EFFICACY OF DOPAMINE D1 AGONIST DEPENDS ON SEVERITY OF PARKINSONISM

多巴胺 D1 激动剂的疗效取决于帕金森病的严重程度

• 批准号: 6591304
• 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/6591304
• 关键词: Mammalia; aging; behavioral /social science research tag; drug adverse effect; nervous system; pharmacology; psychology

Parkinson's disease is a progressive neurodegenerative disease characterized by bradykinesia, rigidity, tremor and postural instability Treatment focuses mainly on dopamine replacement with L-Dopa, which requires conversion to dopamine in the brain, or dopamine agonists, which directly stimulate dopamine receptors Of the two families of dopamine receptors, D1-like ( D1, D5) and D2-like (D2, D3, D4) the D2-like dopamine receptors are the targets of agonists currently used to treat Parkinson's disease These dopamine agonists have been tried as monotherapy at the onset of therapy, as substitutes for L-Dopa in patients with advanced Parkinson's disease and as adjuncts to L-Dopa Both L-Dopa and D2 dopamine agonists produce significant side effects which warrant investigation of other dopaminergic compounds for treating the disease Although D1-like and D2 like agonists are effective antiparkinsonian agents in animal models of Parkinson's disease, the therapeutic eff ectiveness of D1-like agonists as monotherapy in early compared with advanced stages of Parkinson's disease has not been studied To investigate the effects of D1 agonists in mild and advanced parkinsonism in monkeys, we produced two different models of the disease with two dosing regimens of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mild (2 doses of 0 6 mg/kg MPTP, 1 month apart) or advanced (3 doses of 0 6 mg/kg MPTP within 10 days) These models were distinguishable on a rating scale The therapeutic and undesirable side effects of the two full D1 agonists SKF 81297 (300-fold D1/D2 selective) and dihydrexidine (3-fold D1/D2 selective), and two very selective D2 agonists, quinelorane and (+)PHNO were compared in these two models of the disease In normal monkeys (n=3), SKF 81297 did not promote increased motor activity In advanced parkinsonism (n=4), SKF 81297 (0 01 to 3 0 mg/kg) effectively reversed parkinsonian motor deficits In mild parkinsonian monkeys (n=4) , SKF 81297 was relatively ineffective in relieving motor dysfunction Similarly, dihydrexidine (0 1 to 3 0 mg/kg) almost completely reversed advanced parkinsonism and partially improved parkinsonian signs in mild Parkinsonism Although the selective D2-type agonists quinelorane (0 001 to 3 0 mg/kg) or (+)PHNO (0 0001 to 0 1 mg/kg) had little effects in normal monkeys, in mild parkinsonian monkeys, quinelorane improved and (+)PHNO effectively reversed the motor deficits In contrast to the D1 agonists, quinelorane and (+)PHNO induced marked imbalance and dyskinesias in mild parkinsonian monkeys These data demonstrate that 1 the effectiveness of a selective D1 agonist (SKF-81297) depends on the degree of parkinsonism, with promising results in advanced parkinsonism, but poor results in mild parkinsonism; 2 D1 dopamine receptor response may change in the course of neuronal degeneration; 3 D1 agonists are less prone to producing side effects than D2 agonists in mild parkinsonis m 4 D2 agonists are more effective in mild parkinsonism than D1 agonists These findings are relevant for the development of D1 anti-parkinsonian medications and support the need to further investigate receptor response at different stages of Parkinson's disease PUBLICATIONS Goulet M, Madras BK Efficacy of a dopamine D1 receptor agonist depends on severity of Parkinsonism Soc Neurosci Abstr 24 762, 1998

帕金森氏病是一种进行性神经退行性疾病 以Bradykinesia，刚性，震颤和姿势为特征 不稳定性治疗主要集中于多巴胺 l-dopa，需要转化为大脑中的多巴胺，或 多巴胺激动剂，直接刺激多巴胺受体 两个多巴胺受体家族D1样（D1，D5）和D2样家族（D2，D2， D3，D4）D2样多巴胺受体是激动剂的靶标 目前用来治疗帕金森氏病这些多巴胺激动剂 在治疗开始时已尝试作为单一疗法作为替代品 对于患有晚期帕金森氏病的患者的L-DOPA和AS L-DOPA L-DOPA和D2多巴胺激动剂的辅助作品产生 值得调查的重大副作用 多巴胺能化合物用于治疗该疾病，尽管D1样和 D2像激动剂一样是动物中有效的抗帕金森药物 帕金森氏病的模型，是 与高级阶段相比，D1样激动剂作为单一疗法 尚未研究帕金森氏病以调查影响 在猴子中温和和高级帕金森主义中的D1激动剂中，我们 产生了两种不同的疾病模型，有两个给药方案 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）轻度（2剂 0 6 mg/kg MPTP，相距1个月）或高级（3剂量0 6 mg/kg MPTP在10天内）这些模型在评级上是可区分的 扩展两个完整D1的治疗性和不良副作用 激动剂SKF 81297（300倍D1/D2选择性）和二羟化胺 （3倍D1/D2选择性）和两个非常选择性的D2激动剂， 在这两种模型的模型中比较了奎尼洛烷和（+）phno 正常猴子的疾病（n = 3），SKF 81297没有促进 高级帕金森主义的运动活动（n = 4），SKF 81297（0 01至3 0 mg/kg）有效逆转轻度帕金森氏症运动缺陷 帕金森尼猴（n = 4），SKF 81297相对无效 同样，可缓解电动机功能障碍，二羟化（0 1至3 0 mg/kg）几乎完全扭转了高级帕金森氏症和部分逆转 改善了帕金森氏症帕金森氏症的标志，尽管 选择性D2型激动剂Quinelorane（0 001至3 0 mg/kg）或（+）Phno （0 0001至0 1 mg/kg）对普通猴子几乎没有影响，轻度 帕金森尼猴，奎尼洛烷改善了，（+）有效 与D1激动剂相比，扭转了运动缺陷 在 温和的帕金森尼猴子这些数据表明1 选择性D1激动剂（SKF-81297）的有效性取决于 帕金森氏症的程度，有希望的结果 帕金森氏症，但导致轻度帕金森氏症会导致帕金森氏症。 2 D1多巴胺 受体反应可能在神经元变性过程中发生变化。 3 与D2激动剂相比，D1激动剂不太容易产生副作用 在温和的帕金森氏菌中，M 4 D2激动剂在温和的 帕金森主义比D1激动剂这些发现与 开发D1抗Parkinsonian药物并支持需求 进一步研究在不同阶段的受体反应 帕金森氏病出版物Goulet M，Madras BK的功效 多巴胺D1受体激动剂取决于帕金森主义SOC的严重程度 Neurosci Abstr 24 762，1998