Expert Center for Parkinson's Disease, Univ Lille, Inserm, CHU Lille, UMR_S1171, Lille F-59000, France.
Medical Pharmacology Department, Univ Lille, Inserm, CHU Lille, UMR_S1171, Lille F-59000, France.
Neurobiol Dis. 2020 Jun;139:104846. doi: 10.1016/j.nbd.2020.104846. Epub 2020 Mar 20.
Continuous compensation of dopamine represents an ideal symptomatic treatment for Parkinson's disease (PD). The feasibility in intracerebroventricular administration (i.c.v.) of dopamine previously failed because of unresolved dopamine oxidation.
We aim to test the feasibility, safety margins and efficacy of continuous i.c.v. of anaerobic-dopamine (A-dopamine) with a pilot translational study in a non-human primate model of PD.
Continuous and circadian i.c.v. of A-dopamine was administered through a micro-pump connected to a subcutaneous catheter implanted into the right frontal horn of 8 non-human primates treated with 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). A-dopamine was assessed at acute doses previously reported for dopamine as well as evaluating the long term therapeutic index of A-dopamine in comparison to anaerobically prepared L-dopa or methyl ester L-dopa.
Over 60 days of a continuous circadian i.c.v. of A-dopamine improved motor symptoms (therapeutic index from 30 to 70 mg/day) without tachyphylaxia. No dyskinesia was observed even with very high doses. Death after 1 to 10 days (without neuronal alteration) was only observed with doses in excess of 160 mg whereas L-dopa i.c.v. was not effective at any dose. The technical feasibility of the administration regimen was confirmed for an anaerobic preparation of dopamine and for administration of a minimal infusion volume by micro-pump at a constant flow that prevented obstruction.
Continuous circadian i.c.v. of A-dopamine appears to be feasible and shows efficacy without dyskinesia with a safe therapeutic index.
持续补偿多巴胺是治疗帕金森病（PD）的理想对症治疗方法。以前，由于多巴胺氧化问题尚未解决，经脑室内给药（i.c.v.）的方法不可行。
我们旨在通过 PD 非人灵长类动物模型的初步转化研究，测试持续 i.c.v. 给予厌氧多巴胺（A-dopamine）的可行性、安全范围和疗效。
通过与皮下导管相连的微泵，将 A-dopamine 持续且呈昼夜节律性地 i.c.v. 输注到 8 只接受 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）治疗的非人灵长类动物的右额角。A-dopamine 的急性剂量以前曾被报道用于多巴胺，我们评估了 A-dopamine 的长期治疗指数，与厌氧制备的 L-多巴或 L-多巴甲酯进行比较。
在持续昼夜节律性 i.c.v. 输注 A-dopamine 的 60 多天中，运动症状得到改善（治疗指数从 30 至 70mg/天），且无快速耐受。即使给予非常高的剂量也未观察到异动症。只有在剂量超过 160mg 时才会在 1 至 10 天后死亡（无神经元改变），而 L-多巴 i.c.v. 在任何剂量下均无效。该给药方案的技术可行性已通过多巴胺的厌氧制备和微泵以恒定流速持续输注最小输注体积得到证实，可防止阻塞。
昼夜节律性持续 i.c.v. 输注 A-dopamine 似乎可行，且疗效确切，不会引起异动症，具有安全的治疗指数。
