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

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 7days 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 30days 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.

Intracerebroventricular dopamine for Parkinson's disease

“…We confirm that the positive impact of dopamine on dopaminergic neurons of the nigro-striatal pathways was predominantly dependent on dose, but the oxidation state of dopamine is also paramount [7]. …”

“…Recently, the authors have overcome these challenges [7]. Indeed, deleterious effect of dopamine oxidation was avoided by anaerobic preparation of dopamine (A-dopamine: prepared, stored and administered in very low oxygen conditions).…”

“…The study demonstrated that continuous circadian i.c.v. administration of dopamine close to the striatum is feasible, efficient and safe in mouse and rat models of PD, supporting clinical development of this strategy to be revisited in PD patients with L-dopa related complications with dyskinesia [7]. …”

Pathophysiological Mechanisms and Experimental Pharmacotherapy for L-Dopa-Induced Dyskinesia

“…Furthermore, in the MPTP mouse model, A-dopamine induced a dose-dependent increase in nigrostriatal dopaminergic neurons that was not evident with either O-dopamine (aerobically prepared dopamine) or peripheral L-dopa. 137,138 Based on these results, a proof-of-concept phase I/IIb study of continuous ICV A-dopamine administration, with a 1-month phase I trial to assess safety and feasibility and a subsequent 2-month, phase IIb, single-blind, randomized crossover study to assess efficacy on motor fluctuations, including LID, over optimized oral treatment began in September 2020 (ClinicalTrials.gov identifier: NCT04332276). The study will enroll 20 participants and the primary outcome measure is the percentage of time that bradykinesia, as measured by actimetry, exceeds a prespecified target (26).…”

Polymers for extended-release administration

“…However, the short half-life of L-dopa and its variable absorption through the gastro-intestinal tract and the blood-brain barrier limit the efficacy of this treatment. Moreover, the efficiency of L-dopa relies on the enzyme L-amino acid decarboxylase, which declines with the disease progression (Laloux et al, 2017). Solutions that are currently being investigated include a continuous administration of L-dopa, L-dopa implants in the duodenum, and neurostimulating electrodes for deep-brain stimulation in the brain (Sabel et al, 1990;Gershanik and Jenner, 2012;Weaver et al, 2014;Laloux et al, 2017).…”