Effect of levodopa priming on dopamine neuron transplant efficacy and induction of abnormal involuntary movements in parkinsonian rats.
Effect of levodopa priming on dopamine neuron transplant efficacy and induction of abnormal involuntary movements in parkinsonian rats.
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DOI：
10.1002/cne.22037
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发表时间：
2009-07-01
期刊：
影响因子：
--
通讯作者：
Maries-Lad E
中科院分区：
文献类型：
--
作者：
Steece-Collier K;Soderstrom KE;Collier TJ;Sortwell CE;Maries-Lad E
神经移植治疗帕金森病（PD）的临床试验产生了可变的，但总体上令人失望的结果。一个特别令人失望的是多巴胺（DA）神经元移植后异常运动并发症的发展。尽管缺乏一致的益处，但多巴胺神经元替代的效用仍然得到临床和基础数据的支持。在继续努力阐明可能改善这种治疗的因素中，我们使用帕金森病大鼠模型来检查移植前慢性左旋多巴是否影响移植物疗效和/或移植物诱导的运动障碍（GID）诱导。事实上，迄今为止，所有移植的PD患者都有长期左旋多巴的移植前病史。已经确定的是，长期左旋多巴导致过多的长期神经化学改变，以及指示改变的结构和突触可塑性的基因组变化。因此，在纹状体环境中进行治疗性多巴胺末端替代，这种变化可能会导致移植物和宿主脑之间的异常或不适当的连接，并导致次优疗效和/或移植后GID行为。为了研究移植前左旋多巴的影响，一组帕金森病大鼠在移植前接受左旋多巴4周。第二个左旋多巴未处理组被移植，移植物在引入慢性左旋多巴之前成熟9周。我们在这里报告，在帕金森病大鼠，预先暴露于慢性左旋多巴显着降低胚胎多巴胺移植的行为和神经化学疗效。此外，在引入慢性左旋多巴之前的多巴胺末端替代在预防左旋多巴诱导的运动障碍的发展方面非常有效，并且无论移植前左旋多巴状态如何，都会发生GID样行为。
Clinical trials of neural grafting for Parkinson's disease (PD) have produced variable, but overall, disappointing results. One particular disappointment has been the development of aberrant motor complications following dopamine (DA) neuron grafting. Despite a lack of consistent benefit, the utility of dopamine neuron replacement remains supported by clinical and basic data. In a continued effort to elucidate factors that might improve this therapy, we used a parkinsonian rat model to examine whether pre-graft chronic levodopa impacted graft efficacy and/or graft-induced dyskinesia (GID) induction. Indeed, all grafted PD patients to date have had a pre-graft history of long-term levodopa. It is well established that long-term levodopa results in a plethora of long-lasting neurochemical alterations, and genomic changes indicative of altered structural and synaptic plasticity. Thus, therapeutic dopamine terminal replacement in a striatal environment complicated by such changes could be expected to lead to abnormal or inappropriate connections between graft and host brain, and contribute to suboptimal efficacy and/or post-graft GID behaviors. To investigate the impact of pre-graft levodopa, one group of parkinsonian rats received levodopa for 4 weeks prior to grafting. A second levodopa naïve group was grafted and grafts allowed to mature for nine weeks prior to introducing chronic levodopa. We report here that in parkinsonian rats, pre-exposure to chronic levodopa significantly reduces behavioral and neurochemical efficacy of embryonic dopamine grafts. Further, dopamine terminal replacement prior to introduction of chronic levodopa is highly effective at preventing development of levodopa-induced dyskinesias, and GID-like behaviors occur regardless of pre-graft levodopa status.
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影响因子：
6.1
作者：
Carlsson, T;Winkler, C;Kirik, D
通讯作者：
Kirik, D
影响因子：
3.3
作者：
Croft, BG;Fortin, GD;Fon, EA
通讯作者：
Fon, EA
影响因子：
6.1
作者：
Andersson, M;Hilbertson, A;Cenci, MA
通讯作者：
Cenci, MA
影响因子：
3.5
作者：
Cenci, MA
通讯作者：
Cenci, MA
DOI：
10.1073/pnas.77.11.6926
发表时间：
1980-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
GROVES, PM
通讯作者：
GROVES, PM