scholarly journals Gastrointestinal Dopamine in Inflammatory Bowel Diseases: A Systematic Review

2021 ◽  
Vol 22 (23) ◽  
pp. 12932
Author(s):  
Magdalena Kurnik-Łucka ◽  
Paweł Pasieka ◽  
Patrycja Łączak ◽  
Marcin Wojnarski ◽  
Michał Jurczyk
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic System ◽  
Meta Analysis ◽  
Cross Sectional ◽  
Duodenal Ulcers ◽  
Inflammatory Bowel

Background: an increased prevalence of gastro-duodenal ulceration was described almost sixty years ago as prodromal to idiopathic Parkinson’s disease, while duodenal ulcers have been rarely diagnosed in patients with schizophrenia. The cytoprotective role of dopamine in animal models of gastrointestinal ulcerations has also been described. Interestingly, Parkinson’s disease (PD) might share common pathophysiological links with inflammatory bowel disease (IBD) as epidemiological and genetic links already suggest. Thus, the aim of our study was to review the existing literature on the role of the gastrointestinal dopaminergic system in IBD pathogenesis and progression. Methods: a systematic search was conducted according to the PRISMA methodology. Results: twenty-four studies satisfied the predetermined criteria and were included in our qualitative analysis. Due to different observations (cross-sectional studies) as well as experimental setups and applied methodologies (in vivo and in vitro studies) a meta-analysis could not be performed. No ongoing clinical trials with dopaminergic compounds in IBD patients were found. Conclusions: the impairment of the dopaminergic system seems to be a significant, yet underestimated, feature of IBD, and more in-depth observational studies are needed to further support the existing preclinical data.

scholarly journals Immunomodulatory role of Parkinson’s disease 7 in inflammatory bowel disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rita Lippai ◽  
Apor Veres-Székely ◽  
Erna Sziksz ◽  
Yoichiro Iwakura ◽  
Domonkos Pap ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Inflammatory Bowel Disease ◽  
Parkinson's Disease ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Tnf Α ◽  
Inflammatory Bowel ◽  
Ht 29

AbstractRecently the role of Parkinson’s disease 7 (PARK7) was studied in gastrointestinal diseases, however, the complex role of PARK7 in the intestinal inflammation is still not completely clear. Expression and localization of PARK7 were determined in the colon biopsies of children with inflammatory bowel disease (IBD), in the colon of dextran sodium sulphate (DSS) treated mice and in HT-29 colonic epithelial cells treated with interleukin (IL)-17, hydrogen peroxide (H2O2), tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β or lipopolysaccharide (LPS). Effect of PARK7 on the synthesis of IBD related cytokines was determined using PARK7 gene silenced HT-29 cells and 3,4,5-trimethoxy-N-(4-(8-methylimidazo(1,2-a)pyridine-2-yl)phenyl)benzamide (Comp23)—compound increasing PARK7 activity—treated mice with DSS-colitis. PARK7 expression was higher in the mucosa of children with Crohn’s disease compared to that of controls. While H2O2 and IL-17 treatment increased, LPS, TNF-α or TGF-β treatment decreased the PARK7 synthesis of HT-29 cells. PARK7 gene silencing influenced the synthesis of IL1B, IL6, TNFA and TGFB1 in vitro. Comp23 treatment attenuated the ex vivo permeability of colonic sacs, the clinical symptoms, and mucosal expression of Tgfb1, Il1b, Il6 and Il10 of DSS-treated mice. Our study revealed the role of PARK7 in the regulation of IBD-related inflammation in vitro and in vivo, suggesting its importance as a future therapeutic target.

scholarly journals LincRNA-p21 Inhibits Cell Viability and Promotes Cell Apoptosis in Parkinson’s Disease through Activating α-Synuclein Expression

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Xiaonan Xu ◽  
Chengle Zhuang ◽  
Zimu Wu ◽  
Hongyan Qiu ◽  
Haixia Feng ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Apoptosis ◽  
Noncoding Rna ◽  
Long Intergenic Noncoding Rna ◽  
Novel Target ◽  
Underlying Mechanisms

