An evaluation of istradefylline treatment on Parkinsonian motor and cognitive deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque models
An evaluation of istradefylline treatment on Parkinsonian motor and cognitive deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque models
复制标题
DOI：
10.1016/j.neuropharm.2016.07.012
复制
发表时间：
2016-11-01
影响因子：
4.7
通讯作者：
Bezard, Erwan
中科院分区：
文献类型：
--
作者：
Ko, Wai Kin D.;Camus, Sandrine M.;Bezard, Erwan
Istradefylline (KW-6002) 是一种腺苷 A2A 受体拮抗剂，与最佳剂量的 L-3,4-二羟基苯丙氨酸 (L-DOPA) 一起使用，以延长经历运动波动的帕金森病 (PD) 患者的治疗时间。伊曲茶碱用于治疗其他左旋多巴引起的并发症（运动和非运动相关的并发症，即运动障碍和认知障碍）的临床应用仍有待确定。在这项研究中，单独使用伊曲茶碱（60-100 mg/kg）或与最佳和次优剂量的左旋多巴联合使用的急性效应在两种 PD 猴模型中进行了评估：（i）金标准 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 治疗的帕金森病和运动障碍运动症状的猕猴模型，以及 (ii) 慢性低剂量 (CLD) MPTP 治疗的猕猴模型认知（工作记忆和注意力）缺陷的猕猴模型。对 L-DOPA 引发的 MPTP 处理的猕猴进行的行为分析表明，单独使用伊曲茶碱可以特异性缓解姿势缺陷。当与最佳左旋多巴治疗剂量联合使用时，伊曲茶碱可延长起效时间，增强对运动迟缓和运动的治疗效果，但会加剧运动障碍。特定剂量的伊曲茶碱与次优左旋多巴联合治疗可特异性缓解运动迟缓。对 CLD MPTP 治疗的猕猴进行的认知评估表明，服用伊曲茶碱后，左旋多巴引起的注意力和工作记忆缺陷有所降低。总而言之，这些数据支持伊曲茶碱作为帕金森病的辅助治疗在临床上得到更广泛的应用，其中特定的治疗组合可用于控制各种左旋多巴引起的并发症，重要的是维持所需的抗帕金森病反应。 (C) 2016 Elsevier Ltd. 保留所有权利。
Istradefylline (KW-6002), an adenosine A2A receptor antagonist, is used adjunct with optimal doses of L-3,4-dihydroxyphenylalanine (L-DOPA) to extend on-time in Parkinson's disease (PD) patients experiencing motor fluctuations. Clinical application of istradefylline for the management of other L-DOPA-induced complications, both motor and non-motor related (i.e. dyskinesia and cognitive impairments), remains to be determined. In this study, acute effects of istradefylline (60-100 mg/kg) alone, or with optimal and sub-optimal doses of L-DOPA, were evaluated in two monkey models of PD (i) the gold standard 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque model of parkinsonian and dyskinetic motor symptoms and (ii) the chronic low dose (CLD) MPTP-treated macaque model of cognitive (working memory and attentional) deficits. Behavioural analyses in L-DOPA-primed MPTP-treated macaques showed that istradefylline alone specifically alleviated postural deficits. When combined with an optimal L-DOPA treatment dose, istradefylline increased on-time, enhanced therapeutic effects on bradykinesia and locomotion, but exacerbated dyskinesia. Istradefylline treatment at specific doses with sub-optimal L-DOPA specifically alleviated bradykinesia. Cognitive assessments in CLD MPTP-treated macaques showed that the attentional and working memory deficits caused by L-DOPA were lowered after istradefylline administration. Taken together, these data support a broader clinical use of istradefylline as an adjunct treatment in PD, where specific treatment combinations can be utilised to manage various L-DOPA-induced complications, which importantly, maintain a desired anti-parkinsonian response. (C) 2016 Elsevier Ltd. All rights reserved.