Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. J Clin Invest 2013 Aug;123(8):3552-63
Date
07/19/2013Pubmed ID
23863710Pubmed Central ID
PMC3726154DOI
10.1172/JCI65636Scopus ID
2-s2.0-84879710932 (requires institutional sign-in at Scopus site) 196 CitationsAbstract
Epigenetic modifications, including changes in DNA methylation, lead to altered gene expression and thus may underlie epileptogenesis via induction of permanent changes in neuronal excitability. Therapies that could inhibit or reverse these changes may be highly effective in halting disease progression. Here we identify an epigenetic function of the brain's endogenous anticonvulsant adenosine, showing that this compound induces hypomethylation of DNA via biochemical interference with the transmethylation pathway. We show that inhibition of DNA methylation inhibited epileptogenesis in multiple seizure models. Using a rat model of temporal lobe epilepsy, we identified an increase in hippocampal DNA methylation, which correlates with increased DNA methyltransferase activity, disruption of adenosine homeostasis, and spontaneous recurrent seizures. Finally, we used bioengineered silk implants to deliver a defined dose of adenosine over 10 days to the brains of epileptic rats. This transient therapeutic intervention reversed the DNA hypermethylation seen in the epileptic brain, inhibited sprouting of mossy fibers in the hippocampus, and prevented the progression of epilepsy for at least 3 months. These data demonstrate that pathological changes in DNA methylation homeostasis may underlie epileptogenesis and reversal of these epigenetic changes with adenosine augmentation therapy may halt disease progression.
Author List
Williams-Karnesky RL, Sandau US, Lusardi TA, Lytle NK, Farrell JM, Pritchard EM, Kaplan DL, Boison DAuthor
Nikki K. Lytle PhD Assistant Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdenosineAdenosine Kinase
Animals
Anticonvulsants
Azacitidine
Base Sequence
Brain
CpG Islands
DNA (Cytosine-5-)-Methyltransferases
DNA Methylation
Drug Implants
Epigenesis, Genetic
Epilepsy
Male
Mice
Mossy Fibers, Hippocampal
Rats
Rats, Sprague-Dawley
Sequence Analysis, DNA