(Press-News.org) This news release is available in German.
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 Bad Nauheim's Max Planck Institute for Heart and Lung Research and the University of Lübeck 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 Nina Wettschureck's research groups at the Max Planck Institute for Heart and Lung Research in Bad Nauheim and Markus Schwaninger from the Institute of Experimental and Clinical Pharmacology and Toxicology at the University of Lübeck 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 Bad Nauheim and Lübeck hope this will lead to the development of novel therapeutic agents for MS with an improved profile in terms of efficacy and adverse effects.
INFORMATION:
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, 2 April 2014 (doi:10.1172/JCI72151)
Mode of action of new multiple sclerosis drug discovered
Dimethyl fumarate inhibits inflammatory cell infiltration of the central nervous system through blockade of a specific receptor
2014-04-02
ELSE PRESS RELEASES FROM THIS DATE:
Well-rested flies
2014-04-02
This news release is available in German. Elderly flies do not sleep well – they frequently wake up during the night and wander around restlessly. The same is true of humans. For researchers at the Max Planck Institute for Biology of Ageing in Cologne, the sleeplessness experienced by the fruit fly Drosophila is therefore a model case for human sleeping behaviour. The scientists have now discovered molecules in the flies' cells that affect how the animals sleep in old age: if insulin/IGF signalling is active, the quality of the animals' sleep is reduced and they wake ...
Penn Medicine points to new ways to prevent relapse in cocaine-addicted patients
2014-04-02
(PHILADELPHIA) – Relapse is the most painful and expensive feature of drug addiction—even after addicted individuals have been drug-free for months or years, the likelihood of sliding back into the habit remains high. The National Institute on Drug Abuse estimates that 40 to 60 percent of addicted individuals will relapse, and in some studies the rates are as high as 80 percent at six months after treatment. Though some relapse triggers can be consciously avoided, such as people, places and things related to drug use, other subconscious triggers related to the brain's reward ...
The mammography dilemma
2014-04-01
A comprehensive review of 50 year's worth of international studies assessing the benefits and harms of mammography screening suggests that the benefits of the screening are often overestimated, while harms are underestimated. And, since the relative benefits and harms of screening are related to a complex array of clinical factors and personal preferences, physicians and patients need more guidance on how best to individualize their approach to breast cancer screening.
The results of the review by researchers at Harvard Medical School's Department of Health Care Policy ...
Overuse of blood transfusions increases infection risk
2014-04-01
ANN ARBOR, Mich. — Blood transfusions are one of the most common procedures patients receive in the hospital but the more red blood cells they receive, the greater their risk of infection, says a new study led by the University of Michigan Heath System and VA Ann Arbor Healthcare System.
Researchers analyzed 21 randomized controlled trials for the study that appears in today's Journal of the American Medical Association (JAMA).
Elderly patients undergoing hip or knee surgeries were most susceptible, with a 30 percent lower risk of infection when fewer transfusions ...
Medication does not help prevent ED following radiation therapy for prostate cancer
2014-04-01
Among men undergoing radiation therapy for prostate cancer, daily use of the erectile dysfunction drug tadalafil, compared with placebo, did not prevent loss of erectile function, according to a study in the April 2 issue of JAMA.
Erectile dysfunction (ED) is a common condition resulting from many causes, including prostate cancer treatment. An estimated 40 percent of men report ED after radiation therapy, and half of all men use erectile aids following this therapy. Tadalafil is used to treat erectile dysfunction after prostate cancer treatment, but its role as a preventive ...
Outcomes of administering blood transfusions to patients with lower levels of hemoglobin
2014-04-01
Restricting red blood cell (RBC) transfusions among hospitalized patients to those with hemoglobin (the iron-containing protein in RBCs) measures below a certain level is associated with a lower risk of health care-associated infections, according to a study in the April 2 issue of JAMA.
Efforts to prevent health care-associated infection are among the priorities for the U.S. Department of Health and Human Services. The estimated annual direct medical costs of health care-associated infections to U.S. hospitals ranges from $28 billion to $45 billion, with about 1 in ...
The potential conflict of interest for leaders of AMCs serving on pharmaceutical boards
2014-04-01
About 40 percent of pharmaceutical company boards of directors examined had at least one member who held a leadership position at an academic medical center, with annual compensation for these positions averaging approximately $300,000, according to a study in the April 2 issue of JAMA.
