Metabolic Profile in Plasma AND CSF of LEVODOPA-induced Dyskinesia in Parkinson’s Disease: Focus on Neuroinflammation

Santos‐Lobato, Bruno Lopes; Gardinassi, Luiz Gustavo; Bortolanza, Mariza; Peti, Ana Paula Ferranti; Pimentel, Angela Vieira; Faccioli, Lúcia Helena; Del‐Bel, Elaine; Tumas, Vítor

doi:10.1007/s12035-021-02625-1

Cited by 10 publications

(11 citation statements)

References 68 publications

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“…Metabolomic analysis. Untargeted metabolomic data were analyzed as previously described by our group (25,26). Briefly, metabolite was extracted, and samples were transferred to autosampler vials for LC-MS analysis using a TripleTOF5600 1 mass spectrometer (AB SCIEX, Foster City, CA) coupled to an ultra-HPLC system (Nexera ×2; Shimadzu, Kyoto, Japan).…”

Section: Hplc Tandem Mass Spectrometry (Lc-ms/ms)mentioning

confidence: 99%

Acetylcholine, Fatty Acids, and Lipid Mediators Are Linked to COVID-19 Severity

Pérez

Pimentel

Fuzo

et al. 2022

The Journal of Immunology

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on behalf of the ImmunoCOVID Brazilian Research Consortium 3Lipid and cholinergic mediators are inflammatory regulators, but their role in the immunopathology of COVID-19 is still unclear. Here, we used human blood and tracheal aspirate (TA) to investigate whether acetylcholine (Ach), fatty acids (FAs), and their derived lipid mediators (LMs) are associated with COVID-19 severity. First, we analyzed the perturbation profile induced by SARS-CoV-2 infection in the transcriptional profile of genes related to the ACh and FA/LM pathways. Blood and TA were used for metabolomic and lipidomic analyses and for quantification of leukocytes, cytokines, and ACh. Differential expression and coexpression gene network data revealed a unique transcriptional profile associated with ACh and FA/LM production, release, and cellular signaling. Transcriptomic data were corroborated by laboratory findings: SARS-CoV-2 infection increased plasma and TA levels of arachidonic acid, 5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid, 11-hydroxy-5Z,8Z,12E,14Z-eicosatetraenoic acid, and ACh. TA samples also exhibited high levels of PGE 2 , thromboxane B 2 , 12-oxo-5Z,8Z,10E,14Z-eicosatetraenoic acid, and 6-trans-leukotriene B 4 . Bioinformatics and experimental approaches demonstrated robust correlation between transcriptional profile in Ach and FA/LM pathways and parameters of severe COVID-19. As expected, the increased neutrophil-to-lymphocyte ratio, neutrophil counts, and cytokine levels (IL-6, IL-10, IL-1b, and IL-8) correlated with worse clinical scores. Glucocorticoids protected severe and critical patients and correlated with reduced Ach levels in plasma and TA samples. We demonstrated that pulmonary and systemic hyperinflammation in severe COVID-19 are associated with high levels of Ach and FA/LM. Glucocorticoids favored the survival of patients with severe/critical disease, and this effect was associated with a reduction in ACh levels.

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Section: Hplc Tandem Mass Spectrometry (Lc-ms/ms)mentioning

confidence: 99%

Acetylcholine, Fatty Acids, and Lipid Mediators Are Linked to COVID-19 Severity

Pérez

Pimentel

Fuzo

et al. 2022

The Journal of Immunology

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“…15 Neuroinflammation is thought to be involved in the pathogenesis of levodopa-induced dyskinesia. 16,17 The Parkinson's disease group treated with a daily 12 mg/ kg of levodopa for 15 days developed dyskinetic movement. On western blotting, this group further showed a significant increase of both D1R and D2R are responsible for levodopa-induced dyskinesia.…”

Section: Amphiregulin Is Highly Expressed In the Levodopa-induced Dys...mentioning

confidence: 99%

Amphiregulin blockade decreases the levodopa‐induced dyskinesia in a 6‐hydroxydopamine Parkinson's disease mouse model

