dimethyl fumarate
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Author(s):  
Audrey Reynolds ◽  
Maria Gaughan ◽  
Dean Holden ◽  
Vyanka Redenbaugh ◽  
Jean Dunne ◽  
...  

Abstract Objective The disease-modifying therapies (DMT), dimethyl fumarate (DMF) and fingolimod (FTY) improve the outcomes in multiple sclerosis (MS) by reducing relapses and numbers and volume of lesions. They mediate their effects through reduction of immune reactivation, which may potentially lead to lymphopaenia and increased risk of infections. Previous studies have examined the effects of these therapies on lymphocyte subsets; however, the in vivo effects on circulating lymphocyte proliferation require further elucidation. The aim of this study was to determine the effects of DMF and FTY on T-cell proliferation in patients with MS. Method We examined T-cell lymphocyte proliferation and lymphocyte subsets in ten patients (five on DMF, five on FTY) before starting DMT and again 4 to 11 months after being maintained on DMT. Results In the FTY-treated group, the mean percentage proliferation was significantly lower using both assays (PHA assay mean percentage change − 51.2 ± 25.97, p < 0.05; anti-CD3/CD28 assay mean percentage change − 39.74 ± 27.85, p < 0.05). There was no statistical difference in T-cell lymphocyte proliferation in the DMF-treated group for either assay (PHA, p = 0.316; anti-CD3/CD28, p = 0.373). Conclusions This pilot study suggests that the T-lymphocytes of patients on FTY have an abnormal proliferation response as well as being reduced in the circulation.


2022 ◽  
Vol 11 (2) ◽  
pp. 347
Author(s):  
Carla Prezioso ◽  
Marco Ciotti ◽  
Gabriele Brazzini ◽  
Francesca Piacentini ◽  
Sara Passerini ◽  
...  

Markers of JC polyomavirus (JCPyV) activity can be used to evaluate the risk of progressive multifocal leukoencephalopathy (PML) in treated multiple sclerosis (MS) patients. The presence of JCPyV DNA and microRNA (miR-J1-5p), the anti-JCV index and the sequence of the non-coding control region (NCCR) in urine and plasma were determined in 42 MS subjects before treatment (T0), 6 months (T6) and 12 months (T12) after natalizumab, ocrelizumab, fingolimod or dimethyl-fumarate administration and in 25 healthy controls (HC). The number of MS patients with viruria increased from 43% at T0 to 100% at T12, whereas it remained similar for the HC group (35–40%). Viremia first occurred 6 months after treatment in MS patients and increased after 12 months, whereas it was absent in HC. The viral load in urine and plasma from the MS cohort increased over time, mostly pronounced in natalizumab-treated patients, whereas it persisted in HC. The archetypal NCCR was detected in all positive urine, whereas mutations were observed in plasma-derived NCCRs resulting in a more neurotropic variant. The prevalence and miR-J1-5p copy number in MS urine and plasma dropped after treatment, whereas they remained similar in HC specimens. Viruria and miR-J1-5p expression did not correlate with anti-JCV index. In conclusion, analyzing JCPyV DNA and miR-J1-5p levels may allow monitoring JCPyV activity and predicting MS patients at risk of developing PML.


2022 ◽  
Vol 8 (1) ◽  
pp. 205521732110698
Author(s):  
Carrie M Hersh ◽  
Arman Altincatal ◽  
Nicholas Belviso ◽  
Shivani Kapadia ◽  
Carl de Moor ◽  
...  