Long intergenic noncoding RNA-p21 (lincRNA-p21) has been reported to be increased in Parkinson’s disease (PD). However, the function and underlying mechanisms of lincRNA-p21 remain not clear. In order to explore the role of lincRNA-p21 in PD, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce in vivo PD model (C57BL/6 mice) and utilized N-methyl-4-phenylpyridinium (MPP+) to create in vitro PD model (SH-SY5Y cells). Results showed that the expression level of lincRNA-p21 was increased significantly in PD models. High abundance of lincRNA-p21 inhibited viability and promoted apoptosis markedly in SH-SY5Y cells treated with MPP+. Mechanistically, further experiments demonstrated that upregulation of lincRNA-p21 could sponge miR-1277-5p and indirectly increase the expression of α-synuclein to suppress viability and activate apoptosis in SH-SY5Y cells. In short, our study illustrated that lincRNA-p21/miR-1277-5p axis regulated viability and apoptosis in SH-SY5Y cells treated with MPP+ via targeting α-synuclein. LincRNA-p21 might be a novel target for PD.

The Deficiency of Maged1 Attenuates Parkinson's Disease Progression by Inhibiting Apoptosis and Enhancing Autophagy in Mice

2020 ◽  
Author(s):  
Jie Wang ◽  
Wei-Yan You ◽  
Qing Ye ◽  
Jia-Qi Zhang ◽  
Chuan He ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Signaling Pathway ◽  
Knockout Mice ◽  
Gene Transfection ◽  
Motor Deficits ◽  
Mice Model

Abstract Background: Melanoma-associated antigen D1 (Maged1) is expressed in most adult tissues, predominantly in the brain, and has critical functions in the central nervous system in both developmental and adult stages. Loss of Maged1 in mice has been linked to depression, cognitive disorder, circadian rhythm, and drug addiction. However, the role of Maged1 in Parkinson’s disease (PD) remains unclear.Methods: Immunostaining was performed to investigate the expression of Maged1 in the samples from mice and human. To make the acute mice model of PD, C57BL/6 mice and Maged1 knockout mice were injected with 20 mg/kg 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) four times, every 2-hour intervals. SY5Y cells were treated by 200 μM 1-Methyl-4-phenylpyridinium iodide (MPP+). To examine motor balance and coordination, the rotarod test and pole test were used. Then we further investigated the role of Maged1 deficiency in DA neurons by high-performance liquid chromatography, immunohistochemistry, western blot, CCK8 assay, and gene transfection in vivo or in vitro.Results: Maged1 was expressed in DA neurons of samples from mice and human. And the expression of Maged1 was time-dependently upregulated by the treatment with MPTP or MPP+ in vivo or in vitro. Knockout of Maged1 in mice partly rescued the motor deficits and the reduced levels of striatal dopamine and its metabolites by MPTP treatment. Moreover, Maged1 deficiency protected primary DA neurons and differentiated ReNcell VM cells from MPP+ toxicity. Furthermore, along with the overexpression or downregulation of Maged1 in cultured SH-SY5Y cells, the reduced the cell viability by MPP+ treatment was relatively aggerated or attenuated. The effect of Maged1 deficiency may be attributed to the upregulated Akt signaling pathway and the downregulated mTOR signaling pathway, which further attenuated the MPTP or MPP+ -induced cell apoptosis and impairment of autophagy. Consistent with the above data, the degeneration of midbrain and striatum among 15-m Maged1 knockout mice was relatively mild compared to those in 15-m wild-type mice under physiological conditions.Conclusions: Maged1 deficiency-mediated apoptosis inhibition and autophagy enhancement may be a potential pro-survival mechanism during the progression of PD.

scholarly journals Mitochondrial Metabolism as Target of the Neuroprotective Role of Erythropoietin in Parkinson’s Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 121
Author(s):  
Federica Rey ◽  
Sara Ottolenghi ◽  
Toniella Giallongo ◽  
Alice Balsari ◽  
Carla Martinelli ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Extracellular Acidification ◽  
Atp Levels ◽  
Transmission Electron ◽  
First Time ◽  
Glycolytic Rate

