Systemic Inflammation Increases the Susceptibility to Levodopa-Induced Dyskinesia in 6-OHDA Lesioned Rats by Targeting the NR2B-Medicated PKC/MEK/ERK Pathway

Abstract

Background: The long-term administration of levodopa (L-dopa), the gold-standard treatment for Parkinson's disease (PD), is irreparably associated with L-dopa-induced dyskinesia (LID), which dramatically affects the quality of life of patients. However, the underlying molecular mechanisms of how LID exacerbates remain unknown. Neuroinflammation in the striatum plays an active role in LID. These findings prompt an investigation of non-neuronal mechanisms of LID. This study will examine the effects of systemic inflammation in the development and progression of LID.Methods: To evaluate the possible influence of systemic inflammation in the appearance of LID, the PD rats received an intraperitoneal (IP) injection of various concentrations of lipopolysaccharides (LPS, 1, 2, and 5 mg/kg) or saline. One day later, these PD rats started to receive daily treatment with L-dopa (6 mg/kg) along with benserazide (6 mg/kg) or saline for 21 days, and dyskinesia was evaluated at several time points. Moreover, the activation of microglia and astrocytes and the molecular changes in NR2B and mGLUR5 signaling pathways were measured.Results: We found that systemic inflammatory stimulation with LPS exacerbated the intensity of abnormal involuntary movements (AIMs) induced by L-dopa treatment in 6-hydroxydopamine (6-OHDA) lesioned rats. The LPS injection activated the gliocytes and increased the levels of proinflammatory cytokines in the striatum in LID rats. The PD rats that received the LPS injection showed the overexpression of p-NR2B and NR2B, as well as activated PKC/MEK/ERK and NF-κB signal pathways in response to the L-dopa administration. On the contrary, clodronate-encapsulated liposomes (Clo-lipo), which could suppress the inflammatory response induced by peripheral LPS injection, improved behavioral dysfunction, inhibited neuroinflammation, prevented NR2B overexpression, and decreased the phosphorylation of PKC/MEK/ERK and NF-κB signaling pathways.Conclusion: This study suggests that systemic inflammation, by exacerbating preexisting neuroinflammation and facilitating NR2B subunit activity, may play a crucial role in the development of LID. The administration of Clo-lipo restores the effects of LPS and decreases the susceptibility to LID in 6-OHDA lesioned rats.

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

“…IL-1β was reported to activate the cortical neurons through the ionotropic glutamate receptor (N-methyl-D-aspartic acid receptor 2B, NR2B), mediating the downstream signaling pathway ( Davis et al, 2006 ). Our recent study further confirmed that the expression level of TNF-α and IL-1 β positively correlated with the neuron membrane-expressed NR2B receptor-mediated ERK1/2 phosphorylation and the intensity of LID ( Yan et al, 2021 ).…”

“…A recent study reported that intermittent L-dopa administration induced an enhanced neuroinflammation response in the striatum, compared to continuous L-dopa delivery ( Mulas et al, 2016 ). Our recent study reported that the dyskinetic movement severity was significantly exacerbated when the striatal neuroinflammation response was enhanced by a systemic inflammatory stimulus of LPS prior to intermittent L-dopa administration ( Yan et al, 2021 ). By contrast, the dyskinetic movements were greatly reduced in the PD model where the striatal neuroinflammation response was inhibited by a systemic administration of corticosterone prior to intermittent L-dopa stimulation ( Barnum et al, 2008 ).…”

Co-Application of C16 and Ang-1 Improves the Effects of Levodopa in Parkinson Disease Treatment

“…18 Previous studies suggest that systemic inflammatory stimulation exacerbates AIM induced by levodopa treatment in MPTP lesioned mice and increases pro-inflammatory cytokines in the striatum of LID mice. 1,2 In our MPTP-induced PD model, infiltration of inflammatory cells was found in the parenchymal striatum in the levodopa group, which is in accordance with previous studies showing that neuroinflammation could exacerbate levodopa-induced dyskinesia. 19 Inflammation has a pathogenic role in neurodegenerative diseases.…”

“…Dyskinesia (abnormal involuntary movements) has also been shown to affect a majority of PD patients receiving levodopa, which limits its clinical application. 2 Aging is considered a primary risk factor for the development of PD. Aging-related neuroinflammation has been shown to lead to neuronal loss.…”

FRET Visualization of Cyclic Stretch-Activated ERK via Calcium Channels Mechanosensation While Not Integrin β1 in Airway Smooth Muscle Cells

“…Possibly actin cytoskeleton passed the force to trigger the ER Ca 2+ signals ( Kim et al, 2015 ), which is also suggested from our data ( Figures 5A–E ). Ca 2+ signals can further activate PKC to induce Ras-Raf-MEK-ERK pathway ( Liao et al, 2020 ; Yan et al, 2020 ), and our data showed that inhibition of Ras truly blocked the mechanical activation of ERK ( Figures 5D,E ). These data indicate that actin cytoskeleton belongs to the mechanosensing component for ERK activation.…”