1H NMR profiling of the 6-OHDA parkinsonian rat brain reveals metabolic alterations and signs of recovery after N-acetylcysteine treatment

Virel, Ana; Dudka, Ilona; Laterveer, Rutger; Bjerkén, Sara af

doi:10.1016/j.mcn.2019.06.003

Cited by 21 publications

(12 citation statements)

References 52 publications

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“…NAC is inexpensive, FDA-approved, orally absorbed, and enters human cerebrospinal fluid at biologically active concentrations (Berman et al, 2011;Reyes et al, 2016). Thiol repletion using NAC or other agents has been repeatedly cited as a promising approach for slowing PD progression (Ma rtinez-Ba naclocha, 2012;Monti et al, 2019;Reyes et al, 2016;Virel et al, 2019;Zeevalk et al, 2008), and results of the present study provide additional mechanistic support for this approach.…”

Section: Discussionsupporting

confidence: 61%

α-synuclein aggregates induce c-Abl activation and dopaminergic neuronal loss by a feed-forward redox stress mechanism

Ghosh

Won

Wang

et al. 2021

Progress in Neurobiology

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Oxidative stress and α-synuclein aggregation both drive neurodegeneration in Parkinson's disease, and the protein kinase c-Abl provides a potential amplifying link between these pathogenic factors. Suppressing interactions between these factors may thus be a viable therapeutic approach for this disorder. To evaluate this possibility, pre-formed α-synuclein fibrils (PFFs) were used to induce α-synuclein aggregation in neuronal cultures. Exposure to PFFs induced oxidative stress and c-Abl activation in wild-type neurons. By contrast, α-synuclein -deficient neurons, which cannot form α-synuclein aggregates, failed to exhibit either oxidative stress or c-Abl activation. N-acetyl cysteine, a thiol repletion agent that supports neuronal glutathione metabolism, suppressed the PFF -induced redox stress and c-Abl activation in the wild-type neurons, and likewise suppressed α-synuclein aggregation. Parallel findings were observed in mouse brain: PFF-induced α-synuclein aggregation in the substantia nigra was associated with redox stress, c-Abl activation, and dopaminergic neuronal loss, along with microglial activation and motor impairment, all of which were attenuated with oral N-acetyl cysteine. Similar results were obtained using AAV-mediated α-synuclein overexpression as an alternative means of driving α-synuclein aggregation in vivo. These findings show that α-synuclein aggregates induce c-Abl activation by a redox stress mechanism. c-Abl activation in turn promotes α-synuclein aggregation, in a feed-forward interaction. The capacity of N-acetyl cysteine to interrupt this interaction adds mechanistic support its consideration as a therapeutic in Parkinson's disease.

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Section: Discussionsupporting

confidence: 61%

α-synuclein aggregates induce c-Abl activation and dopaminergic neuronal loss by a feed-forward redox stress mechanism

Ghosh

Won

Wang

et al. 2021

Progress in Neurobiology

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“…Both may attenuate and protect against oxidative stress [51][52][53][54][55] that represents the primary cause of neuronal death in PD. In the literature, previous metabolomics studies have reported modifications of glycolysis in brain and blood samples of PD animal models [56][57][58][59] . Glycolysis has also been described as dysregulated in animal models expressing neuropsychiatric symptoms similar to those found in the early stages of PD, such as depression or anxiety 60,61 .…”

Section: Discussionmentioning

confidence: 99%

Early diagnosis of Parkinson’s disease: A cross-species biomarker

Mallet

Dufourd

Decourt

et al. 2021

Preprint

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Background: Care management of Parkinson disease (PD) patients currently remains symptomatic, especially because diagnosis relying on the expression of the cardinal motor symptoms is made too late. Detecting PD earlier therefore represents a key step for developing therapies able to delay or slow down its progression. Methods: We investigated metabolic markers in three different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 2 cohorts of de novo PD patients (n = 95). Serum and brain tissue samples were analyzed by nuclear magnetic resonance spectroscopy and data submitted to advanced multivariate statistics. Results: Our translational strategy reveals common metabolic dysregulations in serum of the different animal models and PD patients. Some of them were mirrored in the tissue samples, possibly reflecting pathophysiological mechanisms associated with PD development. Interestingly, some metabolic dysregulations appeared before motor symptom emergence, and could represent early biomarkers of PD. Finally, we built a composite biomarker with a combination of 6 metabolites. This biomarker discriminated animals mimicking PD from controls, even from the first, non-motor signs and very interestingly, also discriminated PD patients from healthy subjects. Conclusion: From our translational study which included three animal models and two PD patient cohorts, we propose a promising composite biomarker exhibiting a high level of predictivity for PD diagnosis in its early phase, before motor symptoms appearance.

