Administration Of Dimethyl Fumarate Research Articles

A thermosensitive chitosan hydrogel: An attempt for the nasal delivery of dimethyl fumarate

Dimethyl fumarate (DMF) is a drug that is orally administered for the treatment of relapsing-remitting multiple sclerosis. However, DMF causes gastrointestinal side effects and flushing in 43 % of patients, which significantly contributes to treatment discontinuation. To reduce side effects and increase patient compliance, the aim of this study was to develop a thermosensitive chitosan/glycerophosphate hydrogel for the nasal administration of DMF. A binary system of DMF with hydroxypropyl-β-cyclodextrin (HP-β-CD) was made and included in the hydrogel precursor solution. The precursor solution (drug content, DMF stability, thermogelling properties, viscosity), and the resulting thermosensitive hydrogel (mucoadhesion, in vitro DMF permeation) were characterized. HP-β-CD was able to interact with DMF and improve its water solubility. The leader thermosensitive nasal solution, G1 solution, was loaded with approximately 92 % DMF, which remained stable for 21 days. The G1 solution formed a hydrogel in approximately 2–1 min; it had a pH of 6.8 ± 0.06 and caused no significant change in the osmolality of the simulated nasal medium. The G1 hydrogel showed good mucoadhesive properties and released DMF that permeated in vitro in a controlled manner. As a result, G1 is a potential new approach to exploit the intranasal administration of DMF for treating multiple sclerosis.

Dimethyl fumarate alleviates allergic asthma by strengthening the Nrf2 signaling pathway in regulatory T cells.

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.

Frequency of Dimethyl Fumarate-Induced Lymphopenia among Omani Patients with Multiple Sclerosis.

Dimethyl fumarate (DMF) is known to cause lymphopenia when used to treat patients with multiple sclerosis (MS). However, research on DMF therapy in the Arab world, especially in Oman, is scarce. This study aimed to analyse the prevalence of lymphopenia among Omani patients with MS and their reasons for discontinuing DMF therapy. In this retrospective study, the medical records of Omani patients with MS who were treated using DMF at two tertiary hospitals in Muscat, Oman, from February 2017 to February 2023 were reviewed. Their demographic, clinical and laboratory data were retrieved and analysed. Absolute lymphocyte count values at baseline and at the last follow-up, as well as the reasons for discontinuing DMF therapy, were collected. Descriptive and inferential statistical techniques were used for data analysis. Binary-logistic regression analysis was used to identify the risk factors for DMF-induced lymphopenia. A total of 64 Omani patients with MS were included in this study. The majority of the study participants (n = 40; 63%) were female. All included patients started DMF therapy at the mean age of 33 ± 7.7 years. After administration of DMF, 14 (21.9%) patients developed grades 1-3 of lymphopenia. The DMF therapy was discontinued for 23 (36.0%) patients, mainly in response to adverse events or confirmed pregnancy. Female gender was the only significant predictor of DMF-induced lymphopenia (P = 0.037). Most Omani patients with MS had mild lymphopenia (grades 1-2). Early adverse events and pregnancy were the main reasons provided for discontinuing DMF therapy.

Dimethyl fumarate improves cognitive impairment and neuroinflammation in mice with Alzheimer's disease.

Neuroinflammation substantially contributes to the pathology of Alzheimer's disease (AD), the most common form of dementia. Studies have reported that nuclear factor erythroid 2-related factor 2 (Nrf2) attenuates neuroinflammation in the mouse models of neurodegenerative diseases, however, the detailed mechanism remains unclear. The effects of dimethyl fumarate (DMF), a clinically used drug to activate the Nrf2 pathway, on neuroinflammation were analyzed in primary astrocytes and AppNL-G-F (App-KI) mice. The cognitive function and behavior of DMF-administrated App-KI mice were evaluated. For the gene expression analysis, microglia and astrocytes were directly isolated from the mouse cerebral cortex by magnetic-activated cell sorting, followed by quantitative PCR. DMF treatment activated some Nrf2 target genes and inhibited the expression of proinflammatory markers in primary astrocytes. Moreover, chronic oral administration of DMF attenuated neuroinflammation, particularly in astrocytes, and reversed cognitive dysfunction presumably by activating the Nrf2-dependent pathway in App-KI mice. Furthermore, DMF administration inhibited the expression of STAT3/C3 and C3 receptor in astrocytes and microglia isolated from App-KI mice, respectively, suggesting that the astrocyte-microglia crosstalk is involved in neuroinflammation in mice with AD. The activation of astrocytic Nrf2 signaling confers neuroprotection in mice with AD by controlling neuroinflammation, particularly by regulating astrocytic C3-STAT3 signaling. Furthermore, our study has implications for the repositioning of DMF as a drug for AD treatment.

