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 Shipment tracking for "fat parcels" in the body
14.10.2019 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht Antibody-based eye drops show promise for treating dry eye disease
14.10.2019 | University of Illinois at Chicago

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: Novel Material for Shipbuilding

A new research project at the TH Mittelhessen focusses on the development of a novel light weight design concept for leisure boats and yachts. Professor Stephan Marzi from the THM Institute of Mechanics and Materials collaborates with Krake Catamarane, which is a shipyard located in Apolda, Thuringia.

The project is set up in an international cooperation with Professor Anders Biel from Karlstad University in Sweden and the Swedish company Lamera from...

Im Focus: Controlling superconducting regions within an exotic metal

Superconductivity has fascinated scientists for many years since it offers the potential to revolutionize current technologies. Materials only become superconductors - meaning that electrons can travel in them with no resistance - at very low temperatures. These days, this unique zero resistance superconductivity is commonly found in a number of technologies, such as magnetic resonance imaging (MRI).

Future technologies, however, will harness the total synchrony of electronic behavior in superconductors - a property called the phase. There is currently a...

Im Focus: How Do the Strongest Magnets in the Universe Form?

How do some neutron stars become the strongest magnets in the Universe? A German-British team of astrophysicists has found a possible answer to the question of how these so-called magnetars form. Researchers from Heidelberg, Garching, and Oxford used large computer simulations to demonstrate how the merger of two stars creates strong magnetic fields. If such stars explode in supernovae, magnetars could result.

How Do the Strongest Magnets in the Universe Form?

Im Focus: Liquifying a rocky exoplanet

A hot, molten Earth would be around 5% larger than its solid counterpart. This is the result of a study led by researchers at the University of Bern. The difference between molten and solid rocky planets is important for the search of Earth-like worlds beyond our Solar System and the understanding of Earth itself.

Rocky exoplanets that are around Earth-size are comparatively small, which makes them incredibly difficult to detect and characterise using telescopes. What...

Im Focus: Axion particle spotted in solid-state crystal

Scientists at the Max Planck Institute for Chemical Physics of Solids in Dresden, Princeton University, the University of Illinois at Urbana-Champaign, and the University of the Chinese Academy of Sciences have spotted a famously elusive particle: The axion – first predicted 42 years ago as an elementary particle in extensions of the standard model of particle physics.

The team found signatures of axion particles composed of Weyl-type electrons (Weyl fermions) in the correlated Weyl semimetal (TaSe₄)₂I. At room temperature,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

International Symposium on Functional Materials for Electrolysis, Fuel Cells and Metal-Air Batteries

02.10.2019 | Event News

NEXUS 2020: Relationships Between Architecture and Mathematics

02.10.2019 | Event News

Optical Technologies: International Symposium „Future Optics“ in Hannover

19.09.2019 | Event News

 
Latest News

How to control friction in topological insulators

14.10.2019 | Physics and Astronomy

The shelf life of pyrite

14.10.2019 | Earth Sciences

Shipment tracking for "fat parcels" in the body

14.10.2019 | Health and Medicine

VideoLinks
Science & Research
Overview of more VideoLinks >>>