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Experimental Neurology Jan 2024Cuprizone (CPZ)-induced alterations in axonal myelination are associated with a period of neuronal hyperexcitability and increased activity of...
Cuprizone (CPZ)-induced alterations in axonal myelination are associated with a period of neuronal hyperexcitability and increased activity of hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels in the thalamocortical (TC) system. Substances used for the treatment of multiple sclerosis (MS) have been shown to normalize neuronal excitability in CPZ-treated mice. Therefore, we aimed to examine the effects of diroximel fumarate (DRF) and the sphingosine 1-phospate receptor (S1PR) modulator siponimod on action potential firing and the inward current (I) carried by HCN ion channels in naive conditions and during different stages of de- and remyelination. Here, DRF application reduced I current density in ex vivo patch clamp recordings from TC neurons of the ventrobasal thalamic complex (VB), thereby counteracting the increase of I during early remyelination. Siponimod reduced I in VB neurons under control conditions but had no effect in neurons of the auditory cortex (AU). Furthermore, siponimod increased and decreased AP firing properties of neurons in VB and AU, respectively. Computational modeling revealed that both DRF and siponimod influenced thalamic bursting during early remyelination by delaying the onset and decreasing the interburst frequency. Thus, substances used in MS treatment normalize excitability in the TC system by influencing AP firing and I.
Topics: Mice; Animals; Neuroprotective Agents; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Remyelination; Models, Theoretical
PubMed: 37852467
DOI: 10.1016/j.expneurol.2023.114572 -
Multiple Sclerosis Journal -... 2023Multiple sclerosis (MS) comparative effectiveness research needs to go beyond average treatment effects (ATEs) and post-host subgroup analyses.
Overall and patient-specific comparative effectiveness of dimethyl fumarate versus teriflunomide: A novel approach to precision medicine applied to the German NeuroTrans Data Multiple Sclerosis Registry.
BACKGROUND
Multiple sclerosis (MS) comparative effectiveness research needs to go beyond average treatment effects (ATEs) and post-host subgroup analyses.
OBJECTIVE
This retrospective study assessed overall and patient-specific effects of dimethyl fumarate (DMF) versus teriflunomide (TERI) in patients with relapsing-remitting MS.
METHODS
A novel precision medicine (PM) scoring approach leverages advanced machine learning methods and adjusts for imbalances in baseline characteristics between patients receiving different treatments. Using the German NeuroTransData registry, we implemented and internally validated different scoring systems to distinguish patient-specific effects of DMF relative to TERI based on annualized relapse rates, time to first relapse, and time to confirmed disease progression.
RESULTS
Among 2791 patients, there was superior ATE of DMF versus TERI for the two relapse-related endpoints ( = 0.037 and 0.018). Low to moderate signals of treatment effect heterogeneity were detected according to individualized scores. A MS patient subgroup was identified for whom DMF was more effective than TERI ( = 0.013): older (45 versus 38 years), longer MS duration (110 versus 50 months), not newly diagnosed (74% versus 40%), and no prior glatiramer acetate usage (35% versus 5%).
CONCLUSION
The implemented approach can disentangle prognostic differences from treatment effect heterogeneity and provide unbiased patient-specific profiling of comparative effectiveness based on real-world data.
PubMed: 37641619
DOI: 10.1177/20552173231194353 -
Multiple Sclerosis (Houndmills,... Dec 2023Diroximel fumarate (DRF) is approved for adults with relapsing-remitting multiple sclerosis (RRMS) in Europe and for relapsing forms of MS in the United States. DRF and...
BACKGROUND
Diroximel fumarate (DRF) is approved for adults with relapsing-remitting multiple sclerosis (RRMS) in Europe and for relapsing forms of MS in the United States. DRF and dimethyl fumarate (DMF) yield bioequivalent exposure of the active metabolite monomethyl fumarate. Prior studies indicated fewer gastrointestinal (GI)-related adverse events (AEs) with DRF compared with DMF.
OBJECTIVE
To report final outcomes from EVOLVE-MS-1.
METHODS
EVOLVE-MS-1 was an open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in patients with RRMS. The primary endpoint was safety and tolerability; efficacy endpoints were exploratory.
RESULTS
Overall, 75.7% (800/1057) of patients completed the study; median exposure was 1.8 (range: 0.0-2.0) years. AEs occurred in 938 (88.7%) patients, mostly of mild (28.9%) or moderate (50.3%) severity. DRF was discontinued due to AEs in 85 (8.0%) patients, with < 2% discontinuing due to GI or flushing/flushing-related AEs. At Week 96, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (72.7%; < 0.0001); adjusted annualized relapse rate was 0.13 (95% confidence interval: 0.11-0.15).
