title: Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis.
abstract: 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.
authors.affiliation: RS Dow Neurobiology Laboratories, Legacy Research Institute, Portland, Oregon 97232, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Williams-Karnesky
authors.forename: Ursula S
authors.initials: US
authors.lastname: Sandau
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Lusardi
authors.forename: Nikki K
authors.initials: NK
authors.lastname: Lytle
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Farrell
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Pritchard
authors.forename: David L
authors.initials: DL
authors.lastname: Kaplan
authors.forename: Detlev
authors.initials: D
authors.lastname: Boison
mesh_terms: D000241:Adenosine / Q000008:administration & dosage* / Q000494:pharmacology; D000248:Adenosine Kinase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D019175:DNA Methylation; D000077209:Decitabine; D004343:Drug Implants; D044127:Epigenesis, Genetic / Q000187:drug effects*; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics* / Q000517:prevention & control; D008297:Male; D051379:Mice; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017422:Sequence Analysis, DNA
chemical_list: D000927:Anticonvulsants; D004343:Drug Implants; D000077209:Decitabine; D004248:DNA (Cytosine-5-)-Methyltransferases; D000248:Adenosine Kinase; D000241:Adenosine; D001374:Azacitidine