Existing therapies for Parkinson’s disease (PD) are only symptomatic. As erythropoietin (EPO) is emerging for its benefits in neurodegenerative diseases, here, we test the protective effect driven by EPO in in vitro (SH-SY5Y cells challenged by MPP+) and in vivo (C57BL/6J mice administered with MPTP) PD models. EPO restores cell viability in both protective and restorative layouts, enhancing the dopaminergic recovery. Specifically, EPO rescues the PD-induced damage to mitochondria, as shown by transmission electron microscopy, Mitotracker assay and PINK1 expression. Moreover, EPO promotes a rescue of mitochondrial respiration while markedly enhancing the glycolytic rate, as shown by the augmented extracellular acidification rate, contributing to elevated ATP levels in MPP+-challenged cells. In PD mice, EPO intrastriatal infusion markedly improves the outcome of behavioral tests. This is associated with the rescue of dopaminergic markers and decreased neuroinflammation. This study demonstrates cellular and functional recovery following EPO treatment, likely mediated by the 37 Kda isoform of the EPO-receptor. We report for the first time, that EPO-neuroprotection is exerted through restoring ATP levels by accelerating the glycolytic rate. In conclusion, the redox imbalance and neuroinflammation associated with PD may be successfully treated by EPO.

scholarly journals Triggering Receptor Expressed on Myeloid Cells 2 Protects Dopaminergic Neurons by Promoting Autophagy in the Inflammatory Pathogenesis of Parkinson’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Wei Huang ◽  
Qiankun Lv ◽  
Yunfei Xiao ◽  
Zhen Zhong ◽  
Binbin Hu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Human Genetics ◽  
Neurodegenerative Disorder ◽  
Inflammatory Factors ◽  
Inflammatory Mechanism

Parkinson’s disease is a neurodegenerative disorder with an inflammatory response as the core pathogenic mechanism. Previous human genetics findings support the view that the loss of TREM2 function will aggravate neurodegeneration, and TREM2 is one of the most highly expressed receptors in microglia. However, the role of TREM2 in the inflammatory mechanism of PD is not clear. In our study, it was found both in vivo and in vitro that the activation of microglia not only promoted the secretion of inflammatory factors but also decreased the level of TREM2 and inhibited the occurrence of autophagy. In contrast, an increase in the level of TREM2 decreased the expression of inflammatory factors and enhanced the level of autophagy through the p38 MAPK/mTOR pathway. Moreover, increased TREM2 expression significantly decreased the apoptosis of dopaminergic (DA) neurons and improved the motor ability of PD mice. In summary, TREM2 is an important link between the pathogenesis of PD and inflammation. Our study provides a new view for the mechanism of TREM2 in PD and reveals TREM2 as a potential therapeutic target for PD.

scholarly journals Disruption of Mitochondrial Homeostasis: The Role of PINK1 in Parkinson’s Disease

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3022
Author(s):  
Maria Vizziello ◽  
Linda Borellini ◽  
Giulia Franco ◽  
Gianluca Ardolino
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Gene Mutations ◽  
Neuronal Population ◽  
In Vivo Models ◽  
Mitochondrial Homeostasis

The progressive reduction of the dopaminergic neurons of the substantia nigra is the fundamental process underlying Parkinson’s disease (PD), while the mechanism of susceptibility of this specific neuronal population is largely unclear. Disturbances in mitochondrial function have been recognized as one of the main pathways in sporadic PD since the finding of respiratory chain impairment in animal models of PD. Studies on genetic forms of PD have provided new insight on the role of mitochondrial bioenergetics, homeostasis, and autophagy. PINK1 (PTEN-induced putative kinase 1) gene mutations, although rare, are the second most common cause of recessively inherited early-onset PD, after Parkin gene mutations. Our knowledge of PINK1 and Parkin function has increased dramatically in the last years, with the discovery that a process called mitophagy, which plays a key role in the maintenance of mitochondrial health, is mediated by the PINK1/Parkin pathway. In vitro and in vivo models have been developed, supporting the role of PINK1 in synaptic transmission, particularly affecting dopaminergic neurons. It is of paramount importance to further define the role of PINK1 in mitophagy and mitochondrial homeostasis in PD pathogenesis in order to delineate novel therapeutic targets.

Implications of VIP and PACAP in Parkinson’s disease: what do we know so far?

