Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells
Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells
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DOI：
10.1124/jpet.115.230201
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发表时间：
2016-02-01
影响因子：
3.5
通讯作者：
Sharabi, Yehonatan
中科院分区：
文献类型：
--
作者：
Goldstein, David S.;Jinsmaa, Yunden;Sharabi, Yehonatan
根据儿茶酚醛假说，毒性多巴胺代谢产物3，4-二羟基苯乙醛（DOPAL）导致帕金森病中黑质纹状体多巴胺能神经元的损失。单胺氧化酶-A（MAO-A）催化神经元内多巴胺转化为DOPAL，并可作为治疗靶点。“奶酪效应”--由含酪胺的食物引起的阵发性高血压--限制了不可逆的单胺氧化酶-A抑制剂的临床应用。MAO-A/B联合抑制可降低大鼠嗜铬细胞瘤PC 12细胞中DOPAL的产生，但可逆的MAO-A抑制剂或MAO-B抑制剂是否降低内源性DOPAL的产生尚不清楚。我们比较了MAO抑制剂在衰减DOPAL产生方面的效力，并检查了对多巴胺储存、组成性释放、合成和自动氧化的可能的次级影响。在与不可逆MAO-A抑制剂氯吉兰、三种可逆MAO-A抑制剂或MAO-B抑制剂司来吉兰或雷沙吉兰孵育180分钟后，测量细胞和培养基中的儿茶酚浓度。可逆的MAO-A抑制剂通常无效，而氯吉兰（1 nM），雷沙吉兰（500 nM）和司来吉兰（500 nM）降低细胞和培养基中的DOPAL水平。所有这三种药物也增加多巴胺和去甲肾上腺素，减少3，4-二羟基苯丙氨酸，并增加半胱氨酰多巴胺浓度的介质中，这表明增加囊泡摄取和组成性释放，减少多巴胺合成，并增加多巴胺自发氧化。总之，氯吉兰、雷沙吉兰和司来吉兰降低内源性DOPAL的产生。在相对高的浓度下，后一种药物可能失去对MAO-B的选择性。可能抵消潜在毒性氧化产物形成的增加和DOPAL形成的减少可能是MAO-B抑制剂的大型临床试验未能证明帕金森病神经变性减缓的原因。
According to the catecholaldehyde hypothesis, the toxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) contributes to the loss of nigrostriatal dopaminergic neurons in Parkinson's disease. Monoamine oxidase-A (MAO-A) catalyzes the conversion of intraneuronal dopamine to DOPAL and may serve as a therapeutic target. The "cheese effect"-paroxysmal hypertension evoked by tyramine-containing foodstuffs-limits clinical use of irreversible MAO-A inhibitors. Combined MAO-A/B inhibition decreases DOPAL production in rat pheochromocytoma PC12 cells, but whether reversible MAO-A inhibitors or MAO-B inhibitors decrease endogenous DOPAL production is unknown. We compared the potencies of MAO inhibitors in attenuating DOPAL production and examined possible secondary effects on dopamine storage, constitutive release, synthesis, and auto-oxidation. Catechol concentrations were measured in cells and medium after incubation with the irreversible MAO-A inhibitor clorgyline, three reversible MAO-A inhibitors, or the MAO-B inhibitors selegiline or rasagiline for 180 minutes. Reversible MAO-A inhibitors were generally ineffective, whereas clorgyline (1 nM), rasagiline (500 nM), and selegiline (500 nM) decreased DOPAL levels in the cells and medium. All three drugs also increased dopamine and norepinephrine, decreased 3,4-dihydroxyphenylalanine, and increased cysteinyl-dopamine concentrations in the medium, suggesting increased vesicular uptake and constitutive release, decreased dopamine synthesis, and increased dopamine spontaneous oxidation. In conclusion, clorgyline, rasagiline, and selegiline decrease production of endogenous DOPAL. At relatively high concentrations, the latter drugs probably lose their selectivity for MAO-B. Possibly offsetting increased formation of potentially toxic oxidation products and decreased formation of DOPAL might account for the failure of large clinical trials of MAO-B inhibitors to demonstrate slowing of neurodegeneration in Parkinson's disease.