Repurposing dimethyl fumarate as an antiepileptogenic and disease-modifying treatment for drug-resistant epilepsy

BackgroundEpilepsy affects over 65 million people worldwide and significantly burdens patients, caregivers, and society. Drug-resistant epilepsy occurs in approximately 30% of patients and growing evidence indicates that oxidative stress contributes to the development of such epilepsies. Activation of the Nrf2 pathway, which is involved in cellular defense, offers a potential strategy for reducing oxidative stress and epilepsy treatment. Dimethyl fumarate (DMF), an Nrf2 activator, exhibits antioxidant and anti-inflammatory effects and is used to treat multiple sclerosis.MethodsThe expression of Nrf2 and its related genes in vehicle or DMF treated rats were determined via RT-PCR and Western blot analysis. Neuronal cell death was evaluated by immunohistochemical staining. The effects of DMF in preventing the onset of epilepsy and modifying the disease were investigated in the kainic acid-induced status epilepticus model of temporal lobe epilepsy in rats.The open field, elevated plus maze and T-Maze spontaneous alteration tests were used for behavioral assessments.ResultsWe demonstrate that administration of DMF following status epilepticus increased Nrf2 activity, attenuated status epilepticus-induced neuronal cell death, and decreased seizure frequency and the total number of seizures compared to vehicle-treated animals. Moreover, DMF treatment reversed epilepsy-induced behavioral deficits in the treated rats.Moreover, DMF treatment even when initiated well after the diagnosis of epilepsy, reduced symptomatic seizures long after the drug was eliminated from the body.ConclusionsTaken together, these findings suggest that DMF, through the activation of Nrf2, has the potential to serve as a therapeutic target for preventing epileptogenesis and modifying epilepsy.

Dimethyl Fumarate Attenuates Lymphocyte Infiltration and Reduces Infarct Size in Experimental Stroke.

Ischemic stroke is associated with exacerbated tissue damage caused by the activation of immune cells and the initiation of other inflammatory processes. Dimethyl fumarate (DMF) is known to modulate the immune response, activate antioxidative pathways, and improve the blood-brain barrier (BBB) after stroke. However, the specific impact of DMF on immune cells after cerebral ischemia remains unclear. In our study, male mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 min and received oral DMF (15 mg/kg) or a vehicle immediately after tMCAO, followed by twice-daily administrations for 7 days. Infarct volume was assessed on T2-weighted magnetic resonance images on days 1 and 7 after tMCAO. Brain-infiltrating immune cells (lymphocytes, monocytes) and microglia were quantified using fluorescence-activated cell sorting. DMF treatment significantly reduced infarct volumes and brain edema. On day 1 after tMCAO, DMF-treated mice showed reduced lymphocyte infiltration compared to controls, which was not observed on day 7. Monocyte and microglial cell counts did not differ between groups on either day. In the acute phase of stroke, DMF administration attenuated lymphocyte infiltration, probably due to its stabilizing effect on the BBB. This highlights the potential of DMF as a therapeutic candidate for mitigating immune cell-driven damage in stroke.

The Inhibition of Neuropathic Pain Incited by Nerve Injury and Accompanying Mood Disorders by New Heme Oxygenase-1 Inducers: Mechanisms Implicated.