Kambey

Liu

et al. 2023

CNS Neurosci Ther

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BackgroundLevodopa (L‐DOPA) is considered the most reliable drug for treating Parkinson's disease (PD) clinical symptoms. Regrettably, long‐term L‐DOPA therapy results in the emergence of drug‐induced abnormal involuntary movements (AIMs) in most PD patients. The mechanisms underlying motor fluctuations and dyskinesia induced by L‐DOPA (LID) are still perplexing.MethodsHere, we first performed the analysis on the microarray data set (GSE55096) from the gene expression omnibus (GEO) repository and identified the differentially expressed genes (DEGs) using linear models for microarray analysis (Limma) R packages from the Bioconductor project. 12 genes (Nr4a2, Areg, Tinf2, Ptgs2, Pdlim1, Tes, Irf6, Tgfb1, Serpinb2, Lipg, Creb3l1, Lypd1) were found to be upregulated. Six genes were validated on quantitative polymerase chain reaction and subsequently, Amphiregulin (Areg) was selected (based on log2 fold change) for further experiments to unravel its involvement in LID. Areg LV_shRNA was used to knock down Areg to explore its therapeutic role in the LID model.ResultsWestern blotting and immunofluorescence results show that AREG is significantly expressed in the LID group relative to the control. Dyskinetic movements in LID mice were alleviated by Areg knockdown, and the protein expression of delta FOSB, the commonly attributable protein in LID, was decreased. Moreover, Areg knockdown reduced the protein expression of P‐ERK. In order to ascertain whether the inhibition of the ERK pathway (a common pathway known to mediate levodopa‐induced dyskinesia) could also impede Areg, the animals were injected with an ERK inhibitor (PD98059). Afterward, the AIMs, AREG, and ERK protein expression were measured relative to the control group. A group treated with ERK inhibitor had a significant decrease of AREG and phosphorylated ERK protein expression relative to the control group.ConclusionTaken together, our results indicate unequivocal involvement of Areg in levodopa‐induced dyskinesia, thus a target for therapy development.

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“…Metabolomics has attracted attention in recent years, revealing multiple novel metabolic pathways linked to the pathogenesis of PD. Several studies demonstrated altered metabolic profiles in PD, PD subgroups, APS and other neurological conditions [ 97 , 98 , 99 , 100 , 101 , 102 , 103 ]. By utilizing machine learning algorithms, 14 CSF metabolites were identified that enabled distinguishing early PD from controls with high accuracy [ 104 ].…”

Section: Metabolomicsmentioning

confidence: 99%

“…Concerning PD medication-related sequelae, dysregulations in bile acid biosynthesis and glycosphingolipid/glycerophospholipid metabolism were able to distinguish PD patients suffering levodopa-induced dyskinesia (LID) from PD without LID and controls, pointing towards a further association between dysregulated lipid metabolism and neuroinflammation [ 98 ]. Intriguingly, an altered glycosphingolipid metabolic pathway was strongly associated with the severity of dyskinetic movements.…”

Section: Metabolomicsmentioning

confidence: 99%

Update on CSF Biomarkers in Parkinson’s Disease

et al. 2022

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Progress in developing disease-modifying therapies in Parkinson’s disease (PD) can only be achieved through reliable objective markers that help to identify subjects at risk. This includes an early and accurate diagnosis as well as continuous monitoring of disease progression and therapy response. Although PD diagnosis still relies mainly on clinical features, encouragingly, advances in biomarker discovery have been made. The cerebrospinal fluid (CSF) is a biofluid of particular interest to study biomarkers since it is closest to the brain structures and therefore could serve as an ideal source to reflect ongoing pathologic processes. According to the key pathophysiological mechanisms, the CSF status of α-synuclein species, markers of amyloid and tau pathology, neurofilament light chain, lysosomal enzymes and markers of neuroinflammation provide promising preliminary results as candidate biomarkers. Untargeted approaches in the field of metabolomics provide insights into novel and interconnected biological pathways. Markers based on genetic forms of PD can contribute to identifying subgroups suitable for gene-targeted treatment strategies that might also be transferable to sporadic PD. Further validation analyses in large PD cohort studies will identify the CSF biomarker or biomarker combinations with the best value for clinical and research purposes.

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Metabolic Profile in Plasma AND CSF of LEVODOPA-induced Dyskinesia in Parkinson’s Disease: Focus on Neuroinflammation

Cited by 10 publications

References 68 publications

Acetylcholine, Fatty Acids, and Lipid Mediators Are Linked to COVID-19 Severity

Acetylcholine, Fatty Acids, and Lipid Mediators Are Linked to COVID-19 Severity

Amphiregulin blockade decreases the levodopa‐induced dyskinesia in a 6‐hydroxydopamine Parkinson's disease mouse model

Update on CSF Biomarkers in Parkinson’s Disease

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