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“…The manipulation was performed according to the previous study [24]. The defining peaks of the sample metabolites were analyzed in accordance with previous publications [33][34][35][36] and the network database of metabolomics, including the Biological Magnetic Resonance Bank (http:// www.bmrb.wisc.edu/metabolomics) and the Human Metabolome Database (http://www.hmdb.ca/). The partial least squares discriminant analysis (PLS-DA) was performed using SIMCA 14.2 (Umetrics AB, Umea, Sweden) after metabolic data were normalized to constants and scaled.…”

Section: Sample Preparation For Metabolicmentioning

confidence: 99%

“…A previous study reported that the prevalence of anxiety and depressive disorders in IBD patients reached 25.8% and 21.2%, respectively [5]. Recently, a study considered the prevalence to be as high as 33.1% [6].…”

Section: Introductionmentioning

confidence: 98%

Electroacupuncture Attenuated Anxiety and Depression-Like Behavior via Inhibition of Hippocampal Inflammatory Response and Metabolic Disorders in TNBS-Induced IBD Rats

Zhou

Jiang

Kong

et al. 2022

Oxidative Medicine and Cellular Longevity

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This study was designed to explore the potential mechanisms of electroacupuncture (EA) in treating inflammatory bowel disease- (IBD-) related anxiety and mood disorders. A colitis model was induced in rats with 2, 4, 6-trinitrohydrosulfonic acid (TNBS), followed by ST36 and SP6 targeted therapy by EA or sham EA treatment. The elevated plus maze (EPM) and open-field test (OFT) were performed to assess the state of anxiety and depression-like behavior. Tests were carried out by 16S rDNA amplification sequence, 1H nuclear magnetic resonance (1H NMR) spectroscopy, immunofluorescence staining, and enzyme-linked immunosorbent assay (ELISA). The analyses detailed metabolic alterations and the Toll-like receptor 4 (TLR4) signaling pathway/NOD-like receptor protein 3 (NLRP3) inflammasome in rats’ hippocampal region. Furthermore, the activity of the hypothalamic-pituitary adrenal (HPA) axis and gut microbiome was assessed. As a result of treatment, EA significantly improved in the behavioral tests and altered the composition of the gut microbiome through a significant increase in the density of short chain fatty acids (SCFAs) producers mainly including Ruminococcaceae, Phascolarctobacterium, and Akkermansiaceae. EA upregulated the metabolites of the hippocampus mainly containing l-glutamine and gamma-aminobutyric acid (GABA), as well as ZO-1 expression. Whereas the treatment blocked the TLR4/nuclear factor- kappa B (NF-κB) signaling pathways and NLRP3 inflammasomes, along with downregulating the interleukin- (IL-) 1β level. The hyperactivity of the HPA axis was also diminished. In conclusion, EA at ST36 and SP6 attenuated anxiety and depression-like behavior in colitis model rats through their effects on the gut microbiome by modulating the hippocampal inflammatory response and metabolic disorders, as well as the HPA axis. This study provides evidence for clinical application of EA to serve as an adjunctive treatment for IBD-related anxiety and depression.

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1H NMR profiling of the 6-OHDA parkinsonian rat brain reveals metabolic alterations and signs of recovery after N-acetylcysteine treatment

Cited by 21 publications

References 52 publications

α-synuclein aggregates induce c-Abl activation and dopaminergic neuronal loss by a feed-forward redox stress mechanism

α-synuclein aggregates induce c-Abl activation and dopaminergic neuronal loss by a feed-forward redox stress mechanism

Early diagnosis of Parkinson’s disease: A cross-species biomarker

Electroacupuncture Attenuated Anxiety and Depression-Like Behavior via Inhibition of Hippocampal Inflammatory Response and Metabolic Disorders in TNBS-Induced IBD Rats

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