Neuropathic pain is a type of pain that persists for a long time and becomes pathological. Additionally, the anxiodepressive disorders derived from neuropathic pain are difficult to palliate with the current treatments and need to be resolved. Then, using male mice with neuropathic pain provoked by chronic constriction of the sciatic nerve (CCI), we analyzed and compared the analgesic actions produced by three new heme oxygenase 1 (HO-1) inducers, 1m, 1b, and 1a, with those performed by dimethyl fumarate (DMF). Their impact on the anxiety- and depressive-like comportments and the expression of the inflammasome NLRP3, Nrf2, and some antioxidant enzymes in the dorsal root ganglia (DRG) and amygdala (AMG) were also investigated. Results revealed that the administration of 1m, 1b, and DMF given orally for four days inhibited the allodynia and hyperalgesia caused by CCI, while 1a merely reduced the mechanical allodynia. However, in the first two days of treatment, the antiallodynic effects produced by 1m were higher than those of 1a and DMF, and its antihyperalgesic actions were greater than those produced by 1b, 1a, and DMF, revealing that 1m was the most effective compound. At four days of treatment, all drugs exerted anxiolytic and antidepressant effects, decreased the NLRP3 levels, and increased/normalized the Nrf2, HO-1, and superoxide dismutase 1 levels in DRG and AMG. Data indicated that the dual modulation of the antioxidant and inflammatory pathways produced by these compounds, especially 1m, is a new promising therapeutic approach for neuropathic pain and related emotional illnesses.

Ultrastructural Evidence of Synapse Preservation and Axonal Regeneration Following Spinal Root Repair with Fibrin Biopolymer and Therapy with Dimethyl Fumarate.

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.

Dimethyl Fumarate Protects Rats against Testicular Ischemia–Reperfusion Injury

Ischemia–reperfusion injury (IRI) after testicular torsion is linked to significant damage in testicular tissue. Dimethyl fumarate (DMF) activates the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, thereby inducing antioxidant and anti-inflammatory effects. We analyzed the usefulness of DMF in preventing IRI following testicular torsion/detorsion in Sprague-Dawley rats ( n = 32 ). The animals were classified into control (sham), DMF (200 mg/kg/day), IRI, and IRI+DMF (IRI with 200 mg/kg/day DMF) groups. Testicular IRI was induced by detorsion after 1.5 h of torsion. DMF was administered via oral gavage daily from 1 h before testicular detorsion until day 7, when orchiectomy was performed. The testis-to-body weight ratio was calculated. Histopathological evaluation was performed using the Johnsen and Cosentino scores for seminiferous tubules. Malondialdehyde, superoxide dismutase, and total glutathione levels were determined in testicular tissues. Moreover, Nrf2, heme oxygenase 1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), nuclear factor kappa B (NF-κB), and inflammatory cytokine (interleukin 1b (IL1b), IL6, and tumor necrosis factor alpha (TNF-α)) levels were determined through quantitative polymerase chain reaction. Nuclear Nrf2 and cytoplasmic HO-1 and NQO1 protein levels were also evaluated. DMF significantly improved the testis-to-body weight ratio and reduced histopathological damage in the testes. Moreover, it significantly improved the concentration of malondialdehyde, superoxide dismutase, and total glutathione. Furthermore, it inhibited NF-κB and inflammatory cytokine mRNA expression compared with the findings obtained in untreated rats with IRI (all p < 0.05 ). Nrf2, HO-1, and NQO1 expressions (mRNA and protein) were markedly elevated following DMF treatment in rats with IRI (all p < 0.05 ). DMF administration activated the Nrf2 signaling pathway and induced antioxidant and anti-inflammatory effects, thereby improving IRI-induced testicular damage. Thus, DMF may prevent IRI following testicular torsion.

