Marin Concepció, Aguilar Esther, Obeso José A
Laboratori de Neurologia Experimental, Fundació Clínic-Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain.
Mov Disord. 2006 May;21(5):646-53. doi: 10.1002/mds.20780.
Levodopa-induced dyskinesias (LIDs) have been associated with a sequence of events that includes pulsatile stimulation of dopamine receptors. The degree of nigrostriatal degeneration, the half-life of dopaminomimetic agents, and the dose of levodopa used to treat parkinsonian symptoms are factors directly correlated with the development of motor complications in Parkinson's disease patients. Long-acting agents producing continuous dopaminergic stimulation are less likely to prime for dyskinesia than short-acting drugs that produce pulsatile stimulation of dopamine receptors. Inhibition of the enzyme catechol-O-methyl transferase (COMT) by entacapone extends the half-life of levodopa and minimizes variability in plasma levodopa levels. The aim of the present study was to characterize the effect of the early administration of the COMT inhibitor entacapone in the recently described model of LIDs in rats with a nigrostriatal lesion induced by 6-hydroxydopamine (6-OHDA). Male Sprague-Dawley rats received a unilateral 6-OHDA administration in the nigrostriatal pathway. Animals were treated either with levodopa (6 mg/kg, twice at day, i.p.) plus entacapone (30 mg/kg per day, i.p.) or levodopa (6 mg/kg, twice at day, i.p.) plus vehicle for 22 consecutive days. Early administration of entacapone, in association with levodopa, induces a decrease in the severity of dyskinesia and delays their onset in hemiparkinsonian rats. All dyskinesia subtypes evaluated, such as axial, limb, and orofacial dyskinesias, have shown similar reductions. These results suggest that entacapone, by extending levodopa elimination half-life, might reduce its propensity to induce motor complications.
左旋多巴诱发的异动症（LIDs）与一系列事件相关，其中包括多巴胺受体的脉冲式刺激。黑质纹状体变性的程度、多巴胺模拟剂的半衰期以及用于治疗帕金森症状的左旋多巴剂量，都是与帕金森病患者运动并发症发生直接相关的因素。与产生多巴胺受体脉冲式刺激的短效药物相比，产生持续多巴胺能刺激的长效药物引发异动症的可能性较小。恩他卡朋对儿茶酚-O-甲基转移酶（COMT）的抑制作用可延长左旋多巴的半衰期，并使血浆左旋多巴水平的变异性降至最低。本研究的目的是在最近描述的、由6-羟基多巴胺（6-OHDA）诱导黑质纹状体损伤的大鼠LIDs模型中，表征早期给予COMT抑制剂恩他卡朋的效果。雄性Sprague-Dawley大鼠在黑质纹状体通路接受单侧6-OHDA给药。动物连续22天接受左旋多巴（6mg/kg，每天两次，腹腔注射）加恩他卡朋（30mg/kg/天，腹腔注射）或左旋多巴（6mg/kg，每天两次，腹腔注射）加赋形剂治疗。恩他卡朋与左旋多巴联合早期给药，可减轻异动症的严重程度，并延迟偏侧帕金森大鼠异动症的发作。所评估的所有异动症亚型，如轴向、肢体和口面部异动症，均显示出类似程度的减轻。这些结果表明，恩他卡朋通过延长左旋多巴的消除半衰期，可能会降低其诱发运动并发症的倾向。
