Identification of key neuronal mechanisms triggered by dimethyl fumarate in SH-SY5Y human neuroblastoma cells through a metabolomic approach.

Dimethyl fumarate (DMF) is an old drug used for psoriasis treatment that has recently been repurposed to treat relapse-remitting multiple sclerosis, mostly due to its neuro- and immunomodulatory actions. However, mining of a pharmacovigilance database recently ranked DMF as the second pharmaceutical most associated with cognitive adverse events. To our best knowledge, the signaling mechanisms underlying its therapeutic and neurotoxic outcomes remain mostly undisclosed. This work thus represents the first-hand assessment of DMF-induced metabolic changes in undifferentiated SH-SY5Y human neuroblastoma cells, through an untargeted metabolomic approach using gas chromatography-mass spectrometry (GC-MS). The endometabolome was analyzed following 24 h and 96 h of exposure to two pharmacologically relevant DMF concentrations (0.1 and 10 µM). None of these conditions significantly reduced metabolic activity (MTT reduction assay). Our data showed that 24 h-exposure to DMF at both concentrations tested mainly affected metabolic pathways involved in mitochondrial activity (e.g., citric acid cycle, de novo triacylglycerol biosynthesis), and the synthesis of catecholamines and serotonin by changing the levels of their respective precursors, namely phenylalanine (0.68-fold decrease for 10 µM DMF vs vehicle), and tryptophan (1.36-fold increase for 0.1 µM DMF vs vehicle). Interestingly, taurine, whose levels can be modulated via Nrf2 signaling (DMF's primary target), emerged as a key mediator of DMF's neuronal action, displaying a 3.86-fold increase and 0.27-fold decrease for 10 µM DMF at 24 h and 96 h, respectively. A 96 h-exposure to DMF seemed to mainly trigger pathways associated with glucose production (e.g., gluconeogenesis, glucose-alanine cycle, malate-aspartate shuttle), possibly related to the metabolism of DMF into monomethyl fumarate and its further conversion into glucose via activation of the citric acid cycle. Overall, our data contribute to improving the understanding of the events associated with neuronal exposure to DMF.

Dimethyl fumarate induces cardiac developmental toxicity in zebrafish via down-regulation of oxidative stress.

Dimethyl fumarate (DMF) is an immunosuppressant commonly used to treat multiple sclerosis and other autoimmune diseases. Despite known side effects such as lymphopenia, the effect of DMF on cardiac development remains unclear. To assess this, we used zebrafish to evaluate the cardiac developmental toxicity of DMF. Our study showed that DMF reduced the survival rate of zebrafish embryos, with those exposed to 1, 1.3, and 1.6 mg/L exhibiting heart rate reduction, shortened body length, delayed yolk sac absorption, pericardial edema, increased distance from sinus venous to bulbus arteriosus, and separation of cardiomyocytes and endocardial cells at 72 hpf. Heart development-related genes showed disorder, apoptosis-related genes were up-regulated, and the oxidative stress response was down-regulated. Treatment with cysteamine ameliorated the heart development defects. Our study demonstrates that DMF induces cardiac developmental toxicity in zebrafish, possibly by down-regulating oxidative stress responses. This study provides a certain research basis for further study of DMF-induced cardiac developmental toxicity, and provides some experimental evidence for future clinical application and study of DMF.

The first reported case of drug-induced hemolytic anemia caused by dimethyl fumarate in a patient with multiple sclerosis.

BACKGROUND: Drug-induced hemolytic anemia is a rare and potentially fatal complication of drug treatment. Specific laboratory tests are crucial to confirm the diagnosis. CASE REPORT: A 38-year-old woman on treatment with dimethyl fumarate for multiple sclerosis presented with a 7-day history of weakness and fatigue. Laboratory tests revealed profound hemolytic anemia with hemoglobin levels of 4.7 g/dL (reference, 12.5-16.0), decreased haptoglobin, increased reticulocyte count, and increased indirect bilirubin. A first direct antiglobulin test was negative. The patient was started on prednisone 1 mg/kg/day, and dimethyl fumarate was withdrawn. A blood sample was drawn on Day 7 and sent to a reference laboratory. A direct antiglobulin test performed 7 days later was positive. Furthermore, an indirect antiglobulin test was positive only in the presence of the drug. RESULTS: The patient did not receive a blood transfusion, recovered clinically during the following days, and was discharged on Day 7. On Day 36, the patient's RBCs had normalized. She was changed to another disease-modifying treatment for her multiple sclerosis, and at 10-month follow-up she remained stable without any notable adverse effects. CONCLUSION: This case describes the first report of a dimethyl fumarate-induced hemolytic anemia. Laboratory results should always be interpreted within the clinical context. Specific laboratory expertise is often needed, given the complexity of the field.