Effects of 4-octyl itaconate and dimethyl fumarate on growth performance, intestinal microbiota, intestinal and hepatopancreas health of juvenile gibel carp (Carassius gibelio)

Aquaculture needs effective antibiotic alternatives to control outbreaks of intestinal inflammation, as well as liver inflammation and metabolic disorder caused by enteritis. Specific metabolites have been shown to have immunomodulatory effects by the field of immunometabolism. As derivatives of the Krebs cycle metabolites, the itaconate and fumarate, 4-octyl itaconate (OI) and dimethyl fumarate (DMF) have recently attracted a lot of interest as anti-inflammatory medications. To evaluate the effects of oral administration of OI and DMF on fish growth and health, an 8-week feeding experiment followed by induction of enteritis with 2,4,6-trinitrobenzene sulfonic acid (TNBS) was carried out in gibel carp. The results showed that dietary 0.1%DMF improved the growth performance, and 0.1%OI up-regulated the abundance of beneficial intestinal microbiota. Both of OI and DMF alleviated intestinal inflammation by increasing intestinal anti-inflammatory cytokines, and relieved enteritis-induced hepatopancreas injury by inhibiting glycolysis both in vivo and in vitro. The 0.1%DMF also enhanced the tight junction and altered the microbiota to maintain the intestinal barrier. Collectively, dietary supplementation with 0.1% OI and DMF might be novel strategies to prevent enteritis and intestinal inflammation-induced hepatopancreas damage in gibel carp.

Dimethyl fumarate inhibits necroptosis and alleviates systemic inflammatory response syndrome by blocking the RIPK1-RIPK3-MLKL axis

Necroptosis has been implicated in various inflammatory diseases including tumor-necrosis factor-α (TNF-α)-induced systemic inflammatory response syndrome (SIRS). Dimethyl fumarate (DMF), a first-line drug for treating relapsing-remitting multiple sclerosis (RRMS), has been shown to be effective against various inflammatory diseases. However, it is still unclear whether DMF can inhibit necroptosis and confer protection against SIRS. In this study, we found that DMF significantly inhibited necroptotic cell death in macrophages induced by different necroptotic stimulations. Both the autophosphorylation of receptor-interacting serine/threonine kinase 1 (RIPK1) and RIPK3 and the downstream phosphorylation and oligomerization of MLKL were robustly suppressed by DMF. Accompanying the suppression of necroptotic signaling, DMF blocked the mitochondrial reverse electron transport (RET) induced by necroptotic stimulation, which was associated with its electrophilic property. Several well-known anti-RET reagents also markedly inhibited the activation of the RIPK1-RIPK3-MLKL axis accompanied by decreased necrotic cell death, indicating a critical role of RET in necroptotic signaling. DMF and other anti-RET reagents suppressed the ubiquitination of RIPK1 and RIPK3, and they attenuated the formation of necrosome. Moreover, oral administration of DMF significantly alleviated the severity of TNF-α-induced SIRS in mice. Consistent with this, DMF mitigated TNF-α-induced cecal, uterine, and lung damage accompanied by diminished RIPK3-MLKL signaling. Collectively, DMF represents a new necroptosis inhibitor that suppresses the RIPK1-RIPK3-MLKL axis through blocking mitochondrial RET. Our study highlights DMF’s potential therapeutic applications for treating SIRS-associated diseases.

Course of therapy in patients with active relapsing-remitting multiple sclerosis despite first-line treatment.

Treatment of patients with relapsing-remitting multiple sclerosis (RRMS) in Poland begins with first-line therapy; however, the treatment often fails. The aim of this study was to investigate the course of first-line treatment in patients who, despite experiencing an active course of the disease, did not receive more efficacious treatment due to the existing criteria in the drug program. The study included 139 patients from 45 treatment centers. Medical data concerning the course of treatment were collected with the use of specific forms. The most frequently used drugs were β-interferons, and treatment was initiated with these drugs in most cases; however, administration of dimethyl fumarate was also common. The median treatment duration was 30.9 months, with the longest treatment duration observed for β-interferons. The most common reason for therapy switching or termination was treatment failure. First-line therapy in the studied population was based mainly on β-interferons and dimethyl fumarate. For most medications, the discontinuation of therapy or drug switching were very common and the main reason was total or partial treatment failure. These observations suggest the need for earlier implementation of more effective treatment, based on drugs with high efficacy, in the study population.

