Intraventricular dopamine infusion alleviates motor symptoms in a primate model of Parkinson’s disease.
Neurobiology of Disease. 2020-06-01; 139: 104846
DOI: 10.1016/j.nbd.2020.104846
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1. Neurobiol Dis. 2020 Jun;139:104846. doi: 10.1016/j.nbd.2020.104846. Epub 2020 Mar
20.
Intraventricular dopamine infusion alleviates motor symptoms in a primate model
of Parkinson’s disease.
Moreau C(1), Rolland AS(2), Pioli E(3), Li Q(3), Odou P(4), Barthelemy C(5),
Lannoy D(4), Demailly A(6), Carta N(5), Deramecourt V(7), Auger F(2), Kuchcinski
G(8), Laloux C(2), Defebvre L(1), Bordet R(2), Duce J(9), Devedjian JC(2), Bezard
E(10), Fisichella M(6), Devos D(11).
Author information:
(1)Expert Center for Parkinson’s Disease, Univ Lille, Inserm, CHU Lille,
UMR_S1171, Lille F-59000, France.
(2)Medical Pharmacology Department, Univ Lille, Inserm, CHU Lille, UMR_S1171,
Lille F-59000, France.
(3)Motac Neuroscience Ltd, Manchester, United Kingdom.
(4)University of Lille, GRITA EA 7365, France; Pharmacy of CHU of Lille,
University of Lille, France.
(5)Pharmacy of CHU of Lille, University of Lille, France.
(6)InBrain Pharma, Lille, France.
(7)Univ. Lille, INSERM UMRS 1172, CHU Lille, UMRS 1172 LabEx DISTALZ, Lille
F-59000, France.
(8)Department of Neuroradiology, Univ Lille, CHU Lille, Inserm, UMR_S 1171,
Lille, France.
(9)The ALBORADA Drug Discovery Institute, University of Cambridge, Cambridge
Biomedical Campus, Hills Road, Cambridge, UK; Melbourne Dementia Research Centre,
The Florey Institute of Neuroscience and Mental Health, The University of
Melbourne, Parkville, Victoria, Australia.
(10)Motac Neuroscience Ltd, Manchester, United Kingdom; Université de Bordeaux,
Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux F-33000, France;
CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux F-33000,
France.
(11)Medical Pharmacology Department, Univ Lille, Inserm, CHU Lille, UMR_S1171,
Lille F-59000, France. Electronic address: .
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.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.nbd.2020.104846
PMID: 32205254