2020 ◽  
Vol 27 ◽  
Author(s):  
Filipe Resende Oliveira de Souza ◽  
Fabiola Mara Ribeiro ◽  
Patricia Maria d' Almeida Lima
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Vasoactive Intestinal Peptide ◽  
In Vitro Models ◽  
Cytokines And Chemokines ◽  
Pituitary Adenylate Cyclase ◽  
Key Factor

Background: Parkinson’s disease is one of the most common neurodegenerative disorders and, although its etiology remains not yet fully understood, neuroinflammation has been pointed as a key factor for the progres-sion of the disease. Vasoactive intestinal peptide and pituitary adenilate-cyclase activating polypeptide are two neuropeptides that exhibit antiinflammatory and neuroprotective properties, modulating the production of cyto-kines and chemokines and the behaviour of immune cells. However, the role of chemokines and cytokines modu-lated by the endogenous receptors of the peptides vary according to the stage of the disease. Methods: Overview of the relationship between some cytokines and chemokines with vasoactive intestinal peptide, pituitary adenylate cyclase activating polypeptide and their endogenous receptors in the context of Parkinson’s disease neuroinflammation and oxidative stress, as well as the modulation of microglial cells by the peptides in this context. Results: The two peptides exhibit neuroprotective and antiinflammatory properties in models of Parkinson’s dis-ease, as they ameliorate cognitive functions, decrease the levels of neuroinflammation and promote dopaminergic neuronal survival. The peptides have been tested in a variety of in vivo and in vitro models of Parkinson’s disease, demonstrating potential for therapeutic application. Conclusion: More studies are needed to stablish the clinical use of vasoactive intestinal peptide and pituitary ade-nylate cyclase activating polypeptide as safe candidates for treating Parkinson’s disease, as the use of the peptides in different stages of the disease could produce different results concerning effectiveness.

scholarly journals The role of lysosome function in degradation of proteins that are associated with Parkinson's disease

2018 ◽  
Author(s):  
Βασίλειος Παπαδόπουλος
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease

