Nakao Naoyuki, Shintani-Mizushima Aki, Kakishita Koji, Itakura Toru
Department of Neurological Surgery, Wakayama Medical University, Wakayama 641-0012, Japan.
Brain Res Rev. 2006 Sep;52(2):244-56. doi: 10.1016/j.brainresrev.2006.03.001. Epub 2006 Apr 27.
Grafting of catecholamine-producing cells can be a possible therapeutic strategy for attenuating motor symptoms in Parkinson's disease (PD). The potential of autologous sympathetic neurons has been investigated as a donor for cell therapy of PD. The clinical trials of autotransplantation of sympathetic ganglion cells in PD have revealed that the grafts increase the duration of L-DOPA (L-dihydroxy phenyl alanine)-induced beneficial effects, and that the graft-mediated effect is detectable during a follow-up period of at least 1 year postgrafting. In an in vitro analysis of the ability of human sympathetic neurons to release catecholamines, although DA was not detectable under basal conditions, DA levels were significantly increased upon exposure to exogenous L-DOPA. Furthermore, animal experiments with xenografting of human sympathetic ganglionic neurons in the DA-denervated striatum of rats demonstrated that a significant increase in striatal DA levels is noted after systemic L-DOPA treatment, and that the DA levels remain high for longer periods of time in the grafted rats than in control animals with sham surgery. The L-DOPA-induced rise of striatal DA levels was significantly attenuated when given reserpine pretreatment. This suggests that DA derived from exogenously administered L-DOPA is subjected to, at least in part, vesicular storage in grafted sympathetic neurons. Histological examinations indeed showed that the grafts express aromatic-L-amino acid decarboxylase and vesicular monoamine transporter-2, both of which are important molecules for the synthesis and the storage of DA, respectively. Taken together, grafted sympathetic neurons can provide a site for both the conversion of exogenous L-DOPA to DA and the storage of the synthesized DA in the DA-denervated striatum. This might be an explanation for a mechanism by which sympathetic neuron autografts can increase the duration of L-DOPA effects in PD patients. This review article summarizes the clinical effect of transplantation of autologous sympathetic neurons in PD and discusses the underlying mechanism for the effect based on experimental evidence previously obtained.
移植产生儿茶酚胺的细胞可能是减轻帕金森病（PD）运动症状的一种治疗策略。自体交感神经元作为PD细胞治疗的供体潜力已得到研究。PD患者交感神经节细胞自体移植的临床试验表明，移植可延长左旋多巴（L-二羟基苯丙氨酸）诱导的有益作用持续时间，且在移植后至少1年的随访期内可检测到移植介导的效应。在对人交感神经元释放儿茶酚胺能力的体外分析中，虽然在基础条件下未检测到多巴胺（DA），但暴露于外源性左旋多巴后DA水平显著升高。此外，在大鼠多巴胺去神经支配纹状体中异种移植人交感神经节神经元的动物实验表明，全身给予左旋多巴治疗后纹状体DA水平显著升高，且移植大鼠的DA水平在较长时间内保持高于假手术对照动物。给予利血平预处理后，左旋多巴诱导的纹状体DA水平升高显著减弱。这表明外源性给予的左旋多巴衍生的DA至少部分在移植的交感神经元中进行囊泡储存。组织学检查确实显示移植组织表达芳香族L-氨基酸脱羧酶和囊泡单胺转运体-2，这两种分子分别是DA合成和储存的重要分子。综上所述，移植的交感神经元可为外源性左旋多巴转化为DA以及合成的DA在多巴胺去神经支配的纹状体中储存提供场所。这可能解释了交感神经元自体移植可增加PD患者左旋多巴作用持续时间的机制。本文综述总结了自体交感神经元移植在PD中的临床效果，并根据先前获得的实验证据讨论了该效果的潜在机制。
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