Dopaminergic replacement therapies are prescribed widely to improve motor problems in Parkinson’s disease (PD). However, as the disease progresses, the response to levodopa (l-dopa) doses becomes shorter and patients experience symptom recurrence at the end of the dose effect. These so-called OFF periods may become refractory to treatment, and may become associated with disabling motor fluctuations or dyskinesias. In addition to dopamine, glutamate excitotoxicity, resulting from disturbance of the homeostatic balance of neurotransmitters and elevated extracellular levels of glutamate, is potentially an important therapeutic target. Safinamide has been investigated in phase III clinical trials as adjunct therapy to l-dopa in mid- to late-stage fluctuating PD. Adding safinamide to l-dopa increases the time patients’ symptoms are controlled – so-called ON time, without increasing troublesome dyskinesia. Although safinamide has dopaminergic actions, recent data have suggested that the long-term effects of safinamide on dyskinesia are related to safinamide state- and use-dependent inhibition of sodium channels and stimulated glutamate release, rather than reduced dopaminergic stimulation. Safinamide’s unique dual mechanism of action makes it a valuable treatment option for fluctuating PD patients.
Dopamine, glutamate, Parkinson’s disease, safinamide
Jaime Kulisevsky has received honoraria for lecturing or advisory boards from UCB, Zambon, Lundbeck and Abbvie, and research support from Instituto de Salud Carlos III, Spain. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
August 15, 2016 Accepted
October 04, 2016
Jaime Kulisevsky, Movement Disorders Unit, Neurology Department, Sant Pau Hospital, Universitat Autónoma de Barcelona, Mas Casanovas 90 08041 Barcelona, Spain. E: email@example.com
The publication of this interview was funded by Zambon SpA. The views and opinions expressed are those of the author and do not necessarily reflect those of Zambon SpA.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder, with a prevalence that increases with age: 41 in 100,000 in the age group 40–49, rising to 1,903 in 100,000 in those aged over 80 years.1 PD is characterised by striatal dopamine deficiency resulting from progressive degeneration of dopaminergic cells in the pars compacta of the substantia nigra, the brain region responsible for motor control.2 Symptoms of PD include bradykinesia, rigidity, tremor, gait and postural abnormalities, and speech difficulty,3 as well as non-motor symptoms including cognitive dysfunction, mood disorders, sleep disturbance and pain.4
Although PD is incurable, symptoms can be alleviated using dopaminergic therapies including the dopamine precursor levodopa (l-dopa), dopamine agonists and monoamine oxidase (MAO)-B inhibitors that block dopamine degradation, thereby helping restore dopamine levels in the brain.5,6 L-dopa is currently the standard treatment for motor symptoms in PD, but its long-term use has important limitations.5 As the disease progresses, the response to l-dopa doses becomes shorter and patients motor fluctuations, which involve periods of being ON, during which the patient experiences a positive response to medication, and being OFF, during which the patient experiences a re-emergence of the symptoms suppressed during the ON state.7,8 Furthermore, symptoms of PD, including gait and tremor, gradually become resistant to l-dopa.8 Other limitations of the use of l-dopa include the fact that it does not prevent PD progression,9 and many non-motor symptoms do not respond well to l-dopa.9
As well as motor fluctuations, abnormal involuntary movements, known as l-dopa-induced dyskinesia (LID), develop with prolonged use of l-dopa; these may occur at peak effect of l-dopa, at the beginning and end of dose, or between doses (see Figure 1).8,10–12 These movements usually involve the face and the side of the body that is initially affected by the disease, but they commonly progress and affect the neck, upper and lower limbs, and body axis. Chorea and dystonia are the most frequent forms of LIDs, but ballismus and myoclonus can also appear.13,14 Around 40% of patients experience motor fluctuations and LID after 4-6 years of treatment with l-dopa,14 and 60% to 100% may experience LID after 10 years.15,16
Motor fluctuations are the result of alterations of the functional organisation of the basal ganglia circuitry following long-term exposure to l-dopa. Progressive degeneration of the nigro-striatal dopaminergic pathway reduces the ability of nerve terminals to store and release dopamine.17 As a result of this loss of storage capacity, l-dopa induces a more pulsatile stimulation of postsynaptic dopamine receptors, consistent with l-dopa’s short (90-minute) half-life and its rapid cycling pharmacokinetics. This pulsatile stimulation causes functional changes within the basal ganglia, leading to involuntary movements and altered neural activity in the basal ganglia, thalamus cerebral cortex.17
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Dopamine, glutamate, Parkinson’s disease, safinamide