Dimethyl fumarate inhibits inflammatory cell infiltration of the central nervous system through blockade of a specific receptor
Just a few short weeks ago, dimethyl fumarate was approved in Europe as a basic therapy for multiple sclerosis. Although its efficacy has been established in clinical studies, its underlying mode of action was still unknown, but scientists from the University of Lübeck and Bad Nauheim's Max Planck Institute for Heart and Lung Research have now managed to decode it. They hope that this knowledge will help them develop more effective therapeutic agents.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that affects nerve fibres in the brain and spinal cord by damaging their protective myelin sheath. The cause of multiple sclerosis is unknown and the disease has no cure to date, but a range of treatments are available that can have a positive influence on its course.
Basic MS therapy to date generally involved beta interferons or the active substance glatiramer acetate. In both cases, the drug was administered by injections under the skin or into the muscle, which is a cause of considerable discomfort and annoyance to many patients.
By contrast, the active substance dimethyl fumarate (DMF), approved in Europe for MS treatment only a few weeks ago, brings a ray of hope to those affected since it can be taken in tablet form. The efficacy of DMF in clinical studies was at least comparable to that of the more established substances, while its side effects were moderate by comparison.
DMF has been in use for some twenty years as a successful treatment for psoriasis, but little was known about how it influences immune function. Scientists from Markus Schwaninger's research group at the Institute of Experimental and Clinical Pharmacology and Toxicology at the University of Lübeck and Nina Wettschureck from the Max Planck Institute for Heart and Lung Research in Bad Nauheim have explained significant aspects of how DMF works.
In their study, the researchers used a standardised mouse model of multiple sclerosis, whereby drugs trigger an autoimmune response, leading to characteristic reactions within days. In this way, they induced neurological deficits comparable to those observed in MS. "In the group we treated with DMF, the problems with motor function were considerably lower than in the control group," says Wettschureck.
The researchers uncovered the mode of action by treating genetically modified mice in the same way. "In mice that don't have the gene for the receptor called HCA2, DMF was unable to prevent the signs of paralysis," explains Schwaninger. This means that the HCA2 receptor must mediate the therapeutic effect of DMF.
HCA2 is a so-called G protein-coupled membrane receptor which occurs, among other places, on a certain type of white blood cells, neutrophil granulocytes. "In animals treated with DMF, the number of granulocytes that infiltrated the nervous system was much lower than in untreated animals. In animals without the HCA2 receptor, the number of invasive granulocytes remained equally high despite treatment with DMF," stated Wettschureck.
In other experiments involving cell cultures, the scientists found that activation of the HCA2 receptor is responsible for infiltration of the central nervous system by white blood cells. DMF blocks this infiltration, thereby preventing the associated inflammation. "Our study has enabled us to provide the first evidence that DMF's protective effect is due to the HCA2 receptor. However, we are not ruling out the possibility that there may also be other mechanisms," observed Wettschureck.
As a next step, the scientists want to find out why patients respond differently to treatment with DMF. "It may be that individual genetic differences influence the efficacy of DMF," states Schwaninger. Consequently, future therapies could be specifically designed for individual patients, an approach known as personalised medicine.
The researchers also intend to search for additional substances that bind to the HCA2 receptor. "Ideally, we would find a substance of comparable or even greater efficacy, but with fewer side effects," says Wettschureck. The colleagues in Lübeck and Bad Nauheim hope this will lead to the development of novel therapeutic agents for MS with an improved profile in terms of efficacy and adverse effects.
Hui Chen, Julian C. Assmann, Antje Krenz, Mahbubur Rahman, Myriam Grimm, Christian M. Karsten, Jörg Köhl, Stefan Offermanns, Nina Wettschureck, Markus Schwaninger: Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate’s protective effect in EAE. The Journal of Clinical Investigation. doi:10.1172/JCI72151
Rüdiger Labahn | idw - Informationsdienst Wissenschaft
Hot cars can hit deadly temperatures in as little as one hour
24.05.2018 | Arizona State University
3D images of cancer cells in the body: Medical physicists from Halle present new method
16.05.2018 | Martin-Luther-Universität Halle-Wittenberg
The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.
Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
25.05.2018 | Event News
02.05.2018 | Event News
13.04.2018 | Event News
25.05.2018 | Event News
25.05.2018 | Machine Engineering
25.05.2018 | Life Sciences