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Intraventricular dopamine infusion alleviates motor symptoms in a primate model of Parkinson's disease.
Neurobiology of Disease ( IF 5.1 ) Pub Date : 2020-03-20 , DOI: 10.1016/j.nbd.2020.104846 Caroline Moreau 1 , Anne Sophie Rolland 2 , Elsa Pioli 3 , Qin Li 3 , Pascal Odou 4 , Christine Barthelemy 5 , Damien Lannoy 4 , Alexandre Demailly 6 , Natacha Carta 5 , Vincent Deramecourt 7 , Florent Auger 2 , Gregory Kuchcinski 8 , Charlotte Laloux 2 , Luc Defebvre 1 , Regis Bordet 2 , James Duce 9 , Jean Christophe Devedjian 2 , Erwan Bezard 10 , Matthieu Fisichella 6 , David Devos 2
Neurobiology of Disease ( IF 5.1 ) Pub Date : 2020-03-20 , DOI: 10.1016/j.nbd.2020.104846 Caroline Moreau 1 , Anne Sophie Rolland 2 , Elsa Pioli 3 , Qin Li 3 , Pascal Odou 4 , Christine Barthelemy 5 , Damien Lannoy 4 , Alexandre Demailly 6 , Natacha Carta 5 , Vincent Deramecourt 7 , Florent Auger 2 , Gregory Kuchcinski 8 , Charlotte Laloux 2 , Luc Defebvre 1 , Regis Bordet 2 , James Duce 9 , Jean Christophe Devedjian 2 , Erwan Bezard 10 , Matthieu Fisichella 6 , David Devos 2
Affiliation
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BACKGROUND
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.
OBJECTIVES
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.
METHODS
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.
RESULTS
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.
CONCLUSION
Continuous circadian i.c.v. of A-dopamine appears to be feasible and shows efficacy without dyskinesia with a safe therapeutic index.
中文翻译：
脑室内多巴胺输注可减轻帕金森氏病灵长类动物模型中的运动症状。
背景技术多巴胺的连续补偿代表帕金森氏病（PD）的理想对症治疗。由于未解决的多巴胺氧化，先前在脑室内给药多巴胺的可行性失败了。目的我们旨在通过在非人类灵长类动物模型中进行的初步翻译研究来测试厌氧多巴胺（A-多巴胺）连续icv的可行性，安全性和有效性。方法通过连接到皮下导管的微型泵对A-多巴胺进行连续和昼夜节律给药，皮下导管植入8个用1-甲基-4-苯基-1,2,3,6处理的非人类灵长类动物的右额角-四氢吡啶（MPTP）。以先前报道的多巴胺急性剂量评估A-多巴胺，并与厌氧制备的L-多巴或甲酯L-多巴相比，评估A-多巴胺的长期治疗指数。结果连续60天内的A-多巴胺昼夜节律改善了运动症状（治疗指数从30到70 mg / day），而没有心动过速。即使使用非常高的剂量也没有观察到运动障碍。仅在超过160 mg的剂量下观察到1至10天后死亡（无神经元改变），而左旋多巴icv在任何剂量下均无效。对于多巴胺的厌氧制剂以及通过微型泵以恒定流量预防阻塞的最小输注量的给药，已确认了该给药方案的技术可行性。结论连续昼夜节律
更新日期：2020-03-21
中文翻译：
脑室内多巴胺输注可减轻帕金森氏病灵长类动物模型中的运动症状。
背景技术多巴胺的连续补偿代表帕金森氏病（PD）的理想对症治疗。由于未解决的多巴胺氧化，先前在脑室内给药多巴胺的可行性失败了。目的我们旨在通过在非人类灵长类动物模型中进行的初步翻译研究来测试厌氧多巴胺（A-多巴胺）连续icv的可行性，安全性和有效性。方法通过连接到皮下导管的微型泵对A-多巴胺进行连续和昼夜节律给药，皮下导管植入8个用1-甲基-4-苯基-1,2,3,6处理的非人类灵长类动物的右额角-四氢吡啶（MPTP）。以先前报道的多巴胺急性剂量评估A-多巴胺，并与厌氧制备的L-多巴或甲酯L-多巴相比，评估A-多巴胺的长期治疗指数。结果连续60天内的A-多巴胺昼夜节律改善了运动症状（治疗指数从30到70 mg / day），而没有心动过速。即使使用非常高的剂量也没有观察到运动障碍。仅在超过160 mg的剂量下观察到1至10天后死亡（无神经元改变），而左旋多巴icv在任何剂量下均无效。对于多巴胺的厌氧制剂以及通过微型泵以恒定流量预防阻塞的最小输注量的给药，已确认了该给药方案的技术可行性。结论连续昼夜节律
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