3,4-dihydroxyphenylacetaldehyde is the toxic dopamine metabolite in vivo: implications for Parkinson's disease pathogenesis

被引:150
作者
Burke, WJ
Li, SW
Williams, EA
Nonneman, R
Zahm, DS
机构
[1] St Louis Univ, Sch Med, Med Ctr, Dept Neurol, St Louis, MO 63110 USA
[2] St Louis Univ, Med Ctr, Dept Med, St Louis, MO 63110 USA
[3] St Louis Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63104 USA
[4] St Louis Univ, Dept Chem, St Louis, MO 63110 USA
[5] Vet Affairs Med Ctr, St Louis, MO USA
关键词
basal ganglia; neuron death; neurodegenerative disorder; substantia nigra; ventral tegmental area; 3,4-dihydroxyphenylacetaldehyde;
D O I
10.1016/S0006-8993(03)03354-7
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
In Parkinson's disease (PD), there is a highly selective loss of dopamine (DA) neurons in the substantia nigra (SN) greater than in the ventral tegmental area (VTA). The simplest explanation for selective DA neuron loss in PD is that DA is toxic and, because only DA neurons contain significant amounts of DA, this highly localized synthesis of DOPAL accounts for selective vulnerability of DA neurons. However, the large concentrations of DA required to produce in vivo toxicity cast doubt on its role in PD pathogenesis. Alpha-synuclein (alpha-syn) is the major component of the Lewy body, the pathological marker of PD, and is genetically linked to the disease. Recent studies indicate that a-syn neurotoxicity is mediated by a free radical generating metabolite of DA. Here we test the hypothesis that 3,4-dihydroxvphenylacetaldehyde (DOPAL), the monamine oxidase metabolite of DA, mediates DA toxicity in vivo. We injected DOPAL, DA and its oxidative, reduced and methylated metabolites into rat SN and VTA. Five days post-surgery, the injection sites were evaluated in Nissl preparations and with tyrosine hydroxylase (for DA neurons), neuronal nuclear antigen (for neurons) and glial fibrillary acidic protein (for astrocytes) immunoreactivities. Lesion size in SN vs. VTA was compared using morphometry. DOPAL at concentrations as low as 100 ng was toxic to DA SN neurons>DA VTA neurons>glia. Neither DA nor its other metabolites showed evidence of neurotoxicity at fivefold higher doses. However, 20 mug of DA produced lesions in the SN and VTA. We conclude that DOPAL is the toxic DA metabolite in vivo. Implications for a unified hypothesis for PD pathogenesis are discussed. (C) 2003 Elsevier B.V. All rights reserved.
引用
收藏
页码:205 / 213
页数:9
相关论文
共 43 条
[1]   Prevalence of Parkinsonian signs and associated mortality in a community population of older people [J].
Bennett, DA ;
Beckett, LA ;
Murray, AM ;
Shannon, KM ;
Goetz, CG ;
Pilgrim, DM ;
Evans, DA .
NEW ENGLAND JOURNAL OF MEDICINE, 1996, 334 (02) :71-76
[2]  
BERTARBET R, 2000, NAT NEUROSCI, V3, P1302
[3]  
BLASCHKO H, 1952, PHARMACOL REV, V4, P415
[4]  
Burke WJ, 2000, NEUROTOXIC FACTORS IN PARKINSON'S DISEASE AND RELATED DISORDERS, P167
[5]   Quantitation of 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde, the monoamine oxidase metabolites of dopamine and noradrenaline, in human tissues by microcolumn high-performance liquid chromatography [J].
Burke, WJ ;
Chung, HD ;
Li, SW .
ANALYTICAL BIOCHEMISTRY, 1999, 273 (01) :111-116
[6]   Catecholamine monoamine oxidase a metabolite in adrenergic neurons is cytotoxic in vivo [J].
Burke, WJ ;
Li, SW ;
Zahm, DS ;
Macarthur, H ;
Kolo, LL ;
Westfall, TC ;
Anwar, M ;
Glickstein, SB ;
Ruggiero, DA .
BRAIN RESEARCH, 2001, 891 (1-2) :218-227
[7]  
BURKE WJ, IN PRESS CURRENT DRU
[8]   Levodopa-induced neurotoxicity - Does it represent a problem for the treatment of Parkinson's disease? [J].
Fahn, S .
CNS DRUGS, 1997, 8 (05) :376-393
[9]   Dendrodendritic inhibition through reversal of dopamine transport [J].
Falkenburger, BH ;
Barstow, KL ;
Mintz, IM .
SCIENCE, 2001, 293 (5539) :2465-2470
[10]   PRESYNAPTIC AND POSTSYNAPTIC NEUROTOXIC EFFECTS OF DOPAMINE DEMONSTRATED BY INTRASTRIATAL INJECTION [J].
FILLOUX, F ;
TOWNSEND, JJ .
EXPERIMENTAL NEUROLOGY, 1993, 119 (01) :79-88