Goldstein David S, Sullivan Patricia, Holmes Courtney, Kopin Irwin J, Sharabi Yehonatan, Mash Deborah C
Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
Parkinsonism Relat Disord. 2015 Jun;21(6):567-72. doi: 10.1016/j.parkreldis.2015.03.006. Epub 2015 Mar 20.
Parkinson disease (PD) and multiple system atrophy (MSA) share some neuropathologic features (nigrostriatal dopaminergic lesion, alpha-synuclein deposition) but not others (Lewy bodies in PD, glial cytoplasmic inclusions in MSA). In PD evidence has accrued for a vesicular storage defect and decreased aldehyde dehydrogenase (ALDH) activity in residual dopaminergic terminals, resulting in accumulation of the toxic dopamine (DA) metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). In this study we asked whether MSA entails a similar abnormal neurochemical pattern.
DA and its main neuronal metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), norepinephrine (NE) and its main neuronal metabolite 3,4-dihydroxyphenylglycol (DHPG), the catecholamine precursor DOPA, and DOPAL were measured in striatal and frontal cortical tissue from patients with pathologically proven end-stage MSA (N = 15), sporadic PD (N = 17), and control subjects (N = 18).
Compared to the control group, the MSA and PD groups had similarly decreased putamen DA (by 96% and 93%, p < 0.0001), DOPAC (97% and 95%, p < 0.0001), NE (91% and 74%, p < 0.0001), and DHPG (81% and 74%, p < 0.0001). In the MSA and PD groups, ratios of DOPAL:DA were 2.3 and 3.5 times control and DHPG:NE 3.1 and 2.6 times control, while DOPAC:DOPAL ratios were decreased by 61% and 74%. In both diseases cortical NE and DHPG were decreased, while DA and DOPAC were not.
MSA and PD entail a catecholamine metabolic profile indicating impaired vesicular storage, decreased ALDH activity, and DOPAL buildup, which might be part of a common pathway in catecholamine neuronal death. Targeting this pathway by interfering with catecholaldehyde production or effects constitutes a novel treatment approach.
帕金森病（PD）和多系统萎缩（MSA）具有一些共同的神经病理学特征（黑质纹状体多巴胺能病变、α-突触核蛋白沉积），但也有不同之处（PD中有路易小体，MSA中有胶质细胞胞质内包涵体）。在PD中，已有证据表明残余多巴胺能终末存在囊泡储存缺陷和醛脱氢酶（ALDH）活性降低，导致有毒的多巴胺（DA）代谢物3,4-二羟基苯乙醛（DOPAL）蓄积。在本研究中，我们探究MSA是否存在类似的异常神经化学模式。
在病理证实为终末期MSA患者（N = 15）、散发性PD患者（N = 17）及对照受试者（N = 18）的纹状体和额叶皮质组织中，检测DA及其主要神经元代谢物3,4-二羟基苯乙酸（DOPAC）、去甲肾上腺素（NE）及其主要神经元代谢物3,4-二羟基苯乙二醇（DHPG）、儿茶酚胺前体多巴以及DOPAL。
与对照组相比，MSA组和PD组壳核DA（分别降低96%和93%，p < 0.0001）、DOPAC（分别降低97%和95%，p < 0.0001）、NE（分别降低91%和74%，p < 0.0001）以及DHPG（分别降低81%和74%，p < 0.0001）均有相似程度的下降。在MSA组和PD组中，DOPAL:DA比值分别是对照组的2.3倍和3.5倍，DHPG:NE比值分别是对照组的3.1倍和2.6倍，而DOPAC:DOPAL比值分别降低了61%和74%。在这两种疾病中，皮质NE和DHPG均降低，而DA和DOPAC未降低。
MSA和PD具有儿茶酚胺代谢特征，表明囊泡储存受损、ALDH活性降低以及DOPAL蓄积，这可能是儿茶酚胺能神经元死亡共同途径的一部分。通过干扰儿茶醛的产生或作用来靶向该途径构成了一种新的治疗方法。