"Financial relationships between the pharmaceutical industry and physicians have come under increased scrutiny. Less attention has been paid to relationships between industry and the leadership of academic medical centers (AMCs), who wield considerable influence over research, clinical, ...
Experts question routine mammograms in elderly
2014-04-01
Doctors should focus on life expectancy when deciding whether to order mammograms for their oldest female patients, since the harms of screening likely outweigh the benefits unless women are expected to live at least another decade, according to a review of the scientific literature by experts at UCSF and Harvard medical schools.
National guidelines recommend that doctors make individualized screening decisions for women 75 and older. But the analysis, published online Tuesday in JAMA (March 31, 2014), concluded that since this age group was not included in mammography ...
Night owls, unlike early birds, tend to be unmarried risk-takers
2014-04-01
Women who are night owls share the same high propensity for risk-taking as men, according to a recent study by a University of Chicago professor.
The research suggests that sleep patterns are linked with important character traits and behavior, said study author Dario Maestripieri, professor in Comparative Human Development. Night owls—people who tend to stay up late and wake up late in the morning—are different in many important ways from early risers, he found.
"Night owls, both males and females, are more likely to be single or in short-term romantic relationships ...
Like hand-washing, blood transfusions linked to infections
2014-04-01
Blood transfusions are among the most common treatments for hospitalized patients nationwide, but doing them less often reduces infection rates by nearly 20 percent, according to a study in the Journal of the American Medical Association co-authored by Neil Blumberg, M.D., professor at the University of Rochester School of Medicine and Dentistry.
As director of transfusion medicine and the blood bank at UR Medicine, Blumberg for more than 25 years has been investigating how to make blood transfusions safer. The JAMA study is the first to show conclusively, through a study ...
LAST 30 PRESS RELEASES:
Firms that read more perform better
Tightly tied waist cord of saree underskirt may pose cancer risk, warn doctors
10% of children in high-burden tuberculosis settings may develop the disease by age 10
Health experts push for the elimination of a ‘remarkably harmful toxin’
University of Tennessee, Lockheed Martin expand Master Research Agreement
Testing thousands of RNA enzymes helps find first ‘twister ribozyme’ in mammals
Groundbreaking study provides new evidence of when Earth was slushy
International survey of more than 1600 biomedical researchers on the perceived causes of irreproducibility of research results
Integrating data from different experimental approaches into one model is challenging – this study presents a community-based, full-scale in silico model of the rat hippocampal CA1 region that integra
SwRI awarded grant to characterize Las Moras Springs watershed
Water overuse in MATOPIBA could mean failure to meet up to 40% of local demand for crop irrigation
An extra year of education does not protect against brain aging
Researchers from Uppsala and Magdeburg obtain an ERC Synergy Grant to advance cancer immunotherapy
Deaf male mosquitoes don’t mate
Recognizing traumatic brain injury as a chronic condition fosters better care over the survivor’s lifetime
SwRI’s Dr. James Walker receives Distinguished Scientist Award from Hypervelocity Impact Society
A mother’s health problems pose a risk to her children
Ensuring a bright future for diamond electronics and sensors
The American Pediatric Society selects Dr. Maria Trent as the Recipient of the 2025 David G. Nichols Health Equity Award
The first 3D view of the formation and evolution of globular clusters
Towards a hydrogen-powered future: highly sensitive hydrogen detection system
Scanning synaptic receptors: A game-changer for understanding psychiatric disorders
High-quality nanomechanical resonators with built-in piezoelectricity
ERC Synergy Grants for 57 teams tackling major scientific challenges
Nordic research team receives €13 million to explore medieval book culture
The origin of writing in Mesopotamia is tied to designs engraved on ancient cylinder seals
Explaining science through dance
Pioneering neuroendocrinologist's century of discovery launches major scientific tribute series
Gendered bilingualism in post-colonial Korea
Structural safety monitoring of buildings with color variations
[Press-News.org] Mode of action of new multiple sclerosis drug discoveredDimethyl fumarate inhibits inflammatory cell infiltration of the central nervous system through blockade of a specific receptor