Goldstein David S, Jinsmaa Yunden, Sullivan Patti, Holmes Courtney, Kopin Irwin J, Sharabi Yehonatan
Clinical Neurocardiology Section, Clinical Neuroscience Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (D.S.G., Y.J., P.S., C.H., I.J.K.); and Hypertension Unit, Chaim Sheba Medical Center and Tel-Aviv University, Tel-HaShomer, Israel (Y.S.)
Clinical Neurocardiology Section, Clinical Neuroscience Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (D.S.G., Y.J., P.S., C.H., I.J.K.); and Hypertension Unit, Chaim Sheba Medical Center and Tel-Aviv University, Tel-HaShomer, Israel (Y.S.).
J Pharmacol Exp Ther. 2016 Feb;356(2):483-92. doi: 10.1124/jpet.115.230201. Epub 2015 Nov 16.
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.
根据儿茶酚醛假说，有毒的多巴胺代谢产物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丧失。单胺氧化酶A（MAO - A）催化神经元内多巴胺向DOPAL的转化，可能成为一个治疗靶点。“奶酪效应”——含酪胺食物引发的阵发性高血压——限制了不可逆MAO - A抑制剂的临床应用。联合抑制MAO - A/B可降低大鼠嗜铬细胞瘤PC12细胞中DOPAL的生成，但可逆性MAO - A抑制剂或MAO - B抑制剂是否能降低内源性DOPAL的生成尚不清楚。我们比较了MAO抑制剂在减弱DOPAL生成方面的效力，并研究了其对多巴胺储存、组成性释放、合成及自氧化的可能的继发效应。在用不可逆MAO - A抑制剂氯吉兰、三种可逆性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，测定细胞和培养基中的儿茶酚浓度。可逆性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）可降低细胞和培养基中的DOPAL水平。这三种药物还均增加了多巴胺和去甲肾上腺素，降低了3,4 - 二羟基苯丙氨酸，并增加了培养基中半胱氨酰多巴胺的浓度，提示囊泡摄取增加和组成性释放增加、多巴胺合成减少以及多巴胺自发氧化增加。总之，氯吉兰、雷沙吉兰和司来吉兰可降低内源性DOPAL的生成。在相对高浓度时，后两种药物可能会失去对MAO - B的选择性。MAO - B抑制剂大型临床试验未能证明帕金森病神经退行性变减缓可能是由于潜在有毒氧化产物生成增加和DOPAL生成减少之间的抵消作用。