The Challenge of Dimethyl Fumarate Repurposing in Eye Pathologies

Dimethyl fumarate (DMF) is a small molecule currently approved and used in the treatment of psoriasis and multiple sclerosis due to its immuno-modulatory, anti-inflammatory, and antioxidant properties. As an Nrf2 activator through Keap1 protein inhibition, DMF unveils a potential therapeutical use that is much broader than expected so far. In this comprehensive review we discuss the state-of-art and future perspectives regarding the potential repositioning of this molecule in the panorama of eye pathologies, including Age-related Macular Degeneration (AMD). The DMF's mechanism of action, an extensive analysis of the in vitro and in vivo evidence of its beneficial effects, together with a search of the current clinical trials, are here reported. Altogether, this evidence gives an overview of the new potential applications of this molecule in the context of ophthalmological diseases characterized by inflammation and oxidative stress, with a special focus on AMD, for which our gene-disease (KEAP1-AMD) database search, followed by a protein-protein interaction analysis, further supports the rationale of DMF use. The necessity to find a topical route of DMF administration to the eye is also discussed. In conclusion, the challenge of DMF repurposing in eye pathologies is feasible and worth scientific attention and well-focused research efforts.

Dimethyl Fumarate (DMF) Alleviated Post-Operative (PO) Pain through the N-Methyl-d-Aspartate (NMDA) Receptors.

The management of post-operative (PO) pain has generally been shown to be inadequate; therefore, acquiring a novel understanding of PO pain mechanisms would increase the therapeutic options available. There is accumulating evidence to implicate N-methyl-d-aspartate (NMDA) receptors in the induction and maintenance of central sensitization during pain states by reinforcing glutamate sensory transmission. It is known that DMF protects from oxidative glutamate toxicity. Therefore, NMDA receptor antagonists have been implicated in peri-operative pain management. Recent advances demonstrated that dimethyl fumarate (DMF), a non-opioid and orally bioavailable drug, is able to resolve neuroinflammation through mechanisms that drive nociceptive hypersensitivity. Therefore, in this study, we evaluated the role of DMF on pain and neuroinflammation in a mouse model of PO pain. An incision of the hind paw was performed, and DMF at two different doses (30 and 100 mg/kg) was administered by oral gavage for five consecutive days. Mechanical allodynia, thermal hyperalgesia and locomotor dysfunction were evaluated daily for five days after surgery. Mice were sacrificed at day 7 following PO pain induction, and hind paw and lumbar spinal cord samples were collected for histological and molecular studies. DMF administration significantly reduced hyperalgesia and allodynia, alleviating motor disfunction. Treatment with DMF significantly reduced histological damage, counteracted mast cell activation and reduced the nuclear factor kappa-light-chain-enhancer of the activated B cell (NF-κB) inflammatory pathway, in addition to downregulating tumor necrosis factor-α (TNF-α), Interleukin-1β (Il-1β) and Il-4 expression. Interestingly, DMF treatment lowered the activation of NMDA receptor subtypes (NR2B and NR1) and the NMDA-receptor-interacting PDZ proteins, including PSD93 and PSD95. Furthermore, DMF interfered with calcium ion release, modulating nociception. Thus, DMF administration modulated PO pain, managing NMDA signaling pathways. The results suggest that DMF positively modulated persistent nociception related to PO pain, through predominantly NMDA-receptor-operated calcium channels.

Repurposing dimethyl fumarate for gastric ulcer and ulcerative colitis: Evidence of local efficacy without systemic side effect

Ulcerative colitis and gastric ulcer are ulcers of gastrointestinal track, especially associated with elevated oxidative stress and inflammation. Dimethyl fumarate (DMF) is used for the treatment of multiple sclerosis and psoriasis and is considered useful in a variety of conditions associated with inflammation. We have investigated the effect of oral DMF (1, 10, 25, 50, 100, 200 mg/kg) in ethanol-induced gastric ulcers in rats. The effect of oral (15, 30, and 60 mg/kg) and intracecal (15 mg/kg) DMF was also investigated in dextran sulfate sodium (DSS)-induced colitis in mice. Treatment of DMF by oral route prevented the development of ethanol-induced gastric ulcers by decreasing oxidative stress in a dose-related manner. Oral and intracecal administration of DMF attenuated body weight loss, increase in disease activity score, colon length shortening, colon weight loss, inflammation and fibrosis, and decreased myeloperoxidase activity. Oral and intracecal DMF prevented a decrease in hemoglobin and suppressed oxidative stress, and also decreased MCP-1, IL-1ß, and IL-6 levels in the inflamed colon. Unlike oral DMF, intracecal DMF treatment did not reduce spleen weight. The effect of intracecal DMF was similar to the highest tested dose of oral DMF (60 mg/kg). These results demonstrated that intracecal DMF suppresses inflammation and oxidative stress in ethanol and DSS-induced colitis without alteration of spleen weight. This suggests that the localized DMF administration could be beneficial approach of treating gastrointestinal ulcers.

