Contributive Role of TNF-α to L-DOPA-Induced Dyskinesia in a Unilateral 6-OHDA Lesion Model of Parkinson’s Disease

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.

Prevention of L-Dopa-Induced Dyskinesias by MPEP Blockade of Metabotropic Glutamate Receptor 5 Is Associated with Reduced Inflammation in the Brain of Parkinsonian Monkeys

“…Differences in survival time after MPTP and methodological approaches could account for the different results obtained in the MPTP + L-Dopa monkeys between these studies. Several preclinical studies in rodent models of PD have shown that treatment with L-Dopa induces or exacerbates inflammation via a direct involvement of microglia releasing pro-inflammatory cytokines promoting an initiation and/or development of dyskinesias [ 72 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 ]. In fact, the strong positive correlations between Iba1 levels and dyskinetic scores measured in several basal ganglion nuclei in the present study strongly support a direct link between LID and microglial reactivity.…”

The Chemically-Modified Tetracycline COL-3 and Its Parent Compound Doxycycline Prevent Microglial Inflammatory Responses by Reducing Glucose-Mediated Oxidative Stress

“…Under these conditions, microglial cell isolation occurs spontaneously after 14-18 days of culture. When required, purified microglial cells were maintained for up to 1 more week in culture flasks by adding 2-3 mL of DMEM supplemented with penicillin/streptomycin and only 1% of FCS [28]. Subcultures were produced by trypsinizing purified microglial cell cultures with 0.05% trypsin-EDTA for 5 min.…”

Inhibition of BET Protein Function Suppressed the Overactivation of the Canonical NF-κB Signaling Pathway in 6-OHDA-Lesioned Rat Model of Levodopa-Induced Dyskinesia

“…As ERK 1/2 phosphorylation was a crucial upstream event prior to the IEG transcription, we speculated that JQ1-blocked ERK 1/2 phosphorylation might be attributed to its suppression of the NF-κB-mediated gene expression of TNF-α and IL-1 β. With intermittent L-dopa stimulation, an increased cortico-striatal synaptic glutamate elicited an elevation of glia-derived TNF-α, which further enhanced the release of glutamate from the cortical neurons in a self-reinforcing manner ( Dos Santos Pereira et al, 2021 ). The hyperactivity of cortico-striatal glutamatergic transmission positively contributed to the occurrence of LID by inducing neuron-expressed receptor-mediated ERK1/2 phosphorylation ( Picconi et al, 2018 ).…”

“…Increasing studies have reported that BET proteins were involved in the canonical NF-κB activation pathway in autoinflammation disorders, injury, infection, and chronic morbid conditions, and inhibition of the BET protein function effectively suppresses the NF-κB-mediated pro-inflammatory expression, alleviating the neuroinflammation response in these pathological conditions ( Jahagirdar et al, 2017 ; Wang et al, 2018 ; Sánchez-Ventura et al, 2019 ; Zhou et al, 2019 ). In the DA-denervated striatum of LID animal models, the inflammatory status is characterized by the overexpression of pro-inflammatory substances of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and inducible nitric oxide synthase (iNOS), which has been reported to be involved in the mechanisms of LID ( Barnum et al, 2008 ; Bortolanza et al, 2015 ; Dos Santos Pereira et al, 2021 ). A recent study reported that a BET inhibitor JQ1 efficiently alleviated LID; however, its association with the impact of inhibition of the BET protein function on the NF-κB-mediated neuroinflammation in the striatum remains unknown.…”