CONCLUSION
DRF was generally well tolerated over 2 years, with few discontinuations due to AEs; radiological measures indicated decreased disease activity from baseline. These outcomes support DRF as a treatment option in patients with RRMS.
Topics: Adult; Humans; Multiple Sclerosis, Relapsing-Remitting; Immunosuppressive Agents; Multiple Sclerosis; Dimethyl Fumarate; Recurrence
PubMed: 37905526
DOI: 10.1177/13524585231205708 -
Frontiers in Immunology 2024Allergic asthma is a widely prevalent inflammatory condition affecting people across the globe. T cells and their secretory cytokines are central to the pathogenesis of...
Allergic asthma is a widely prevalent inflammatory condition affecting people across the globe. T cells and their secretory cytokines are central to the pathogenesis of allergic asthma. Here, we have evaluated the anti-inflammatory impact of dimethyl fumarate (DMF) in allergic asthma with more focus on determining its effect on T cell responses in allergic asthma. By utilizing the ovalbumin (OVA)-induced allergic asthma model, we observed that DMF administration reduced the allergic asthma symptoms and IgE levels in the OVA-induced mice model. Histopathological analysis showed that DMF treatment in an OVA-induced animal model eased the inflammation in the nasal and bronchial tissues, with a particular decrease in the infiltration of immune cells. Additionally, RT-qPCR analysis exhibited that treatment of DMF in an OVA-induced model reduced the expression of inflammatory cytokine (IL4, IL13, and IL17) while augmenting anti-inflammatory IL10 and Foxp3 (forkhead box protein 3). Mechanistically, we found that DMF increased the expression of Foxp3 by exacerbating the expression of nuclear factor E2-related factor 2 (Nrf2), and the in-vitro activation of Foxp3+ Tregs leads to an escalated expression of Nrf2. Notably, CD4-specific Nrf2 deletion intensified the allergic asthma symptoms and reduced the in-vitro iTreg differentiation. Meanwhile, DMF failed to exert protective effects on OVA-induced allergic asthma in CD4-specific Nrf2 knock-out mice. Overall, our study illustrates that DMF enhances Nrf2 signaling in T cells to assist the differentiation of Tregs, which could improve the anti-inflammatory immune response in allergic asthma.
Topics: Animals; Female; Mice; Asthma; Cytokines; Dimethyl Fumarate; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Ovalbumin; Signal Transduction; T-Lymphocytes, Regulatory
PubMed: 38711519
DOI: 10.3389/fimmu.2024.1375340 -
Polymers Jul 2023Spinal cord injury causes critical loss in motor and sensory function. Ventral root avulsion is an experimental model in which there is the tearing of the ventral...
Spinal cord injury causes critical loss in motor and sensory function. Ventral root avulsion is an experimental model in which there is the tearing of the ventral (motor) roots from the surface of the spinal cord, resulting in several morphological changes, including motoneuron degeneration and local spinal cord circuitry rearrangements. Therefore, our goal was to test the combination of surgical repair of lesioned roots with a fibrin biopolymer and the pharmacological treatment with dimethyl fumarate, an immunomodulatory drug. Thus, adult female Lewis rats were subjected to unilateral ventral root avulsion of L4-L6 roots followed by repair with fibrin biopolymer and daily treatment with dimethyl fumarate (15 mg/Kg; gavage) for 4 weeks, the survival time post-surgery being 12 weeks; n = 5/group/technique. Treatments were evaluated by immunofluorescence and transmission electron microscopy, morphometry of the sciatic nerve, and motor function recovery. Our results indicate that the combination between fibrin biopolymer and dimethyl fumarate is neuroprotective since most of the synapses apposed to alfa motoneurons were preserved in clusters. Also, nerve sprouting occurred, and the restoration of the 'g' ratio and large axon diameter was achieved with the combined treatment. Such parameters were combined with up to 50% of gait recovery, observed by the walking track test. Altogether, our results indicate that combining root restoration with fibrin biopolymer and dimethyl fumarate administration can enhance motoneuron survival and regeneration after proximal lesions.
PubMed: 37571065
DOI: 10.3390/polym15153171 -
Multiple Sclerosis Journal -... 2024The use of non-specific immunosuppressants (NSIS) to treat multiple sclerosis (MS) remains prevalent in certain geographies despite safety concerns, likely due to...
BACKGROUND
The use of non-specific immunosuppressants (NSIS) to treat multiple sclerosis (MS) remains prevalent in certain geographies despite safety concerns, likely due to resource limitations.
OBJECTIVE
To use MSBase registry data to compare real-world outcomes in adults with relapsing-remitting MS (RRMS) treated with dimethyl fumarate (DMF) or NSIS (azathioprine, cyclosporine, cyclophosphamide, methotrexate, mitoxantrone or mycophenolate mofetil) between January 1, 2014 and April 1, 2022.
