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

Abstract

L-dopa-induced dyskinesia (LID) is the most frequent motor complication associated with chronic L-dopa treatment in Parkinson’s disease (PD). Recent advances in the understanding of the pathophysiological mechanisms underlying LID suggest that abnormalities in multiple neurotransmitter systems, in addition to dopaminergic nigrostriatal denervation and altered dopamine release and reuptake dynamics at the synaptic level, are involved in LID development. Increased knowledge of neurobiological LID substrates has led to the development of several drug candidates to alleviate this motor complication. However, with the exception of amantadine, none of the pharmacological therapies tested in humans have demonstrated clinically relevant beneficial effects. Therefore, LID management is still one of the most challenging problems in the treatment of PD patients. In this review, we first describe the known pathophysiological mechanisms of LID. We then provide an updated report of experimental pharmacotherapies tested in clinical trials of PD patients and drugs currently under study to alleviate LID. Finally, we discuss available pharmacological LID treatment approaches and offer our opinion of possible issues to be clarified and future therapeutic strategies.

Molecular Mechanisms and Therapeutic Strategies for Levodopa-Induced Dyskinesia in Parkinson’s Disease: A Perspective Through Preclinical and Clinical Evidence

“…At an advanced stage of PD, a vast portion of dopaminergic neurons are lost, and the serotonergic terminal is mainly providing the DA release and conversion, which are devoid of the molecular mechanism for DA release management and feedback control. As a result, the DA concentration cannot be regulated, which leads to an abnormal swing in extracellular DA concentration following oral administration of L-DOPA ( Mosharov et al, 2015 ; Fabbrini and Guerra, 2021 ). Fluctuations in the dopamine release patterns from the presynaptic neuron terminals give rise to abnormal responses, which were then carried out by postsynaptic neurons.…”

“…There are two types of glutamatergic receptors: First is ionotropic glutamatergic receptors (iGluRs) that mediate fast excitatory neurotransmission, and the second one is metabotropic glutamatergic receptors (mGluR) that mediate slow excitatory neurotransmission. iGluRs are classified into NMDA, AMPA, and kainite (KA) receptors ( Morin and Di Paolo, 2014 ; Fabbrini and Guerra, 2021 ). Higher striatal expression of NMDA and AMPA receptors was reported previously in MPTP-treated dyskinetic monkeys ( Morin and Di Paolo, 2014 ).…”

“…Generally, dyskinesia appears in the neck, jaw, tongue, face, waist, shoulder, trunk, and leg ( Li et al, 2020 ). There are three types of dyskinesias identified to date, off-period dystonia, peak dose dyskinesia, and diphasic dyskinesia ( Fabbrini and Guerra, 2021 ). Off-time dyskinesia is usually encountered during the night or early morning.…”

Long-term changes in short-interval intracortical facilitation modulate motor cortex plasticity and L-dopa-induced dyskinesia in Parkinson's disease

“…A further novel finding was the negative relationship between the degree of SICF alterations at baseline and the effect of long-term treatment with safinamide on UDysRS-III scores in patients with LID, i.e., the more altered the SICF at S0, the more positive the safinamide-related effect on LID (less worsening or even LID improvement at S2). LID pathophysiology is complex and involves abnormalities in multiple neurotransmitter systems, including dopaminergic, serotoninergic, adrenergic, and glutamatergic, and in the interaction among these systems [5,6,8]. The correlation between SICF alterations at baseline and LID changes at S2 suggests that patients with greater abnormalities in SICF-related glutamatergic circuits are those in whom safinamide produced more beneficial effects on LID.…”

“…A strong relationship between increased glutamatergic activity and the development of L-dopa-induced dyskinesia (LID) is also present in PD [1,5,6]. The role of enhanced glutamatergic transmission in LID has been confirmed by clinical-pharmacological studies, which have shown that antiglutamatergic drugs may improve dyskinesia in patients [7,8].…”