Specific forms of epilepsy may manifest as early as in the first weeks of life. A new laboratory study shows that a preventive therapeutic strategy can be successful if it is applied within a time window critical to brain development. The study, which was conducted by a team of German and French scientists and headed by Prof. Dirk Isbrandt of the German Center for Neurodegenerative Diseases (DZNE) and the University of Cologne, has just been published in Nature Medicine.
Using the substance bumetanide in newborn mice, the scientists succeeded in attenuating the disease progression, allowing the animals to develop almost normally. These research results could pave the way for the development of new therapeutic strategies in humans.
This sequence of images shows individual neurons in the background (cell nuclei are blue colored). The traces in the foreground illustrate electrical activity of individual neurons. Kv7 potassium channel dysfunction results in hyperactivity of neurons manifesting in a rapid succession of action potential bursts. Image: DZNE/Stephan Marguet and Malte Stockebrand
Isbrandt and his colleagues conducted experiments in mice with a genetic defect similar to a natural human variant that can cause epilepsy as early as the neonatal period. This mutation results in dysfunctional ion channels in the membranes of nerve cells, thus perturbing the communication between cells.
Possible symptoms include jerking or twitching movements, but can also include more subtle behavioral impairments. Early disease symptoms can be mild, but long-term outcomes may be severe, and include pronounced cognitive impairment.
'This genetic defect has an impact on a specific ion channel in the cell membrane, the so-called Kv7 or M channel. The defect disturbs the ionic balance, which has a direct effect on the excitability of neurons’, explains Isbrandt, who is a researcher for the DZNE and who also holds a professorship for Experimental Neurophysiology at the University of Cologne.
'Epilepsy in newborns, for example, can be caused by hypoxia, hemorrhage, or infections. In the absence of birth injuries, Kv7-channel mutations, or other ion channel mutations, are often an underlying cause. There are hardly any efficacious therapies for these patients.’
Studies in mice
Isbrandt and his colleagues had previously discovered that the Kv7 channel is especially important for early brain development. Isbrandt says, ‘In newborn mice, the first two postnatal weeks are of critical importance, whereas in adult mice, the physiology of the brain has changed to the point where this channel plays a less prominent role.’
At this stage, that is, for the first two weeks of life, the scientists treated mice carrying a mutation of the Kv7 channel using the substance ‘bumetanide’, which has previously been shown to help neurons mantaining their ionic balance. Surprisingly, bumetanide turned out to be even more efficacious than expected, and the later disease symptoms of early Kv7 ion channel dysfunction were almost completely prevented.
The right timing
Treatment within the two-week neonatal period normalized the brain activity of mice and, to a large extent, also their behavior. No epileptic seizures occurred in the adult period, in spite of the continued presence of the genetic defect. ‘The two-week therapy almost completely prevented the consequences of Kv7 channel deficiency, because we treated the mice at a defined period critical to brain development’, summarizes Isbrandt.
Unlike mice treated with bumetanide within this time window, their littermates carrying the same genetic defect developed epilepsy. Both brain activity and structure were altered. In addition, the affected animals displayed hyperactivity and other behavioral abnormalities.
Potential therapeutic approach in humans
In adult patients, bumetanide is used for the treatment of kidney and heart diseases. There are also trials studying the treatment of epileptic seizures in newborns with bumetanide. However, these studies are aimed at the attenuation of acute symptoms, not at long-term disease prevention.
‘Our goal was to show whether prevention can in principle work. Our study demonstrates the right timing is of the essence’, says Isbrandt. ‘These results therefore underscore a strategic approach, which is to identify the period critical to a disease’s development during which treatment will have the maximum preventive power.’
‘In mice, the first two postnatal weeks approximately correspond to the last trimester of pregnancy in humans’, explains Isbrandt. ‘Thus, therapeutic treatment for related human conditions would presumably have to start in the womb, but currently this approach is far-fetched. A more immediate approach would be to treat premature babies known to be at high risk for the development of epilepsies, but it has yet to be determined whether such an intervention can be implemented.’
This research was supported by grants from the Federal Ministry of Education and Research (BMBF) as part of the research program „NGFN-Plus“, and by the German Research Foundation (DFG).
„Treatment during a vulnerable developmental period rescues a genetic epilepsy“, Stephan Lawrence Marguet, Vu Thao Quyen Le-Schulte, Andrea Merseburg, Axel Neu, Ronny Eichler, Igor Jakovcevski, Anton Ivanov , Ileana Livia Hanganu-Opatz, Christophe Bernard, Fabio Morellini, Dirk Isbrandt, Nature Medicine, DOI: 10.1038/nm.3987
Dr. Marcus Neitzert | idw - Informationsdienst Wissenschaft
A promising target for kidney fibrosis
21.04.2017 | Brigham and Women's Hospital
Stem cell transplants: activating signal paths may protect from graft-versus-host disease
20.04.2017 | Technische Universität München
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
25.04.2017 | Earth Sciences
25.04.2017 | Life Sciences
25.04.2017 | Earth Sciences