Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mode of action of new multiple sclerosis drug discovered

02.04.2014

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.


Section of mouse spinal cord under a fluorescence microscope. DMF works on the immune cells (red), which are responsible for damaging the nerve fibres. Cell nuclei appear as blue. Uni Lübeck

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.


Original publication:

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
Further information:
http://www.uni-luebeck.de

Further reports about: DMF MS action animals granulocytes nervous protective receptor sclerosis therapeutic

More articles from Health and Medicine:

nachricht New concept: Can Resuscitation be delayed?
31.03.2015 | Europäische Akademie Bozen - European Academy Bozen/Bolzano

nachricht For drivers with telescopic lenses, driving experience and training affect road test results
30.03.2015 | Wolters Kluwer Health

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Lizard activity levels can help scientists predict environmental change

Research study provides new tools to assess warming temperatures

Spring is here and ectotherms, or animals dependent on external sources to raise their body temperature, are becoming more active. Recent studies have shown...

Im Focus: Hannover Messe 2015: Saving energy with smart façades

Glass-fronted office buildings are some of the biggest energy consumers, and regulating their temperature is a big job. Now a façade element developed by Fraunhofer researchers and designers for glass fronts is to reduce energy consumption by harnessing solar thermal energy. A demonstrator version will be on display at Hannover Messe.

In Germany, buildings account for almost 40 percent of all energy usage. Heating, cooling and ventilating homes, offices and public spaces is expensive – and...

Im Focus: Nonoxide ceramics open up new perspectives for the chemical and plant engineering

Outstanding chemical, thermal and tribological properties predestine silicon carbide for the production of ceramic components of high volume. A novel method now overcomes the procedural and technical limitations of conventional design methods for the production of components with large differences in wall thickness and demanding undercuts.

Extremely hard as diamond, shrinking-free manufacturing, resistance to chemicals, wear and temperatures up to 1300 °C: Silicon carbide (SiSiC) bundles all...

Im Focus: Experiment Provides the Best Look Yet at 'Warm Dense Matter' at Cores of Giant Planets

In an experiment at the Department of Energy's SLAC National Accelerator Laboratory, scientists precisely measured the temperature and structure of aluminum as...

Im Focus: Energy-autonomous and wireless monitoring protects marine gearboxes

The IPH presents a solution at HANNOVER MESSE 2015 to make ship traffic more reliable while decreasing the maintenance costs at the same time. In cooperation with project partners, the research institute from Hannover, Germany, has developed a sensor system which continuously monitors the condition of the marine gearbox, thus preventing breakdowns. Special feature: the monitoring system works wirelessly and energy-autonomously. The required electrical power is generated where it is needed – directly at the sensor.

As well as cars need to be certified regularly (in Germany by the TÜV – Technical Inspection Association), ships need to be inspected – if the powertrain stops...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

World Conference On Regenerative Medicine 2015: Registration And Abstract Submission Now Open

25.03.2015 | Event News

University presidents from all over the world meet in Hamburg

19.03.2015 | Event News

10. CeBiTec Symposium zum Big Data-Problem

17.03.2015 | Event News

 
Latest News

Measurement of components in 3D under water

01.04.2015 | HANNOVER MESSE

Better method for forecasting hurricane season

01.04.2015 | Earth Sciences

Sensor + Test 2015: Cost-effective production of magnetic sensors

01.04.2015 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>