Kish Stephen J, Tong Junchao, Hornykiewicz Oleh, Rajput Ali, Chang Li-Jan, Guttman Mark, Furukawa Yoshiaki
Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Brain. 2008 Jan;131(Pt 1):120-31. doi: 10.1093/brain/awm239. Epub 2007 Oct 22.
Interest in serotonergic involvement in Parkinson's disease (PD) has focussed recently on the possibility that the remaining serotonin neurons innervating striatum (caudate and putamen) might release dopamine as a 'false transmitter'--an action that could have both beneficial and harmful (e.g. promotion of levodopa-induced dyskinesias) consequences. Evidence for a brain serotonergic disturbance in PD is derived in large part from findings of decreased binding of different radioligands to the serotonin transporter (SERT), one 'marker' of serotonin neurons. However, it is not known whether the reported changes in SERT binding reflect actual changes in levels of SERT protein or whether concentrations of all serotonin markers are similarly and markedly decreased in the two striatal subdivisions. We measured levels of SERT immunoreactivity, and for comparison, protein levels of tryptophan hydroxylase (TPH; the marker synthetic enzyme) using a Western blot procedure, as well as concentrations of serotonin, its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and dopamine by HPLC in post-mortem striatum of patients with PD and normal controls. Whereas concentrations of dopamine were severely decreased (caudate, -80%; putamen, -98%) and showed little (caudate) or no (putamen) overlap between individual control and patient values, levels of all four serotonin markers were less markedly reduced (-30% to -66%) with some patients having distinctly normal levels. Unlike the preferential loss of dopamine in putamen, the caudate was affected more than putamen by loss of all serotonin markers: serotonin (-66% versus -51%), 5-HIAA (-42% versus -31%), SERT (-56% versus -30%) and TPH (-59% versus -32%). Striatal serotonin concentration was similar in the subset of patients reported to have had dyskinesias versus those not reported to have had this drug complication. Previous findings of decreased SERT binding are likely explained by loss of SERT protein. Reduced striatal levels of all of the key serotonergic markers (neurotransmitter and metabolite, transporter protein, synthesizing enzyme protein) provide strong evidence for a serotonergic disturbance in PD, but with some patients affected much more than others. The more marked caudate reduction suggests that raphe neurons innervating this area are more susceptible to 'damage' than those innervating putamen and that any functional impairment caused by striatal serotonin loss might primarily involve the caudate. Questions related to the, as yet undetermined, clinical consequences in PD of a striatal serotonin deficiency (caudate: cognitive impairment?) and preservation (putamen: levodopa-induced dyskinesias?) should be addressed in prospective brain imaging and pharmacological studies.
最近，对帕金森病（PD）中血清素参与情况的关注集中在支配纹状体（尾状核和壳核）的剩余血清素神经元可能释放多巴胺作为“假递质”的可能性上——这种作用可能产生有益和有害（例如促进左旋多巴诱导的运动障碍）的后果。PD中脑血清素紊乱的证据在很大程度上来自于不同放射性配体与血清素转运体（SERT）结合减少的发现，SERT是血清素神经元的一个“标志物”。然而，尚不清楚所报道的SERT结合变化是否反映了SERT蛋白水平的实际变化，或者在两个纹状体亚区中所有血清素标志物的浓度是否同样显著降低。我们使用蛋白质印迹法测量了SERT免疫反应性水平，并为作比较测量了色氨酸羟化酶（TPH；标志物合成酶）的蛋白水平，以及通过高效液相色谱法测量了PD患者和正常对照者死后纹状体中血清素、其代谢物5-羟吲哚乙酸（5-HIAA）和多巴胺的浓度。虽然多巴胺浓度严重降低（尾状核，-80%；壳核，-98%），且个体对照和患者值之间几乎没有（尾状核）或没有（壳核）重叠，但所有四种血清素标志物的水平降低幅度较小（-30%至-66%），一些患者的水平明显正常。与壳核中多巴胺的优先丧失不同，尾状核受所有血清素标志物丧失的影响比壳核更大：血清素（-66%对-51%）、5-HIAA（-42%对-31%）、SERT（-56%对-30%）和TPH（-59%对-32%）。据报道有运动障碍的患者亚组与未报告有这种药物并发症的患者亚组的纹状体血清素浓度相似。先前报道的SERT结合减少的发现可能是由于SERT蛋白的丧失。所有关键血清素标志物（神经递质和代谢物、转运体蛋白、合成酶蛋白）的纹状体水平降低为PD中的血清素紊乱提供了有力证据，但一些患者受影响的程度比其他患者大得多。尾状核更明显的减少表明，支配该区域的中缝神经元比支配壳核的中缝神经元更容易受到“损伤”，并且纹状体血清素丧失引起的任何功能损害可能主要涉及尾状核。与纹状体血清素缺乏（尾状核：认知障碍？）和保留（壳核：左旋多巴诱导的运动障碍？）在PD中尚未确定的临床后果相关的问题，应在前瞻性脑成像和药理学研究中加以解决。
