Elsevier

Neurobiology of Disease

Volume 103, July 2017, Pages 24-31
Neurobiology of Disease

Continuous cerebroventricular administration of dopamine: A new treatment for severe dyskinesia in Parkinson's disease?

https://doi.org/10.1016/j.nbd.2017.03.013Get rights and content
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Highlights

  • Continuous i.c.v. infusion of anaerobic dopamine is safe in neurotoxin models of PD.

  • Infusion of anaerobic dopamine restores motor function and dyskinesia in PD models.

  • Tachyphylaxia avoidance and large therapeutic index with anaerobic dopamine infusion.

  • Anaerobic dopamine aligned to circadian release is a new therapeutic concept for PD.

  • An alternative therapeutic for patients suffering from L-dopa related complications.

Abstract

In Parkinson's disease (PD) depletion of dopamine in the nigro-striatal pathway is a main pathological hallmark that requires continuous and focal restoration. Current predominant treatment with intermittent oral administration of its precursor, Levodopa (l-dopa), remains the gold standard but pharmacological drawbacks trigger motor fluctuations and dyskinesia. Continuous intracerebroventricular (i.c.v.) administration of dopamine previously failed as a therapy because of an inability to resolve the accelerated dopamine oxidation and tachyphylaxia. We aim to overcome prior challenges by demonstrating treatment feasibility and efficacy of continuous i.c.v. of dopamine close to the striatum. Dopamine prepared either anaerobically (A-dopamine) or aerobically (O-dopamine) in the presence or absence of a conservator (sodium metabisulfite, SMBS) was assessed upon acute MPTP and chronic 6-OHDA lesioning and compared to peripheral l-dopa treatment. A-dopamine restored motor function and induced a dose dependent increase of nigro-striatal tyrosine hydroxylase positive neurons in mice after 7 days of MPTP insult that was not evident with either O-dopamine or l-dopa. In the 6-OHDA rat model, continuous circadian i.c.v. injection of A-dopamine over 30 days also improved motor activity without occurrence of tachyphylaxia. This safety profile was highly favorable as A-dopamine did not induce dyskinesia or behavioral sensitization as observed with peripheral l-dopa treatment. Indicative of a new therapeutic strategy for patients suffering from l-dopa related complications with dyskinesia, continuous i.c.v. of A-dopamine has greater efficacy in mediating motor impairment over a large therapeutic index without inducing dyskinesia and tachyphylaxia.

Abbreviations

DA
dopamine
i.c.v
intra-cerebro-ventricular
l-dopa
levodopa
MPTP
1 méthyl-4-phenyl-1,2,3,6 terahydropyridine
6-OHDA
6-hydroxydopamine
PD
Parkinson's disease
SMBS
sodium metabisulfite
SNpc
substantia nigra pars compacta

Keywords

Parkinson's disease
Dopamine
l-dopa related motor complications
Treatment–disease modifying effect

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1

Co-last authors.