Silky Brain Implants May Help Stop Spread of Epilepsy
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 and that novel silk-based polymers, engineered to release the anticonvulsant adenosine, might prove to be efficacious
According to a new study published in the Journal of Clinical Investigation (July 25, 2013), silk implants placed in the brain of laboratory animals and designed to release a specific chemical, adenosine, may help stop the progression of epilepsy. According to the authors, 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 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 authors also demonstrated 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.
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 the findings that 10 days of adenosine delivery prevented the sprouting of mossy fibers for at least three months in rats, the authors predict that the benefits of the adenosine therapy may extend even longer. However, the authors added, this assumption needs to be validated in long-term experiments that go beyond three months.
As part of the study design, the rats did not receive the implants until they had experienced a number of seizures. The authors noted that many studies investigating anti-epileptic drugs often test the treatments too early. According to the authors, 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. To support this hypothesis, the study found that the adenosine-releasing silk did not completely abolish seizures in their animal model but reduced them four-fold.
The findings show that the implants are safe to use in rats and suggest that they may one day be used in the clinic as the 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. Clinical applications could be the prevention of epilepsy following head trauma or the prevention of seizures that often – in about 50% 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.
However, before the silk implants are ready for their close-up, future studies will need to determine their optimal use and safety in humans. And there is a need to look into the efficacy of different doses of adenosine, the duration of adenosine release, and various time points of intervention. In addition, future studies also need to demonstrate how long the effects of the adenosine-releasing silk implant will last.