ИНДУКЦИЯ ТРАНСКРИПЦИОННОГО ФАКТОРА NRF2 УГНЕТАЕТ ПРОДУКЦИЮ АКТИВНЫХ ФОРМ КИСЛОРОДА И АЗОТА В ПЕЧЕНИ КРЫС ПРИ МОДЕЛИРОВАНИИ МЕТАБОЛИЧЕСКОГО СИНДРОМА В УСЛОВИЯХ КРУГЛОСУТОЧНОГО ОСВЕЩЕНИЯ

Aim: To evaluate the effect of dimethyl fumarate, an Nrf2 inducer, on the production of reactive oxygen and nitrogen species in the liver of rats when modeling metabolic syndrome under round-the-clock lighting. Material and methods. Dimethyl fumarate in a 10% dimethyl sulfoxide solution at a dose of 15 mg/kg was administered intraperitoneally to white rats while modeling the metabolic syndrome (a 20% aqueous fructose solution for drinking and a diet enriched with carbohydrates and lipids). The rate of generation of the superoxide anion radical (•О ), the activity of total NO synthase (NOS) as well as its constitutive and inducible isoforms (cNOS, iNOS), the content of peroxynitrites of alkali and alkaline earth metals were determined in the liver homogenate of rats. Results. The administration of dimethyl fumarate under the experimental conditions significantly restrained the •О production in the liver tissues by microsomes and NOS – by 48.9%, by mitochondria – by 47.3%, by leukocyte NADPH oxidase – by 45.6%; it also reduced NOS activity (total and iNOS) by 33.1% and 35.9%, respectively, and the concentration of peroxynitrites by 39.7% as compared with the values of the control group which received only the solvent (10% dimethyl sulfoxide solution). The cNOS activity and coupling index exceeded the control group result 2.95 and 5.5 times, respectively. Conclusion. The administration of dimethyl fumarate, an Nrf2 inductor, to rats during the simulation of the metabolic syndrome by round-the-clock lighting is an effective means of limiting the production of reactive oxygen and nitrogen species in the liver tissues.

INDUCTION OF NRF2 TRANSCTIPTION FACTOR INHIBITS FORMATION OF RACTIVE OXYGEN AND NITROGEN SPECIES IN LIVER OF RATS UNDER MODELLING METABOLIC SYNDROME BY EXPOSURE TO ROUND-THE-CLOCK LIGHTING

Aim: To evaluate the effect of dimethyl fumarate, an Nrf2 inducer, on the production of reactive oxygen and nitrogen species in the liver of rats under the conditions of modeling the metabolic syndrome with roundthe-clock illumination. Dimethyl fumarate in 10% dimethyl sulfoxide solution in a dose of 15 mg/kg was administered intraperitoneally to white rats over the modeled metabolic syndrome (a 20% aqueous fructose solution for drinking and a diet enriched with carbohydrates and lipids). In the liver homogenate of rats, the rate of generation of the superoxide anion radical (•О 2 ), the activity of total NO synthase (NOS), its constitutive and inducible isoforms (cNOS, iNOS), and the content of peroxynitrites of alkali and alkaline earth metals were determined. The administration of dimethyl fumarate under the experimental conditions significantly restrained the •О 2 production by microsomes and NOS in the liver tissues by 48.9%, by mitochondria by 47.3%, by leukocyte NADPH oxidase by 45.6%; it also reduced NOS activity (total and iNOS) by 33.1% and 35.9%, respectively, and the concentration of peroxynitrites by 39.7% compared with the values of the control group that received only the solvent (10% dimethyl sulfoxide solution). The cNOS activity and coupling index exceeded the control result in 2.95 and 5.5 times, respectively. The introduction of the Nrf2 inductor, dimethyl fumarate, during the simulation of the metabolic syndrome by round-the-clock lighting to rats is an effective means of limiting the production of reactive oxygen and nitrogen species in the liver tissues.

