Gene therapy inhibits epilepsy in animals

For the first time, researchers have inhibited the development of epilepsy after a brain insult in animals. By using gene therapy to modify signaling pathways in the brain, neurology researchers found that they could significantly reduce the development of epileptic seizures in rats.

"We have shown that there is a window to intervene after a brain insult to reduce the risk that epilepsy will develop," said one of the lead researchers, Amy R. Brooks-Kayal, M.D., a pediatric neurologist at The Children's Hospital of Philadelphia and associate professor of Neurology and Pediatrics at the University of Pennsylvania School of Medicine. "This provides a 'proof of concept' that altering specific signaling pathways in nerve cells after a brain insult or injury could provide a scientific basis for treating patients to prevent epilepsy."

Dr. Brooks-Kayal and Shelley J. Russek, Ph.D., of Boston University School of Medicine were senior authors of the study in the Nov. 1 Journal of Neuroscience.

Working in a portion of the brain called the dentate gyrus, the researchers focused on one type of cell receptor, type A receptors, for the neurotransmitter gamma-aminobutyric acid (GABA). When GABA(A) receptors are activated, they inhibit the repetitive, excessive firing of brain cells that characterizes a seizure. Seizures are thought to occur, at least in part, because of an imbalance between two types of neurotransmitters: the glutamate system, which stimulates neurons to fire, and the GABA system, which inhibits that brain activity.

GABA's inhibitory role is considered particularly important in the dentate gyrus because the dentate gyrus acts as a gateway for brain activity into the hippocampus, an area that is critical to generating seizures in temporal lobe epilepsy, the most common type of epilepsy in children and adults.

GABA(A) receptors are made up of five subunits--proteins that play important roles in brain development and in controlling brain activity. Previous animal research by Dr. Brooks-Kayal's group had found that rats with epilepsy had lower levels of the alpha1 subunits of these receptors and higher levels of alpha4 subunits. Therefore, the researchers used gene delivery to alter the expression of the alpha1 subunit to see if this would have an effect on later seizure development.

To carry the gene that alters the expression of the protein, they used an adeno-associated virus vector, injected into the rats' brains. The researchers later injected the rats with pilocarpine, a drug that causes status epilepticus (SE), a convulsive seizure, shortly after injection.

They then evaluated the rats for later development of spontaneous seizures or epilepsy, which usually occurs after an initial SE injury. Rats that had received the gene therapy had elevated levels of alpha1 proteins and either did not develop spontaneous seizures, or took three times as long to experience a spontaneous seizure, compared to rats that did not receive the delivered gene.

In this short-term study, said Dr. Brooks-Kayal, it was impossible to tell whether the increased alpha1 subunit levels were only suppressing seizures or whether they would permanently prevent epilepsy from developing.

"In people, an initial episode of SE or an injury such as severe head trauma is known to raise the risk of later developing epilepsy, so this study suggests that strategies aimed at modifying signaling pathways in the brain after such an insult may help prevent epilepsy," said Dr. Brooks-Kayal. "The approach would likely be different than in this proof-of-concept animal study that involved injecting agents directly into the brain. This study, does, however, lay the foundation for a potential drug therapy that might act on the same signaling pathways, to prevent epilepsy after a brain insult such as an episode of SE."

Source: Children's Hospital of Philadelphia

Related stories:

Direct recording shows brain signal persists even in dreamless sleep
Neuroscientists at Washington University School of Medicine in St. Louis have taken one of the first direct looks at one of the human brain's most fundamental "foundations": a brain signal that never switches off and may support many cognitive functions.
Balancing the brain
Neuroscientists at Children's Hospital Boston have identified the first known "master switch" in brain cells to orchestrate the formation and maintenance of inhibitory synapses, essential for proper brain function. The factor, called Npas4, regulates more than 200 genes that act in various ways to calm down over-excited cells, restoring a balance that is thought to go askew in some neurologic disorders. The findings appear in the September 24 advance online edition of the journal Nature.
Deep brain stimulation offers hope to people with treatment-resistant illnesses
Every day during a four-year deep depression, Sean Miller thought of ending his life. Nothing relieved the emotional darkness - not therapy, not medication, not loving attention from family and friends.
How memories are made, and recalled
What makes a memory? Single cells in the brain, for one thing. For the first time, scientists at UCLA and the Weizmann Institute of Science in Israel have recorded individual brain cells in the act of calling up a memory, thus revealing where in the brain a specific memory is stored, and how it is able to recreate it.
Brain surgery is getting easier on patients
Dr. Edward Duckworth is part of a new generation of neurosurgeons who are making brain surgery a lot easier on patients. At Loyola University Hospital, Duckworth is using less-invasive techniques to remove tumors, to repair life-threatening aneurysms and to dramatically reduce seizures in epilepsy patients.
Epilepsy linked to higher risk of drowning
People with epilepsy appear to have a much higher risk of drowning compared to people without epilepsy, according to a study published in the August 19, 2008, issue of Neurology, the medical journal of the American Academy of Neurology. Previous studies have shown a higher risk most likely due to seizures but this study is one of the first to show exactly how high the risk may be.
When neurons fire up: Study sheds light on rhythms of the brain
In our brains, groups of neurons fire up simultaneously for just milliseconds at a time, in random rhythms, similar to twinkling lightning bugs in our backyards. New research from neuroscientists at Indiana University and the University of Montreal provides a model -- a rhyme and reason -- for this random synchronization.
First steps towards a new approach to epilepsy treatment
The most prestigious funding body in the world for epilepsy has financially backed Australian research into new approaches to treat the condition.

News discussion:

Medicine & Health news