Silk implants could stop epilepsy spread
Silk implants placed in the brain and designed to release a specific chemical, adenosine, may help stop the progression of epilepsy, according to a new study published in the Journal of Clinical Investigation.
The epilepsies are a group of neurological disorders associated with recurring seizures that tend to become more frequent and severe over time. Adenosine decreases neuronal excitability and helps stop seizures. Earlier studies have suggested abnormally low levels of adenosine may be linked to epilepsy.
Rebecca L. Williams-Karnesky and her colleagues from Legacy Research Institute and Oregon Health and Sciences University (OHSU) both in Portland and Tufts University in Boston, looked at long-term effects of an adenosine-releasing silk-implant therapy in rats and examined the role of adenosine in causing epigenetic changes that may be associated with the development of epilepsy.
The investigators argue that adenosine’s beneficial effects are due to epigenetic modifications (chemical reactions that change the way genes are turned on or off without altering the DNA code, the letters that make up our genetic background). 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 (demethylated), genes are more likely to turn on.
The results reported in the paper provided evidence that changing adenosine levels affects DNA methylation in the brain. Specifically, greater amounts of adenosine were associated with lower levels of DNA methylation. The investigators also demonstrate 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.
Excitatory circuits in the brain
One mechanism involved in a specific type of epilepsy is an increase in mossy fibre 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 Dr Boison, senior author of the paper from Legacy Research Institute and OHSU.
The rats did not receive the implants until they had experienced a number of seizures. The researchers noted that many studies investigating anti-epileptic drugs often test the treatments too early. 'If the therapy interferes with the trigger for epilepsy development then the trigger is weakened and subsequent epilepsy is less severe. However, this is not necessarily indicative of a stop in the progression of the disease,' said Dr Boison. They found that the adenosine-releasing silk did not completely abolish seizures in their animal model but reduced them four-fold.
'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
Safety in humans
Future studies will need to determine the optimal use and safety of the implants in humans. According to Dr Boison, 'We need to look into the efficacy of different doses of adenosine, the duration of adenosine release, and various time points of intervention.'
Future studies also need to demonstrate how long the effects of the adenosine-releasing silk implant will last.
This work could be important for the 25-30 percent of people with epilepsy who do not have effective therapies. The research may help prevent epilepsy in people who have some event that places them at risk, such as individuals who have experienced head trauma.