Inhibition of Gasdermin D-Mediated Pyroptosis Attenuates the Severity of Seizures and Astroglial Damage in Kainic Acid-Induced Epileptic Mice.

Objective: Our study aimed to explore whether gasdermin D (GSDMD)-mediated pyroptosis is involved in the mechanism of kainic acid-induced seizures. Methods: C57BL/6 mice were randomly divided into sham and epilepsy groups. The epilepsy group was intrahippocampally injected with kainic acid to induce status epilepticus (SE), and the sham group was injected with an equal volume of saline. Dimethyl fumarate (DMF) was used as the GSDMD N-terminal fragments (GSDMD-N) inhibitor and suspended in 0.5% sodium carboxymethyl cellulose (CMC) for orally administration. The epilepsy group was divided into SE + CMC and SE + DMF groups. In the SE + DMF group, DMF was orally administered for 1 week before SE induction and was continued until the end of the experiment. An equal volume of CMC was administered to the sham and SE + CMC groups. Recurrent spontaneous seizures (SRSs) were monitored for 21 days after SE. Western blot analysis and immunofluorescent staining was performed. Results: The expression of GSDMD increased at 7–21 days post-SE, and GSDMD-N expression was significantly elevated 7 days after SE in both ipsilateral and contralateral hippocampus. GSDMD-positive cells were co-labeled with astrocytes, but not neurons or microglia. Astroglial damage occurs following status epilepticus (SE). Damaged astrocytes showed typical clasmatodendrosis in the CA1 region containing strong GSDMD expression at 7–21 days post-SE, accompanied by activated microglia. In the SE + DMF group, the expression of GSDMD-N was significantly inhibited compared to that in the SE + CMC group. After administration of DMF, SRSs at 7–21 days after SE were significantly decreased, and the number of clasmatodendritic astrocytes, microglia, and the expression of inflammatory factors such as IL-1β and IL-18 were significantly attenuated. Conclusion: GSDMD-mediated pyroptosis is involved in the mechanism of kainic acid-induced seizures. Our study provides a new potential therapeutic target for seizure control.

Diagnostic Value of JC Polyomavirus Viruria, Viremia, Serostatus and microRNA Expression in Multiple Sclerosis Patients Undergoing Immunosuppressive Treatment.

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.

Primary diffuse large B‐cell lymphoma of the central nervous system with rapidly progressing lesions after dimethyl fumarate treatment, showing relapsing and remitting symptoms: A case report

AbstractBackgroundWe present a case of B‐cell type primary central nervous system lymphoma that rapidly progressed after dimethyl fumarate (DMF) administration.Case presentationAn asymptomatic white matter lesion of the left frontal lobe was observed in a 56‐year‐old Japanese man on magnetic resonance imaging during a medical checkup. For the subsequent 5 months, the sporadic white matter lesion showed no change and no contrast effect. He suddenly presented with right upper limb paralysis on day 74. After improvement, he had a recurrence of right upper limb paralysis and diminished vision loss. Based on the 2017 revised McDonald criteria, two attacks, objective clinical evidence of one lesion and cerebrospinal fluid oligoclonal band assay positivity, he was diagnosed with relapsing–remitting multiple sclerosis and administered DMF. Three months after DMF administration, he developed new brain lesions that progressed rapidly; additional immunotherapy was ineffective. He was pathologically diagnosed with B‐cell type primary central nervous system lymphoma using brain biopsy on day 301.ConclusionPatients with rapidly progressing white matter lesions after DMF administration should be suspected for B‐cell type primary central nervous system lymphoma and pathologically diagnosed using brain biopsy.