Background Prior studies suggest comparable effectiveness of dimethyl fumarate (DMF) and fingolimod (FTY) in multiple sclerosis (MS) using relapse, Expanded Disability Status Score (EDSS), and magnetic resonance imaging (MRI) lesion metrics. Objective Compare the real-world effectiveness of DMF versus FTY using quantitative, validated neuroperformance tests, MRI, and serum neurofilament light chain (sNfL) outcomes while controlling for between-group differences. Methods Patients were eligible if on DMF or FTY when first enrolled in the MS Partners Advancing Technology and Health Solutions (MS PATHS) network and had ≥1-year follow-up in MS PATHS. Sensitivity analysis included a subgroup who started DMF/FTY ≤2 years from enrolment. After propensity score weighting, differences in means and in mean 1-year change of neuroperformance and MRI outcomes were compared. sNfL levels were assessed. This was a non-randomized comparison. Results In the overall cohort, no significant differences were observed between DMF ( n = 702) and FTY ( n = 600) in neuroperformance or MRI outcomes including brain volume loss; mean time (SD) since treatment initiation was 1.98 (0.68) years for DMF and 2.02 (0.75) years for FTY. A sensitivity analysis controlling for DMF and FTY treatment duration yielded similar results. Conclusion In this study, DMF and FTY demonstrated similar effects on physical and cognitive neuroperformance and MRI outcomes. Direct comparisons to other fumarates and S1P receptor modulators were not conducted.


2022 ◽  
Vol Volume 15 ◽  
pp. 33-52
Author(s):  
Danuta Wrona ◽  
Irena Majkutewicz ◽  
Grzegorz Świątek ◽  
Joanna Dunacka ◽  
Beata Grembecka ◽  
...  

Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 26
Author(s):  
Mikah S. Brandes ◽  
Jonathan A. Zweig ◽  
Anita Tang ◽  
Nora E. Gray

In Parkinson’s disease (PD), brain oxidative stress and mitochondrial dysfunction contribute to neuronal loss as well as motor and cognitive deficits. The transcription factor NRF2 has emerged as a promising therapeutic target in PD because it sits at the intersection of antioxidant and mitochondrial pathways. Here, we investigate the effects of modulating NRF2 activity in neurons isolated from a A53T α-synuclein (A53TSyn) mouse model of synucleinopathy. Embryonic hippocampal neurons were isolated from A53TSyn mice and their wild type (WT) littermates. Neurons were treated with either the NRF2 activator dimethyl fumarate (DMF) or the NRF2 inhibitor ML385. Reactive oxygen species (ROS), dendritic arborization and dendritic spine density were quantified. Mitochondrial bioenergetics were also profiled in these neurons. A53TSyn neurons had increased ROS and reduced basal and maximal mitochondrial respiration relative to WT neurons. A53TSyn neurons also displayed decreased dendritic arborization and reduced spine density. Treatment with DMF reduced ROS levels and improved both mitochondrial function and arborization, while inhibition of NRF2 with ML385 exacerbated these endpoints. Modulation of NRF2 activity had a significant effect on mitochondrial function, oxidative stress, and synaptic plasticity in A53TSyn neurons. These data suggest that NRF2 may be a viable target for therapeutic interventions in PD.


Author(s):  
V Nuthan Kumar Babu ◽  
Navneet Khurana

Parkinson’s disease (PD) is the common physical movement disorder, and it is 2nd most progressive widespread neurodegenerative disorder all over the world, and it is reported that and essential 10 million, over 0.3 % of the total world population. A thoughtful reduction of the neurotransmitter dopamine (DA) in the striatum is the main cause of these motor symptoms, collectively known as parkinsonism. Mitochondria serves as most important organelle in most of the cells and are essential for life and it is also called as heart for all cellular metabolisms. The main and most important role of mitochondria is generation of ATP via oxidative phosphorylation. In this study will study about how complex Ⅰ deficiency effects the mitochondrial and oxidative stress and reactive oxygen species which cause mitochondrial dysfunction and we also study emerging therapies for Parkinson disease with the help of coenzyme Q10 and some genes like FUN-14, FUNDC-1 and dimethyl fumarate or BG-12 in some phases of clinical trials and also by cell transplantation therapy and in future this study helps in finding how this sporadic Parkinson disease occurs in parkinsonism.


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