Havelund Jesper F, Andersen Andreas D, Binzer Michael, Blaabjerg Morten, Heegaard Niels H H, Stenager Egon, Faergeman Nils J, Gramsbergen Jan Bert
Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, Odense, Denmark.
J Neurochem. 2017 Sep;142(5):756-766. doi: 10.1111/jnc.14104. Epub 2017 Jul 11.
L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective drug in the symptomatic treatment of Parkinson's disease, but chronic use is associated with L-DOPA-induced dyskinesia in more than half the patients after 10 years of treatment. L-DOPA treatment may affect tryptophan metabolism via the kynurenine pathway. Altered levels of kynurenine metabolites can affect glutamatergic transmission and may play a role in the development of L-DOPA-induced dyskinesia. In this study, we assessed kynurenine metabolites in plasma and cerebrospinal fluid of Parkinson's disease patients and controls. Parkinson patients (n = 26) were clinically assessed for severity of motor symptoms (UPDRS) and L-DOPA-induced dyskinesia (UDysRS). Plasma and cerebrospinal fluid samples were collected after overnight fasting and 1-2 h after intake of L-DOPA or other anti-Parkinson medication. Metabolites were analyzed in plasma and cerebrospinal fluid of controls (n = 14), Parkinson patients receiving no L-DOPA (n = 8), patients treated with L-DOPA without dyskinesia (n = 8), and patients with L-DOPA-induced dyskinesia (n = 10) using liquid chromatography-mass spectrometry. We observed approximately fourfold increase in the 3-hydroxykynurenine/kynurenic acid ratio in plasma of Parkinson's patients with L-DOPA-induced dyskinesia. Anthranilic acid levels were decreased in plasma and cerebrospinal fluid of this patient group. 5-Hydroxytryptophan levels were twofold increased in all L-DOPA-treated Parkinson's patients. We conclude that a higher 3-hydroxykynurenine/kynurenic acid ratio in plasma may serve as a biomarker for L-DOPA-induced dyskinesia. Longitudinal studies including larger patients cohorts are needed to verify whether the changes observed here may serve as a prognostic marker for L-DOPA-induced dyskinesia.
左旋3,4-二羟基苯丙氨酸（L-多巴）是帕金森病症状治疗中最有效的药物，但长期使用会使超过半数的患者在治疗10年后出现L-多巴诱导的运动障碍。L-多巴治疗可能通过犬尿氨酸途径影响色氨酸代谢。犬尿氨酸代谢产物水平的改变会影响谷氨酸能传递，并可能在L-多巴诱导的运动障碍的发生中起作用。在本研究中，我们评估了帕金森病患者和对照组血浆及脑脊液中的犬尿氨酸代谢产物。对26例帕金森病患者的运动症状严重程度（统一帕金森病评定量表，UPDRS）和L-多巴诱导的运动障碍（异动症评定量表，UDysRS）进行了临床评估。在空腹过夜后以及摄入L-多巴或其他抗帕金森药物1 - 2小时后采集血浆和脑脊液样本。使用液相色谱 - 质谱分析法对14例对照组、8例未接受L-多巴治疗的帕金森病患者、8例接受L-多巴治疗但无运动障碍的患者以及10例有L-多巴诱导的运动障碍的患者的血浆和脑脊液中的代谢产物进行了分析。我们观察到，患有L-多巴诱导的运动障碍的帕金森病患者血浆中3-羟基犬尿氨酸/犬尿酸的比值增加了约四倍。该患者组血浆和脑脊液中的邻氨基苯甲酸水平降低。所有接受L-多巴治疗的帕金森病患者的5-羟色氨酸水平增加了两倍。我们得出结论：血浆中较高的3-羟基犬尿氨酸/犬尿酸比值可能作为L-多巴诱导的运动障碍的生物标志物。需要纳入更大患者队列的纵向研究来验证此处观察到的变化是否可作为L-多巴诱导的运动障碍的预后标志物。
