Faro Lilian R F, Justo Lorenzo A, Alfonso Miguel, Durán Rafael
Department of Functional Biology and Health Sciences, Faculty of Biology, University of Vigo, Campus Lagoas-Marcosende, 36310, Vigo, Spain.
Department of Functional Biology and Health Sciences, Faculty of Biology, University of Vigo, Campus Lagoas-Marcosende, 36310, Vigo, Spain.
Neuropharmacology. 2020 Jul;171:108083. doi: 10.1016/j.neuropharm.2020.108083. Epub 2020 Apr 15.
Isatin is an endogenous indole that inhibits monoamine oxidase (MAO). When exogenously administered, it increases the striatal dopamine and acetylcholine levels and presents neuroprotective effects in the brain. Previous studies show that intrastriatal administration of isatin increased the in vivo dopamine release from striatum in a concentration-dependent form. In the present work, we investigated the effects of combined administration of isatin together with other substances actually used in antiparkinsonian pharmacotherapy on in vivo dopamine overflow. For this, we co-administered isatin with the MAO inhibitors selegiline and clorgyline, l-DOPA, the catechol-o-methyl-transferase (COMT) inhibitors tropolone and dinitrocatechol, with the dopaminergic agonist ropinirole, and with the psychostimulant caffeine, in order to evaluate possible synergies between these substances to increase the dopamine extracellular levels in freely moving rats. Intrastriatal administration of isatin (10 mM, 60 min) significantly increased dopamine release to 1164 ± 152%, compared to the baseline. Co-administration of isatin together with selegiline (1 mM) or clorgyline (1 mM) alone or in combinations showed a similar profile to increase in vivo dopamine release. Intrastriatal infusion of isatin together with antiparkinsonian drugs l-DOPA (25 μM), tropolone (1 mM), dinitrocatechol (100 μM), amantadine (5 mM) and caffeine (5 mM) significantly elevated extracellular dopamine levels more than any single drug, showing a good neurochemical synergy by improving the effect of isatin on the extracellular dopamine levels in the striatum. Infusion of isatin + ropinirole (5 mM) did not change the isatin-induced increase in dopamine overflow. These results could be useful to carry out further investigations with a possible clinical application.
异吲哚酮是一种内源性吲哚，可抑制单胺氧化酶（MAO）。外源性给药时，它会增加纹状体多巴胺和乙酰胆碱水平，并在大脑中呈现神经保护作用。先前的研究表明，纹状体内注射异吲哚酮会以浓度依赖的形式增加纹状体中多巴胺的体内释放。在本研究中，我们研究了异吲哚酮与抗帕金森病药物治疗中实际使用的其他物质联合给药对体内多巴胺溢出的影响。为此，我们将异吲哚酮与MAO抑制剂司来吉兰和氯吉兰、左旋多巴、儿茶酚-O-甲基转移酶（COMT）抑制剂托酚酮和二硝基邻苯二酚、多巴胺能激动剂罗匹尼罗以及精神兴奋剂咖啡因联合给药，以评估这些物质之间可能的协同作用，从而提高自由活动大鼠的细胞外多巴胺水平。与基线相比，纹状体内注射异吲哚酮（10 mM，60分钟）可使多巴胺释放显著增加至1164±152%。异吲哚酮与司来吉兰（1 mM）或氯吉兰（1 mM）单独或联合给药显示出类似的增加体内多巴胺释放的情况。纹状体内注射异吲哚酮与抗帕金森病药物左旋多巴（25 μM）、托酚酮（1 mM）、二硝基邻苯二酚（100 μM）、金刚烷胺（5 mM）和咖啡因（5 mM）联合使用，可显著提高细胞外多巴胺水平，比任何单一药物都更有效，通过改善异吲哚酮对纹状体细胞外多巴胺水平的作用，显示出良好的神经化学协同作用。注射异吲哚酮+罗匹尼罗（5 mM）并没有改变异吲哚酮诱导的多巴胺溢出增加。这些结果可能有助于进行进一步的研究，并可能应用于临床。
