It’s been postulated that the neuromodulator adenosine might be an endogenous anticonvulsant molecule, and deficiencies in adenosine-based neuromodulatory system may contribute to epileptogenesis. Furthermore, the evidence has surfaced that this inhibitory neurotransmitter might also be involved in the biochemical aspects of sleep.
Researchers from Legacy Research Institute, Oregon Health and Sciences University, and Tufts University decided to introduce adenosine to the brain using an implant developed out of silk that can slowly release the neurotransmitter after implantation. Their study, just published in Journal of Clinical Investigation, is pointing to the idea that adenosine is used by the body to turn certain genes on and off, an epigenetic process that doesn’t require making changes to the DNA code. In particular, the team found that brains that had higher levels of adenosine had lower levels of DNA methylation, or blocking of DNA by methyl groups that can prevent which genes can be transcribed. The implant has so far demonstrated safety in animal models, and researchers hope to one day be able to use it to help patients suffering from epilepsy prevent dangerous seizures.
From the National Institutes of Health:
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 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 epilepsy had already been established,” Dr. Boison continued.
Study in Journal of Clinical Investigation: Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis
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