Neuroinflammation and Dyskinesia: A Possible Causative Relationship?

Abstract

Levodopa (L-DOPA) treatment represents the gold standard therapy for Parkinson's disease (PD) patients. L-DOPA therapy shows many side effects, among them, L-DOPA-induced dyskinesias (LIDs) remain the most problematic. Several are the mechanisms underlying these processes: abnormal corticostriatal neurotransmission, pre- and post-synaptic neuronal events, changes in gene expression, and altered plasticity. In recent years, researchers have also suggested non-neuronal mechanisms as a possible cause for LIDs. We reviewed recent clinical and pre-clinical studies on neuroinflammation contribution to LIDs. Microglia and astrocytes seem to play a strategic role in LIDs phenomenon. In particular, their inflammatory response affects neuron-glia communication, synaptic activity and neuroplasticity, contributing to LIDs development. Finally, we describe possible new therapeutic interventions for dyskinesia prevention targeting glia cells.

Keywords: L-DOPA-induced dyskinesias (LIDs); Parkinson’s disease; levodopa (L-DOPA); neuroinflammation; non-neuronal mechanism.

Figure 2

The involvement of neuroinflammation in LID. LIDs are abnormal involuntary movements due to the daily treatment with L-DOPA. Several are the mechanisms underlying these processes: abnormal corticostriatal neurotransmission, pre- and post-synaptic neuronal events, changes in gene expression, and altered plasticity. In recent years, researchers have also suggested non-neuronal mechanisms as a possible cause for LID. Indeed, cytokines, when secreted in excess by microglia, are involved in LID development affecting corticostriatal synaptic plasticity and glutamatergic transmission [68,69,70]. Among the causes of the inflammatory response are the increased oxidation due to excessive DA concentration, and astroglia transport and distribution of L-DOPA from the blood to brain tissues. Indeed, astrocytes take up L-DOPA through an amino acid transporter, named L-type amino acid transporter 1 or sodium-independent neutral amino acid transporter (LAT1). Astrocytes appear to act as a DA storage facility and to release it only based on its extracellular concentration. Additionally, astroglia presents as a DA transporter, able to internalize DA derived from L-DOPA metabolism. Indeed, astrocytes also possess monoamine oxidase (MAO-B) and catechol-O-methyltransferase (COMT) and thus participate in L-DOPA metabolism [68,82,83,84,85] (Figure created in BioRender.com). GLU: glutamatergic neuron and glutamate; SPNs: striatal projection neurons.

Figure 1

Different types of levodopa-induced dyskinesias. The figure accurately describes the different types of levodopa-induced dyskinesias. Diphasic dyskinesias occur early in the effect of levodopa treatment, before the peak of clinical benefit on motor symptoms is reached, and may recur as the drug effect wanes until it disappears. Peak dyskinesias coincide with the full antiparkinsonian benefit of levodopa during the “on” period, whereas “off” period dyskinesias occur when levodopa is no longer effective.