Abstract
Glutamate is the major excitatory neurotransmitter in the central nervous system and, as such, many brain regions, including the basal ganglia, are rich in glutamatergic neurons. The importance of the basal ganglia in the control of voluntary movement has long been recognised, with the effect of dysfunction of the region exemplified by the motor symptoms seen in Parkinson’s disease (PD). However, the basal ganglia and the associated glutamatergic system also play a role in the modulation of emotion, nociception and cognition, dysregulation of which result in some of the non-motor symptoms of PD (depression/anxiety, pain and cognitive deficits). Thus, while the treatment of PD has traditionally been approached from the perspective of dopaminergic replacement, using agents such as levodopa and dopamine receptor agonists, the glutamatergic system offers a novel treatment target for the disease. Safinamide has been approved in over 20 countries globally for fluctuating PD as add-on therapy to levodopa regimens for the management of ‘off’ episodes. The drug has both dopaminergic and non-dopaminergic pharmacological effects, the latter including inhibition of abnormal glutamate release. The effect of safinamide on the glutamatergic system might present some advantages over dopamine-based therapies for PD by providing efficacy for motor (levodopa-induced dyskinesia) as well as non-motor (anxiety, mood disorders, pain) symptoms. In this article, we discuss the potential role of glutamatergic inhibition on these symptoms, using illustrative real-world examples of patients we have treated with safinamide.
Highlights
Glutamate is the principal excitatory neurotransmitter in the mammalian central nervous system (CNS)
While glutamate is an important component of a healthy CNS, excessive glutamate concentrations or hyperactivity of glutamatergic nerve terminals can lead to neuronal damage and may be involved in the neurodegeneration associated with Parkinson’s disease (PD) [1,2]
Glutamate is synthesised from its precursor glutamine, which is released from glial cells and taken into presynaptic terminals of glutamatergic neurons by excitatory amino acid transporters (EAATs)
Summary
Glutamate is the principal excitatory neurotransmitter in the mammalian central nervous system (CNS). While the pathophysiology of LID is complex, overactivity of glutamatergic corticostriatal projections is a critical factor in the dysfunction of the direct pathway and the development of LID [15] These findings suggest that a drug that reduces glutamatergic activity may even have an anti-dyskinetic effect. Abnormal cortical facilitation was found in PD patients experiencing LID (n = 20), indicating overactive glutamatergic neurotransmission in the primary motor cortex [17]. Safinamide is a dual-mechanism drug that acts on both dopaminergic and non-dopaminergic targets, dopaminergic and glutamatergic neurotransmission It selectively and reversibly inhibits monoamine oxidase-B (MAO-B), restoring striatal dopaminergic tone and reduces subthalamic/nigral glutamatergic hyperactivity through use-dependent sodium channel blockade, which prevents calcium channel opening and results in the inhibition of abnormal glutamate release [6,7]. Safinamide significantly reduced ‘off’ time and increased ‘on’ time without troublesome dyskinesia in patients receiving levodopa who were experiencing wearing-off phenomenon [10,11,12,13]
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