Objective: We aim to overcome these challenges by demonstrating that continuous i.c.v. of Anaerobic-dopamine (A-dopamine,Patent #WO2015173258 A1) close to the striatum is a feasible and highly efficient treatment in 3 models of PD: acute MPTP intoxicated mice, unilateral 6-OHDA lesioning rats and chronic MPTP-intoxicated non-human primates (NHPs).

Background: Dopamine depletion of the nigro-striatal pathway is the main pathological hallmark of Parkinson’s disease (PD), which would require a continuous circadian and focal restoration of the striatal level of dopamine.  Continuous intracerebroventricular administration (i.c.v.) of dopamine previously failed due to dopamine oxidation and tachyphylaxia.

Method: Protocols were approved by an Ethical Committee to induce MPTP neurotoxicity on 5 months old C57Bl/6 J mice or 6-OHDA neurotoxicity in 5 month old Wistar rats. Experimental procedures  have been previously described (Laloux et al., 2017).   Behavioral assessment plus Nigro-striatal tyrosine hydroxylase staining and analysis and striatum analysis by HPLC were realized in mice and rats. Eight MPTP intoxicated  non-human primate models (NHPs) received chronic A-dopamine treatment after surgical pump implantation under stereotaxic surgery.

Results: Seven days continuous i.c.v of A-dopamine restored motor function in MPTP treated mice and induced a dose dependent neuroprotection of the nigro-striatal dopaminergic neurons that was not evident with either i.c.v. of aerobic dopamine (O-dopamine) or peripheral administration of L-dopa. In the unilateral 6-OHDA-lesioned rat model, continuous circadian i.c.v of A-dopamine over 30 days improved motor activity without occurrence of dyskinesia or tachyphylaxia. Continuous circadian icv of A-dopamine improved the MPTP treated NHPs on the motor segmental symptoms (i.e. reaching task) by about 40 %. The effect was delayed and long lasting without tachyphylaxia over 60 days but requiring slow titration. Importantly, no dyskinesia was triggered even with very high doses. A 3-fold increase of the minimum efficient dose remained well tolerated, conferring a large therapeutic index.

Conclusion: Continuous circadian i.c.v. administration of A-dopamine has a greater efficiency on mediating motor handicap within a large therapeutic index without inducing dyskinesia and tachyphylaxia.

References: Laloux, C., Petrault, M., Lecointe, C., Devos, D., Bordet, R., 2012. Differential susceptibility to the PPAR-γ agonist pioglitazone in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine rodent models of Parkinson’s disease. Pharmacol. Res. 65, 514–522. Laloux, F Gouel, C Lachaud, K Timmerman , B Do Van, et al. 2017. Continuous cerebroventricular administration of dopamine: A new treatment for severe dyskinesia in Parkinson’s disease? Neurobiol of Disease 2017 Jul;103:24-31.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/continuous-circadian-intracerebroventricular-administration-of-anaerobic-dopamine-a-new-therapeutic-concept-for-parkinsons-disease/