Levodopa-induced dyskinesia: interplay between the N-methyl-D-aspartic acid receptor and neuroinflammation

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder of middle-aged and elderly people, clinically characterized by resting tremor, myotonia, reduced movement, and impaired postural balance. Clinically, patients with PD are often administered levodopa (L-DOPA) to improve their symptoms. However, after years of L-DOPA treatment, most patients experience complications of varying severity, including the “on-off phenomenon”, decreased efficacy, and levodopa-induced dyskinesia (LID). The development of LID can seriously affect the quality of life of patients, but its pathogenesis is unclear and effective treatments are lacking. Glutamic acid (Glu)-mediated changes in synaptic plasticity play a major role in LID. The N-methyl-D-aspartic acid receptor (NMDAR), an ionotropic glutamate receptor, is closely associated with synaptic plasticity, and neuroinflammation can modulate NMDAR activation or expression; in addition, neuroinflammation may be involved in the development of LID. However, it is not clear whether NMDA receptors are co-regulated with neuroinflammation during LID formation. Here we review how neuroinflammation mediates the development of LID through the regulation of NMDA receptors, and assess whether common anti-inflammatory drugs and NMDA receptor antagonists may be able to mitigate the development of LID through the regulation of central neuroinflammation, thereby providing a new theoretical basis for finding new therapeutic targets for LID.

Neuroinflammation and Dyskinesia: A Possible Causative Relationship?

“…As a voltage-and ligand-gated cation channel, NMDAR presents a composition with different subunits. GluN1 and GluN2 are the most available isoforms, although we can also find GluN2A, GluN2B, GluN2C, and GluN2D [10,[53][54][55]. These subunits will affect channel functions through their composition, distribution, and phosphorylation.…”

“…The forms of synaptic plasticity that will be evaluated here are LTP (long-term potentiation) and LTD (long-term depression), which can be directly altered by inflammatory processes [1,2]. Indeed, synaptic plasticity and the induction of LTP and LTD are controlled by the phosphorylation grade of NMDAR isoforms, which in turn trigger learning and memory processes [10,18,56,57]. Motor signals, which reach the basal ganglia from the cortex, depend on the bidirectional control of synaptic plasticity by LTP and LTD.…”

“…Motor signals, which reach the basal ganglia from the cortex, depend on the bidirectional control of synaptic plasticity by LTP and LTD. In the PD condition, even if the cortex sends information to the basal ganglia, the striatum loses the capacity to export appropriate signals; this phenomenon is amplified during LID onset [10,58]. In LID pathology, NMDAR can induce an overactivation of LTP which, with the contemporary lack of LTD, leads to redundant movements due to the abnormal motor information, as demonstrated in rat models [10].…”

“…Unfortunately, the lifelong treatment needed involves several adverse reactions and side effects, among which levodopa-induced dyskinesias (LIDs) are the most urgent problem to be solved. LIDs are characterized by abnormal involuntary movements, such as stereotypic, choreiform, and throwing movements, as well as dystonia [9,10] involving the head, neck, trunk, and limbs [8,11]. About 80% of patients suffer from this inconvenience, which worsens their disability and their quality of life [8], after an average of 6.5 years of L-DOPA treatment [9,10].…”

“…LIDs are characterized by abnormal involuntary movements, such as stereotypic, choreiform, and throwing movements, as well as dystonia [9,10] involving the head, neck, trunk, and limbs [8,11]. About 80% of patients suffer from this inconvenience, which worsens their disability and their quality of life [8], after an average of 6.5 years of L-DOPA treatment [9,10]. However, in rodent PD models, exemplars did not manifest LID after 6-OHDA lesion and L-DOPA treatment [12], and about 6-22% of PD patients did not ever suffer LID [9,[13][14][15][16][17].…”