Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study may explain how a well-known epilepsy and pain drug works

14.10.2009
A Duke University Medical Center researcher who spent years looking for the signals that prompt the brain to form new connections between neurons has found one that may explain precisely how a well-known drug for epilepsy and pain actually works.

The finding may also point to new therapies for brain injury and neuropathic pain.

The role of neurons in the brain and nervous system is well known, but astrocytes, a different type of brain cell, still are largely a mystery. Duke scientist Cagla Eroglu, Ph.D. has discovered a receptor that receives messages from astrocytes so that the brain can form excitatory synapses, the cell-to-cell connections that can become overactive in conditions such as epilepsy. Working with a team of scientists from other institutions, Eroglu found this receptor is also blocked by the anti-convulsant drug gabapentin (Neurontin™).

The study will appear in the Oct. 16 issue of Cell.

"The study links astrocytes and their role in synapse formation to diseases, so if the normal process goes wrong, this may explain why people get epilepsy, why epilepsy gets worse, or why they have neuropathic pain," said Eroglu, assistant professor in the Duke Department of Cell Biology. "It's a fine balance, because synapse formation has to occur during development for neurons to transmit brain signals, but if this happens in an uncontrolled manner in the adult brain, it could lead to these debilitating conditions."

Eroglu spent years looking for this neuronal receptor, which prompts synapse formation. "The key clue came when we chopped thrombospondin, a protein that comes from astrocytes and triggers establishment of synapses, into small fragments and put it onto neurons. We found that a specific portion of thrombospondin, the EGF-like domain, was equally effective as the whole protein. This gave me the clue that was necessary to identify its neuronal receptor. However it took me a while to do so."

On advice she heard from a lecture by another scientist, Nobel laureate Linda Buck – "Spend more time thinking about your experiments and your results before designing new experiments" – Eroglu took a short break from her bench-work, went home, and reasoned her way through several possibilities, finally settling on the idea that a receptor for the molecule gabapentin might be a key to regulating the formation of synapses. Excited, she returned to the lab and verified the interaction between proteins. "When I discovered that gabapentin completely blocked synapse formation between isolated neurons, I could not sleep for days until I replicated the results."

The research also points to the need for further research on gabapentin's actions, Eroglu said. The drug gabapentin strongly blocks the receptor, reducing synapse formation in rodents.

"The question is whether gabapentin might be linked with or interfere with cognitive ability, especially in the developing fetus of a woman taking the drug to control epilepsy," Ergolu said. "But of course this needs to be balanced with the mother's need to prevent her from having seizures."

"Likewise, while it is rare that a young child is given gabapentin for seizures, I think scientists need to study whether this possibly could be linked with side effects of this drug in children such as hyperactivity, irritability and maybe even cognitive problems," she said.

Gabapentin may also be a boon for certain conditions that haven't yet been studied, she said. For example, in soldiers who have severe head wounds, many go on to develop epilepsy in the months after their injuries. "Maybe their injuries trigger the development of excess excitatory synaptic connections, and blocking or modulating this preemptively with gabapentin could help to prevent in this situation."

She said that understanding how the receptor works could also help patients who have neuropathic pain because of advanced diabetes or an injury.

"Neuropathic pain is not perceived by patients in the same way as other types of pain." Eroglu said. "Regular anti-analgesic drugs do not successfully ease this type of pain. Based on our findings it is possible that aberrant new synaptic connections that occur after injury contribute to neuropathic pain, and gabapentin might work by breaking this cycle of synapse formation."

The research was supported by grants from the National Institute of Drug Addiction, the National Heart, Lung and Blood Institute, the National Institutes of Health, the Human Frontiers Scientific Program long-term fellowships, and the Helen Hay Whitney postdoctoral fellowship.

The senior author of the work is Dr. Eroglu's mentor Ben A. Barres, of the Department of Neurobiology at Stanford University School of Medicine in Stanford, Calif.,. Other authors include Nicola J. Allen, Michael W. Susman, Chan Young Park, Chandrani Chakraborty, Sara B. Mulinyawe, Andrew D. Huberman, Eric M. Green, and Ricardo Dolmetsch, of the Stanford Department of Neurobiology; Jack Lawler, of the Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School in Boston; Nancy A. O'Rourke, Engin Özkan, K. Christopher Garcia, and Stephen J. Smith, all of the Department of Molecular and Cellular Physiology at Stanford (Özkan and Garcia are also in the Stanford Department of Structural Biology and Howard Hughes Medical Institute); Z. David Luo, of the Department of Anesthesiology & Perioperative Care, University of California, Irvine; Arnon Rosenthal, of MazoRx Inc., Redwood City, Calif.; and Deane F. Mosher and Douglas S. Annis of the Department of Medicine, Medical Sciences Center, University of Wisconsin, Madison.

Mary Jane Gore | EurekAlert!
Further information:
http://www.duke.edu

More articles from Life Sciences:

nachricht A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

nachricht On the way to developing a new active ingredient against chronic infections
21.08.2017 | Deutsches Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

Nagoya physicists resolve long-standing mystery of structure-less transition

21.08.2017 | Materials Sciences

Chronic stress induces fatal organ dysfunctions via a new neural circuit

21.08.2017 | Health and Medicine

Scientists from the MSU studied new liquid-crystalline photochrom

21.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>