PARKINSONISM-INDUCING NEUROTOXIN, N-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE - UPTAKE OF THE METABOLITE N-METHYL-4-PHENYLPYRIDINE BY DOPAMINE NEURONS EXPLAINS SELECTIVE TOXICITY
PARKINSONISM-INDUCING NEUROTOXIN, N-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE - UPTAKE OF THE METABOLITE N-METHYL-4-PHENYLPYRIDINE BY DOPAMINE NEURONS EXPLAINS SELECTIVE TOXICITY
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DOI：
10.1073/pnas.82.7.2173
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发表时间：
1985-01-01
影响因子：
11.1
通讯作者：
SNYDER, SH
中科院分区：
文献类型：
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作者：
JAVITCH, JA;DAMATO, RJ;SNYDER, SH
N-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）在人、猴和小鼠中产生神经病理学和临床异常，与特发性帕金森病非常相似。N-甲基-4-苯基吡啶（MPP+）是MPTP由单胺氧化酶B形成的代谢产物，通过多巴胺和去甲肾上腺素摄取系统分别蓄积到纹状体和大脑皮质突触体中，而MPTP本身不蓄积。药物抑制[3 H]MPP+或[3 H]多巴胺摄取进入纹状体突触体的效力非常相似，抑制[3 H]MPP+或[3 H]去甲肾上腺素摄取进入皮质突触体的效力也非常相似。在大鼠纹状体和皮质中，[3 H]MPP+摄取的Km值分别为170和65 nM，Vmax值分别为2和0.1 nmol/g组织/min，与[3 H]多巴胺摄取的值相似。大鼠脑切片[~ 3 H]MPP ~+蓄积的放射自显影显示尾壳核和延髓核内有高密度。马吲哚阻断多巴胺摄取可防止MPTP诱导的黑质纹状体多巴胺神经元损伤，表明MPP+浓度进入多巴胺神经元解释了MPTP对它们的选择性破坏。
N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces neuropathological and clinical abnormalities in humans, monkeys and mice that closely resemble idiopathic parkinsonism. N-Methyl-4-phenylpyridine (MPP+), a metabolite of MPTP formed by monoamine oxidase B, is accumulated into striatal and cerebral cortical synaptosomes by the dopamine and norepinephrine uptake systems, respectively, whereas MPTP itself is not accumulated. The potencies of drugs in inhibiting [3H]MPP+ or [3H]dopamine uptake into striatal synaptosomes are very similar, as are potencies inhibiting [3H]MPP+ or [3H]norepinephrine uptake into cortical synaptosomes. The Km values for [3H]MPP+ uptake are 170 and 65 nM and the Vmax values are 2 and 0.1 nmol/g of tissue per min in rat striatum and cortex, respectively, similar to values for [3H]dopamine uptake. Autoradiography of accumulated [3H]MPP+ in slices of rat brain shows high densities in the caudate-putamen and nucleus accumbens. Blockade of dopamine uptake by mazindol prevents MPTP-induced damage to nigrostriatal dopamine neurons, indicating that MPP+ concentration into dopamine neurons explains their selective destruction by MPTP.