METHODS
Treatment outcomes were compared using inverse probability of treatment weighting (IPTW) Cox regression. Outcomes were annualized relapse rates (ARRs), time to discontinuation, time to first relapse (TTFR) and time to 24-week confirmed disability progression (CDP) or 24-week confirmed disability improvement (CDI; in patients with baseline Expanded Disability Status Scale [EDSS] score ≥2).
RESULTS
After IPTW, ARR was similar for DMF (0.13) and NSIS (0.16; = 0.29). There was no difference in TTFR between cohorts (hazard ratio [HR]: 0.98; = 0.84). The DMF cohort experienced longer times to discontinuation (HR: 0.75; = 0.001) and CDP (HR: 0.53; = 0.001), and shorter time to CDI (HR: 1.99; < 0.008), versus the NSIS cohort.
CONCLUSION
This analysis supports the use of DMF to treat patients with relapsing forms of MS, and may have implications for MS practices in countries where NSIS are commonly used to treat RRMS.
PubMed: 38800132
DOI: 10.1177/20552173241247182 -
Micromachines Oct 2023Intracortical microelectrode arrays (MEAs) can be used in a range of applications, from basic neuroscience research to providing an intimate interface with the brain as...
Intracortical microelectrode arrays (MEAs) can be used in a range of applications, from basic neuroscience research to providing an intimate interface with the brain as part of a brain-computer interface (BCI) system aimed at restoring function for people living with neurological disorders or injuries. Unfortunately, MEAs tend to fail prematurely, leading to a loss in functionality for many applications. An important contributing factor in MEA failure is oxidative stress resulting from chronically inflammatory-activated microglia and macrophages releasing reactive oxygen species (ROS) around the implant site. Antioxidants offer a means for mitigating oxidative stress and improving tissue health and MEA performance. Here, we investigate using the clinically available antioxidant dimethyl fumarate (DMF) to reduce the neuroinflammatory response and improve MEA performance in a rat MEA model. Daily treatment of DMF for 16 weeks resulted in a significant improvement in the recording capabilities of MEA devices during the sub-chronic (Weeks 5-11) phase (42% active electrode yield vs. 35% for control). However, these sub-chronic improvements were lost in the chronic implantation phase, as a more exacerbated neuroinflammatory response occurs in DMF-treated animals by 16 weeks post-implantation. Yet, neuroinflammation was indiscriminate between treatment and control groups during the sub-chronic phase. Although worse for chronic use, a temporary improvement (<12 weeks) in MEA performance is meaningful. Providing short-term improvement to MEA devices using DMF can allow for improved use for limited-duration studies. Further efforts should be taken to explore the mechanism behind a worsened neuroinflammatory response at the 16-week time point for DMF-treated animals and assess its usefulness for specific applications.
PubMed: 37893339
DOI: 10.3390/mi14101902 -
Journal of Alzheimer's Disease Reports 2024Parkinson's disease (PD) is a progressive neurodegenerative disorder linked to the loss of dopaminergic neurons in the substantia nigra. Mitophagy, mitochondrial...
BACKGROUND
Parkinson's disease (PD) is a progressive neurodegenerative disorder linked to the loss of dopaminergic neurons in the substantia nigra. Mitophagy, mitochondrial selective autophagy, is critical in maintaining mitochondrial and subsequently neuronal homeostasis. Its impairment is strongly implicated in PD and is associated with accelerated neurodegeneration.
OBJECTIVE
To study the positive effect of dimethyl fumarate (DMF) on mitophagy via the NRF2/BNIP3/PINK1 axis activation in PD disease models.
METHODS
The neuroprotective effect of DMF was explored in and PD models. MTT assay was performed to determine the DMF dose followed by JC-1 assay to study its mitoprotective effect in MPP exposed SHSY5Y cells. For the study, C57BL/6 mice were divided into six groups: Normal Control (NC), Disease Control (DC), Sham (Saline i.c.v.), Low Dose (MPP iodide+DMF 15 mg/kg), Mid Dose (MPP iodide+DMF 30 mg/kg), and High Dose (MPP iodide+DMF 60 mg/kg). The neuroprotective effect of DMF was assessed by performing rotarod, open field test, and pole test, and biochemical parameter analysis using immunofluorescence, western blot, and RT-PCR.
RESULTS
DMF treatment significantly alleviated the loss of TH positive dopaminergic neurons and enhanced mitophagy by increasing PINK1, Parkin, BNIP3, and LC3 levels in the MPP iodide-induced PD mice model. DMF treatment groups showed good locomotor activity and rearing time when compared to the DC group.
