Abstract
Our present objective was to better characterize the mechanisms that regulate striatal neuroinflammation in mice developing L-DOPA-induced dyskinesia (LID). For that, we used 6-hydroxydopamine (6-OHDA)-lesioned mice rendered dyskinetic by repeated intraperitoneal injections of 3,4-dihydroxyphenyl-L-alanine (L-DOPA) and quantified ensuing neuroinflammatory changes in the dopamine-denervated dorsal striatum. LID development was associated with a prominent astrocytic response, and a more moderate microglial cell reaction restricted to this striatal area. The glial response was associated with elevations in two pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β. Treatment with the phytocannabinoid cannabidiol and the transient receptor potential vanilloid-1 (TRPV-1) channel antagonist capsazepine diminished LID intensity and decreased TNF-α levels without impacting other inflammation markers. To possibly reproduce the neuroinflammatory component of LID, we exposed astrocyte and microglial cells in culture to candidate molecules that might operate as inflammatory cues during LID development, i.e., L-DOPA, dopamine, or glutamate. Neither L-DOPA nor dopamine produced an inflammatory response in glial cell cultures. However, glutamate enhanced TNF-α secretion and GFAP expression in astrocyte cultures and promoted Iba-1 expression in microglial cultures. Of interest, the antidyskinetic treatment with cannabidiol + capsazepine reduced TNF-α release in glutamate-activated astrocytes. TNF-α, on its own, promoted the synaptic release of glutamate in cortical neuronal cultures, whereas cannabidiol + capsazepine prevented this effect. Therefore, we may assume that the release of TNF-α by glutamate-activated astrocytes may contribute to LID by exacerbating corticostriatal glutamatergic inputs excitability and maintaining astrocytes in an activated state through a self-reinforcing mechanism.
Highlights
L-DOPA-induced dyskinesia (LID) represents a common and severe motor complication after dopamine-replacement therapy in Parkinson’s disease
6-hydroxydopamine hydrochloride (6-OHDA; #H4381, diluted in 0.9% saline), L-DOPA hydrochloride (#D1507, diluted in 0.9% saline), benserazide hydrochloride (#B7283, diluted in 0.9% saline), dopamine hydrochloride (DA; #H8502, diluted in distilled water), glutamate acid monosodium salt hydrate (Glu; #G5889 diluted in distilled water), capsazepine (CPZ; #C191, diluted in 50% DMSO-saline or 25% DMSO-distilled water), lipopolysaccharide (LPS; Escherichia coli strain O26:B6; #L8274, diluted in distilled water) and Tumor Necrosis Factor-α human (TNF-α, #T6674, diluted in distilled water) were all obtained from Sigma-Aldrich
Despite the fact that tumor necrosis factor-α (TNF-α) was reported capable of activating both microglial cells (Neniskyte et al, 2014) and astrocytes (Trindade et al, 2020) at a concentration of 50 ng/ml, we found that such a concentration had no significant impact on extracellular glutamate levels in astrocyte (Figure 9B) and microglial cell cultures (Figure 9C), suggesting that the modulatory effect of TNF-α on glutamate levels is restricted to neuronal cells in the current setting
Summary
L-DOPA-induced dyskinesia (LID) represents a common and severe motor complication after dopamine-replacement therapy in Parkinson’s disease. The corticostriatal glutamatergic neurotransmission becomes progressively dysregulated, and maladaptive changes develop in medium spiny neurons of the dopamine-denervated striatum (Calon et al, 2003; Picconi et al, 2003; Robelet et al, 2004; Cenci, 2007; Rylander et al, 2009; Sgambato-Faure and Cenci, 2012). Such changes are characterized by extensive morphological and molecular aberrant readjustments, including supersensitivity of D1 dopamine receptors, which become abnormally activated by synaptic dopamine, leading to hyperactivation of cAMPdependent signaling and downstream signaling events (Darmopil et al, 2009; Cenci, 2014)
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