 6 mg/kg mptp是 管理I v 1个月相隔1个月，高级帕金森主义是由 在10天内管理3剂0 6 mg/kg MPTP，I V电动机 使用一般活动的评分量表评估功能， 运动活动，胸肌，刚性，姿势，失衡，震颤 频率，身体冻结和进食能力大多数行为 在正常（0），轻微（1）和不存在（2）缩放的情况下测量 两种剂量方案的影响导致了温和的高级形式 帕金森主义在统计上可区分的 其他和正常动物的显着差异是较高的 身体冻结，进食能力，刚性和一般的发生率 高级帕金森主义震颤频率的活动更为明显 在温和的帕金森氏症中，量表也允许 运动障碍和失衡的评分两种模型用于 有效评估的治疗和不良副作用 两个完整的D1激动剂和两个非常有选择性的D2激动剂这些数据 证明1个轻度和严重的帕金森氏症可以由两个 MPTP 2的不同剂量方案引起的电动机功能障碍 通过两种给药方案可以通过 评分量表和这些差异在统计上显着3 帕金森氏症SM的两种模型与普通动物有区别3 D1和D2激动剂的治疗有效性取决于 帕金森主义的程度此模型可用于评估 不同程度的运动障碍的抗帕金森药