Focal striatal dopamine may potentiate dyskinesias in parkinsonian monkeys
Focal striatal dopamine may potentiate dyskinesias in parkinsonian monkeys
复制标题
DOI：
10.1016/j.expneurol.2005.10.022
复制
发表时间：
2006-02-01
影响因子：
5.3
通讯作者：
Eberling, JL
中科院分区：
文献类型：
--
作者：
Bankiewicz, KS;Daadi, M;Eberling, JL
在帕金森病猴中，通过腺相关病毒（AAV）基因转移芳香族L-氨基酸脱羧酶（AADC）后，纹状体神经元将L-多巴转化为多巴胺（DA）。我们研究了AAV-AADC是否可以减少或消除MPTP治疗的猴子中L-多巴诱导的运动障碍（LID）和副作用。5只猴子通过双侧MPTP损伤而患帕金森病。使用急性剂量反应方案确定左旋多巴的最佳治疗剂量。慢性左旋多巴治疗3周后，将AAV-AADC或对照载体双侧注射到纹状体中。用与术前相同的左旋多巴剂量以及长期口服左旋多巴治疗对动物进行6个月的评估。在大于5 mg/kg的剂量下观察到术前LID。AAV-AADC治疗的动物在整个6个月的随访期内显示出L-多巴治疗剂量的平均7.3倍降低。仅AAV-AADC处理的猴即使在亚临床剂量下也易患运动障碍。免疫组化分析显示纹状体内AADC病灶轮廓分明。这些结果表明，高水平的局灶性DA产生的L-多巴管理，并可能是负责运动障碍的恶化。这可能类似于PD患者在胎儿中脑移植后出现停药或“失控”运动障碍的局灶性多巴胺能活性。(c)2005年爱思唯尔公司All rights reserved.
Striatal neurons convert L-dopa to dopamine (DA) following gene transfer of aromatic L-amino acid decarboxylase (AADC) via adeno-associated virus (AAV) in parkinsonian monkeys. We investigated whether AAV-AADC could reduce or eliminate L-dopa-induced dyskinesias (LIDs) and side effects in MPTP-treated monkeys. Five monkeys were made parkinsonian by bilateral MPTP lesions. The optimal therapeutic dose Of L-dopa was determined using an acute dose response regimen. After 3 weeks of chronic L-dopa treatment, AAV-AADC or control vector was bilaterally injected into the striatum. Animals were assessed for 6 months with the same L-dopa dosing as presurgery as well as chronic oral L-dopa treatment. Presurgery LID was observed at doses greater than 5 mg/kg. The AAV-AADC-treated animals displayed an average 7.3-fold decrease in the therapeutic dose Of L-dopa throughout the 6-month follow-up period. Only AAV-AADC-treated monkeys were susceptible to dyskinesias even at sub-clinical doses. Immunohistochemical analysis revealed well-delineated foci of AADC within the striatum. These results suggest that high levels of focal DA were generated in response to L-dopa administration and may be responsible for the exacerbation of dyskinesias. This may be similar to focal dopaminergic activity in PD patients that developed off-drug or "runaway" dyskinesias following fetal rnesencephalic grafts. (c) 2005 Elsevier Inc. All rights reserved.