A New Concept of Continuous Dopaminergic Stimulation by Cerebroventricular Administration of A-dopamine (Dopamine Stored in Anaerobia) for Severe Motor Fluctuations in Parkinson's Disease?

Parkinson's disease (PD) is the second most frequent neurodegenerative disorder worldwide. The loss of dopamine through denervation in the striatum as a result of progressive neuronal degeneration in the substantia nigra pars compacta (SNpc), is the primary neurotransmitter marker of the disease. Since dopamine does not cross the digestive mucosa or the blood brain barrier, its lipophilic precursor L-dopa has been employed and remains the pivotal oral medication. However, after persistent use over several years, many pharmacokinetic drawbacks contribute to the occurrence of motor fluctuations and dyskinesia. Indeed L-dopa has a short half-life, limited and variable reabsorption through the digestive and blood brain barriers and potentially harmful peripheral distribution. Moreover, L-dopa requires the aromatic L-amino acid decarboxylase for the synthesis of dopamine, which declines in the striatum with disease progression. Intermittent oral doses of L-dopa induce discontinuous stimulation of striatal dopamine receptors that in turn contribute to dysfunctional dopaminergic pathways. Thus, continuous dopamine administration is considered more physiologically appropriate by preventing oscillations in neurotransmitter concentration.

It has been previously demonstrated that intracerebroventricular (i.c.v.) administered dopamine with an anti-oxidant adjuvant (sodium metabisulfite; SMBS) transiently improved motor handicap and increased dopamine in rat brains with unilateral neurotoxin 6-hydroxydopamine (6-OHDA)-induced damage as well as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated monkeys. The clinical feasibility of this administrative route has been supported by two PD patient case reports of dopamine infusion to the frontal ventricle, whereby a reduction in motor handicap was observed. Indeed, human case reports described a good tolerance to dopamine infusion over 1 year with a smooth control of motor symptoms. However, both preclinical and clinical reports also highlight two overriding problems that prevented further development; occurrence of tachyphylaxis and oxidation of dopamine causing enhanced dopamine metabolism and oxidative stress.

These prior challenges had been overcome by demonstrating that dopamine oxidation can be avoided by preparing, storing and administering dopamine in very low oxygen conditions (<0.01% of O2 = anaerobia = A-dopamine). In vitro, a positive effect of dopamine was observed on non-oncogenic dopaminergic neurons (LHUMES) survival. In vivo, A-dopamine restored motor function and induced a dose dependent increase of nigro-striatal dopaminergic neurons in mice after 7 days of MPTP intoxication that was not evident with either dopamine prepared aerobically (O-dopamine) or in the presence of a conservator (sodium metabisulfite, SMBS) 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 tachyphylaxis. This safety profile was highly favorable, as A-dopamine did not induce dyskinesia or behavioral sensitization as observed with peripheral L-dopa treatment. In MPTP monkeys, A-dopamine improved the doparesponsive motor symptoms without inducing any dyskinesia or tachyphylaxis during 2 months. Indicative of a new therapeutic strategy for patients suffering from L-dopa related complications with dyskinesia, continuous i.c.v of A-dopamine had greater efficacy in mediating motor impairment over a large therapeutic index without inducing dyskinesia and tachyphylaxis.

In addition, greater advances in programmable pumps now minimize tachyphylaxis by allowing administration of a lower effective dopamine dose in accordance with the circadian cycle. Of note, PD patients from previous studies received O-dopamine and at the same dose throughout a 24 hours cycle. Prior experience obtained from the use of an apomorphine pump and duodopa® has identified the need to differentiate between diurnal and nocturnal minimum efficient dose in order to avoid worsening motor fluctuations.

Thus, continuous circadian i.c.v. administration of dopamine close to the striatum is feasible, efficient and safe in models of PD, supporting clinical development of this strategy to be revisited in PD patients with L-dopa related complications with dyskinesia.