Οι μεταλλάξεις του γονιδίου της γλυκοσερεβροσιδάσης (GBA1) αποτελούν τον πιο συχνό γενετικό παράγοντα κινδύνου για την εμφάνιση νόσου του Parkinson (PD). Επιπλέον, οι μεταλλάξεις του GBA1 έχουν συσχετιστεί με ελαττωμένη ενεργότητα του λυσοσωμιακού ενζύμου της γλυκοσερεβροσιδάσης (GCase) σε ασθενείς με PD, αλλά και ασθενείς PD που δεν φέρουν μετάλλαξη στο GBA1 παρουσιάζουν επίσης ελαττωμένη ενεργότητα της GCase στο κεντρικό νευρικό σύστημα. Συνολικά, φαίνεται πως η ενεργότητα του συγκεκριμένου ενζύμου διαδραματίζει σημαντικό ρόλο στην παθογένεια της PD. Όσον αφορά τον μηχανισμό δια του οποίου μεσολαβείται η συνεισφορά των μεταλλάξεων του GBA1 στον κίνδυνο εμφάνισης της νόσου, είναι πιθανότερα η μεταβολή της λυσοσωμιακής οδού αποικοδόμησης πρωτεϊνών. Η α-συνουκλεΐνη, η πρωτεΐνη που κατέχει κεντρικό ρόλο στην παθογένεια της PD, έχει δειχθεί ότι εκκρίνεται εξωκυττάρια, τόσο ως ελεύθερη πρωτεΐνη, όσο και ως περιεχόμενο των εξωσωμάτων. Είναι πιθανό η δυσλειτουργία του μονοπατιού της ενδοκυττάρωσης μέσω δυσλειτουργίας της GCase να συμβάλλει σε αλλαγή της έκκρισης εξωσωμάτων και της σχετιζόμενης με εξωσώματα α-συνουκλεΐνης. Ο σκοπός της παρούσας μελέτης ήταν να εξεταστεί η αλλαγή στη συσσώρευση και την έκκριση της α-συνουκλεΐνης μέσω χειρισμών στη μορφή και την ενεργότητα του λυσοσωμιακού ενζύμου της GCase. Στο πρώτο στάδιο της διατριβής, κατασκευάστηκαν τέσσερις αδενοϊοί που εμπεριείχαν την αγρίου τύπου (WT), τις μεταλλαγμένες μορφές N370S και D409V της GCase ή το γονίδιο για την πράσινη φθορίζουσα πρωτεΐνη (GFP) ως μάρτυρα. Οι ιοί χρησιμοποιήθηκαν για τη μόλυνση πρωτοταγών καλλιεργειών φλοιϊκών νευρώνων από μύες. Η μεσολαβούμενη από αδενοϊό υπερέκφραση της WT GCase οδήγησε σε σημαντική μείωση της έκκρισης εξωσωμάτων in vitro. Η ποσότητα της α-συνουκλεΐνης τόσο ενδοκυττάρια όσο και εξωκυττάρια παρουσίασε τάση αύξησης η οποία δεν ήταν στατιστικά σημαντική. Στο δεύτερο στάδιο της διατριβής, σε νέα in vitro πειράματα η συμβολή της ενεργότητας της GCase ελέγχθηκε με την υπερέκφραση της α-συνουκλεΐνης μέσω αδενοϊών, παρουσία ή μη του κονδουριτολικού β-εποξειδίου ομοιοπολικού αναστολέα (CBE), εκλεκτικού αναστολέα της GCase. Εκ νέου, παρουσία του αναστολέα CBE, παρατηρήθηκε τάση αύξησης της α-συνουκλεΐνης, που δεν ήταν στατιστικά σημαντική. Στο τρίτο στάδιο της διατριβής, διενεργήθηκαν in vivo πειράματα. Eπιλέχθηκαν διαγονιδιακοί μύες οι οποίοι ήταν ετερόζυγοι για την μετάλλαξη A53T του γονιδίου της α-συνουκλεΐνης (SNCA). Σε αυτό το μοντέλο ήταν δυνατή η χρόνια αναστολή του ενζύμου της GCase, μέσω της διαπεριτοναϊκής χορήγησης του CBE σε περιοδικά διαστήματα ώστε να προσομοιαστεί η συνεχώς μειωμένη ενεργότητα της GCase σε ασθενείς PD. Πράγματι, η ενδοκυττάρια ολιγομερής μορφή της α-συνουκλεΐνης ήταν στατιστικά σημαντικά αυξημένη στους μύες που έλαβαν τον αναστολέα CBE. Μάλιστα, η αναστολή της GCase προκάλεσε μία αθρόα αύξηση των εγκεφαλικών εξωσωμάτων και της ολιγομερούς α-συνουκλεΐνης που εμπεριέχεται σε εξωσώματα. Στη συνέχεια, για να ελεγχθεί ο ρόλος της μεταλλαγμένης GCase σε ένα χρόνιο μοντέλο της PD, χρησιμοποιήθηκαν ιοί για την υπερέκφραση μεταλλαγμένης GCase στους διαγονιδιακούς για την A53T α-συνουκλεΐνη μύες. Χρησιμοποιώντας τη μέθοδο της διαπίδυσης μπορέσαμε να μετρήσουμε την εκκρινόμενη α-συνουκλεΐνη στο ραβδωτό σώμα ζώντων μυών. Με ιδιαίτερο ενδιαφέρον παρατηρήσαμε ότι οι μύες που υπερεξέφραζαν την μεταλλαγμένη N370S GCase είχαν αυξημένη έκκριση α-συνουκλεΐνης. Σε περαιτέρω πειράματα στα εν λόγω ζώα, φάνηκε ότι αυτή η αύξηση της έκκρισης της α-συνουκλεΐνης οφειλόταν σε δυσλειτουργία του λυσοσώματος, όπως αναδείχθηκε με ανοσοϊστοχημική χρώση για τον δείκτη αυτοφαγίας LC3.Συνοψίζοντας, η παρούσα διδακτορική διατριβή οδήγησε σε ενδιαφέροντα, καινούρια ευρήματα. Τα αποτελέσματα των ανωτέρω πειραμάτων αποτελούν τα πρώτα στοιχεία για το ότι η μειωμένη ενεργότητα της φυσιολογικής GCase ή η υπερέκφραση μεταλλαγμένης GCase σε ένα χρόνιο in vivo περιβάλλον οδηγούν σε αύξηση της έκκρισης της α-συνουκλεΐνης. Φάνηκε ότι αυτή η μεταβολή οφείλεται, τουλάχιστον εν μέρει, σε δυσλειτουργία της αυτοφαγίας. Αυτή η δράση της GCase μπορεί να οδηγεί σε ενίσχυση της διάδοσης της α-συνουκλεΐνης η οποία με τη σειρά της να συμβάλλει στην εξέλιξη της παθοφυσιολογίας στην PD που σχετίζεται με μεταλλάξεις στο γονίδιο GBA1. Η σχετιζόμενη με εξωσώματα ολιγομερής α-συνουκλεΐνη μπορεί να αποτελέσει θεραπευτικό στόχο αλλά και να διερευνηθεί περαιτέρω ως πιθανός βιοδείκτης. Η μελέτη των παραγόντων που την επηρεάζουν, όπως η GCase, μπορεί πράγματι να έχει κλινική σημασία.

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