CONCLUSIONS
DMF confers neuroprotection by activating the BNIP3/PINK1/Parkin pathway, enhancing the autophagosome formation via LC3, and improving mitophagy in PD models, and could be a potential therapeutic option in PD.
PubMed: 38405353
DOI: 10.3233/ADR-230128 -
Multiple Sclerosis and Related Disorders Dec 2023Dimethyl fumarate (DMF) is a common treatment for multiple sclerosis (MS), but its mechanisms of action are not fully understood. Targeted proteomics offers insights...
BACKGROUND
Dimethyl fumarate (DMF) is a common treatment for multiple sclerosis (MS), but its mechanisms of action are not fully understood. Targeted proteomics offers insights into effects of DMF and biomarkers for treatment responses.
OBJECTIVES
To assess influence of DMF on inflammation- and neuro-associated proteins in plasma and cerebrospinal fluid (CSF) in MS and to reveal biomarkers for predicting treatment responses.
METHODS
Using the high-sensitivity and high-specificity method of proximity extension assay (PEA), we measured 182 inflammation- and neuro-associated proteins in paired plasma (n = 28) and CSF (n = 12) samples before and after one year of DMF treatment. Disease activity was evaluated through clinical examination and MRI. Statistical tests, network analysis, and regression models were used.
RESULTS
Several proteins including T-helper 1 (Th1)-associated proteins (CXCL10, CXCL11, granzyme A, IL-12p70, lymphotoxin-alpha) were consistently decreased in CSF, while IL-7 was increased after one year of treatment. The changes in plasma protein levels did not follow the same pattern as in CSF. Logistic regression models identified potential biomarker candidates (including plexins and neurotrophins) for prediction of treatment response.
CONCLUSIONS
DMF treatment induced prominent changes in CSF proteins, consistently reducing Th1-associated pro-inflammatory proteins. Neurodegeneration-related CSF proteins were able to predict treatment response. Protein biomarkers hold promise for personalized medicine.
Topics: Humans; Dimethyl Fumarate; Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis; Biomarkers; Inflammation; Immunosuppressive Agents
PubMed: 37952502
DOI: 10.1016/j.msard.2023.105126 -
Farmacia Hospitalaria : Organo Oficial... 2023Multiple sclerosis is a chronic demyelinating disease of the central nervous system and long-term disabling. Different disease-modifying treatments are available. These... (Observational Study)
Observational Study
UNLABELLED
Multiple sclerosis is a chronic demyelinating disease of the central nervous system and long-term disabling. Different disease-modifying treatments are available. These patients, despite being generally young, have high comorbidity and risk of polymedication due to their complex symptomatology and disability.
OBJECTIVE PRIMARY
To determine the type of disease-modifying treatment in patients seen in Spanish hospital pharmacy departments.
SECONDARY OBJECTIVES
to determine concomitant treatments, determine the prevalence of polypharmacy, identify the prevalence of interactions and analyze pharmacotherapeutic complexity.
METHOD
Observational, cross-sectional, multicentre study. All patients with a diagnosis of multiple sclerosis and active disease-modifying treatment who were seen in outpatient clinics or day hospitals during the second week of February 2021 were included. Modifying treatment, comorbidities and concomitant treatments were collected to determine multimorbidity pattern, polypharmacy, pharmacotherapeutic complexity (Medication Regimen Complexity Index) and drug-drug interactions.
RESULTS
1407 patients from 57 centres in 15 autonomous communities were included. The most frequent form of disease presentation was the relapsing remitting form (89.3%). The most prescribed disease-modifying treatment was dimethyl fumarate (19.1%), followed by teriflunomide (14.0%). Of the parenteral disease-modifying treatments, the two most prescribed were glatiramer acetate and natalizumab with 11.1% and 10.8%. 24.7% of the patients had 1 comorbidity and 39.8% had at least 2 comorbidities. 13.3% belonged to at least one of the defined patterns of multimorbidity and 16.5% belonged to 2 or more patterns. The concomitant treatments prescribed were psychotropic drugs (35.5%); antiepileptic drugs (13.9%) and antihypertensive drugs and drugs for cardiovascular pathologies (12.4%). The presence of polypharmacy was 32.7% and extreme polypharmacy 8.1%. The prevalence of interactions was 14.8%. Median pharmacotherapeutic complexity was 8.0 (IQR: 3.3-15.0).
CONCLUSIONS
We have described the disease-modifying treatment of patients with multiple sclerosis seen in Spanish pharmacy services and characterized concomitant treatments, the prevalence of polypharmacy, interactions, and their complexity.
Topics: Humans; Cross-Sectional Studies; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Spain
PubMed: 37394376
DOI: 10.1016/j.farma.2023.05.005