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.

Keywords: N-methyl-D-aspartate receptor; Parkinson’s disease; levodopa; levodopa-induced dyskinesia; neuroinflammation.

Figure 1

Mechanisms of damage to DA neurons by activated microglia. Microglia-mediated neuroinflammation and neuroprotective mechanisms in the pathogenesis of PD. Microglia turns into an activated M1 phenotype when exposed to stimuli such as infection, trauma, and intoxication. M1 phenotype microglia secrete pro-inflammatory factors, which further induce neuroinflammatory and neurotoxic mechanisms in the human brain through processes such as enhanced phagocytic activity and increased IL-1β, TNF-α, and ROS generation, damaging DAergic neurons. On the other hand, the presence and stimulation of anti-inflammatory factors can lead to an activated M2 phenotype. The neuroprotective mechanism of M2 microglia against PD involves the release of anti-inflammatory cytokines into the brain and the upregulation of neuroprotective trophic factors. The anti-inflammatory cytokines include IL-4, IL-10, and so on, which inhibit persistent neuroinflammation and consequently protect the DAergic neurons. Disease occurs when this balance in the organism is disrupted.

Figure 2

Mechanisms of damage to DA neurons by activated astrocytes. Astrocyte-mediated neuroinflammation and neuroprotective mechanisms in the pathogenesis of PD. Upon exposure to inflammatory stimuli, astrocytes become activated A1 phenotype. A1 phenotype astrocytes secrete pro-inflammatory factors such as IL-1β, TNF-α, and other inflammatory factors, which further induce neuroinflammation and neurotoxicity mechanisms in the human brain, damaging DAergic neurons. A1 phenotype astrocytes secrete pro-inflammatory factors such as IL-1β, TNF-α, and other inflammatory factors. On the other hand, the neuroprotective mechanism of activated A2 phenotype astrocytes against PD includes the release of anti-inflammatory cytokines into the brain as well as the upregulation of neuroprotective trophic factors, anti-inflammatory cytokines including TGF-β, which inhibit persistent neuroinflammation and thus protect DAergic neurons. Disease occurs when this balance in the organism is disrupted.

Figure 3

Interactions between microglia and astrocytes and mechanisms of damage to DA neurons. Both microglia and astrocytes have differentiated pro-inflammatory phenotypes that are neurotoxic and injurious to DAergic neurons, whereas the neuroprotective phenotypes are neuroprotective and protective of DAergic neurons. Under certain specific circumstances, the pro-inflammatory and anti-inflammatory phenotypes of microglia can be switched. Pro-inflammatory microglia secrete IL-1α, IL-1β, TNF-α, and complement component 1q (C1q), which can convert astrocytes to a pro-inflammatory phenotype. Pro-inflammatory astrocytes secrete IL-1β, TNF-α, Granulocyte-macrophage colony-stimulating factor (GM-CSF), and chemokine C-C motif ligand 2 (CCL2), which in turn activate pro-inflammatory microglia. The phenotypic transition of astrocytes remains to be clarified. Dashed lines with question marks indicate possible relationships, but evidence of a direct association is lacking.

Figure 4

Correlations between neuroinflammation, NMDAR, and LID. Mutual activation of microglia and astrocytes and the release of inflammatory factors such as TNF-α and IL-1β. The release of inflammatory factors promotes the expression of the GluN1 and GluN2 subunits of the NMDAR in postsynaptic neurons, allowing the binding of excitatory neuronal Glu and NMDAR released from presynaptic neurons and the inward flow of Ga²⁺ to act on neuronal synaptic plasticity by regulating the LTP and MAPK/ERK phosphorylation pathways through calmodulin-dependent kinase II (CaMKII). The release of inflammatory factors, on the other hand, directly promotes the development of neuroinflammation in the brain, secondary to the death of DA neurons, which leads to the development of PD and the development of LID in patients with PD after years of L-DOPA administration by exacerbating the inflammatory response in the brain tissue and thus creating a vicious circle.