Silk designed to release adenosine when implanted in the brain of lab rats may help stop the progression of epilepsy, a new study published in the Journal of Clinical Investigation says.
Epilepsies are a cluster of neurological disorders associated with recurring seizures which have a propensity for becoming more frequent and severe over time. Adenosine is known to decrease neuronal excitability and help stop seizures. Abnormally low levels of adenosine may be linked to epilepsy, earlier studies have suggested.
The researcher postulate that adenosine’s beneficial effects are because of epigenetic modifications, chemical reactions that change the way genes are turned on or off without altering the DNA code. Specifically, these changes happen when a molecule known as a methyl group blocks a portion of DNA, affecting which genes are accessible and can be turned on. If methyl groups have been taken away, or demethylated, genes are more likely to turn on.
Elevated Methylated DNA
Results reported in the paper gave evidence that changing adenosine levels affects DNA methylation in the brain. In particular, greater amounts of adenosine were associated with lower levels of DNA methylation.
Investigators also showeed that rats induced to develop epilepsy have higher levels of methylated DNA. Of particular note, epileptic rat brains that had received the adenosine-releasing silk implants exhibited DNA methylation levels close to brains of normal rats and this significantly lessened the worsening of the epilepsy over time.
“We know that there are mutations that are associated with epilepsy. However, there are few people such as Dr. Detlev Boison who are doing this type of work, focusing not just on genetic mutations but how the genes are regulated,” said Vicky Whittemore, Ph.D., program director at National Institute of Neurological Disorders and Stroke.
Mossy Fiber Sprouting
One mechanism involved in a specific type of epilepsy is an increase in mossy fiber sprouting, the formation of new excitatory circuits in the part of the brain where seizures commonly originate. At the end of the experiment, animals that had been treated with the adenosine-releasing silk implant showed less sprouting than animals that were not given the drug.
“Based on our findings that 10 days of adenosine delivery prevented the sprouting of mossy fibers for at least three months in rats, we predict that the benefits of our adenosine therapy may extend even longer. However, this assumption needs to be validated in long-term experiments that go beyond three months,” said senior author Dr. Detlev Boison.
“To avoid interference with the epilepsy-triggering mechanisms, we waited until all animals developed an early stage of epilepsy. In this model, the disease is life-long: seizures become more frequent and worsen with time. Therefore, we challenged ourselves to attempt treatment at a stage where epilepsy had already been established,” Dr. Boison explained.
Results show that the implants are safe to use in rats and imply that they may one day be used on humans.
“Adenosine-releasing silk is a biodegradable implant. The release of adenosine occurs for 10 days and then the silk will completely dissolve. This is an ideal set-up for a transient preventative treatment,” said Dr. Boison. “Clinical applications could be the prevention of epilepsy following head trauma or the prevention of seizures that often — in about 50 percent of patients — follow conventional epilepsy surgery. In this case, adenosine-releasing silk might be placed into the resection cavity in order to prevent future seizures.”
Since from 25 to 30 percent of people with epilepsy are candidates for any effective therapies, this research is important. “This research may help us to prevent epilepsy in people who suffer some event that places them at risk for the disorder, such as individuals who have experienced head trauma,” said Dr. Whittemore.
Rebecca L. Williams-Karnesky et al. “Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis.” Journal of Clinical Investigation, July 25, 2013. doi:10.1172/JCI65636
Image courtesy of Dr. Boison, from Legacy Research Institute and OHSU