Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis
Rebecca L. Williams-Karnesky, Ursula S. Sandau, Theresa A. Lusardi, Nikki K. Lytle, Joseph M. Farrell, Eleanor M. Pritchard, David L. Kaplan, Detlev Boison
Rebecca L. Williams-Karnesky, Ursula S. Sandau, Theresa A. Lusardi, Nikki K. Lytle, Joseph M. Farrell, Eleanor M. Pritchard, David L. Kaplan, Detlev Boison
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Research Article Neuroscience

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

Rebecca L. Williams-Karnesky, Ursula S. Sandau, Theresa A. Lusardi, Nikki K. Lytle, Joseph M. Farrell, Eleanor M. Pritchard, David L. Kaplan, Detlev Boison

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Figure 5

ADO-releasing silk implants prevent mossy fiber sprouting.

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ADO-releasing silk implants prevent mossy fiber sprouting. (A) Transient...
(A) Transient ADO augmentation therapy in epileptic rats prevents mossy fiber sprouting in the dentate gyrus. Top row: representative low magnification images of Timm staining of mossy fibers in hippocampus in naive animals, KA9wk animals, animals 21 weeks after KA (sham), and animals 21 weeks after KA that received polymers releasing either 0 ng (control) or 250 ng ADO/d for a duration of 10 days (implanted at KA9wk). Middle row: higher magnification images that depict Timm granules (black arrows) that correspond to mossy fiber synaptic terminals present in animals 21 weeks after KA (sham and 0 ng ADO/d animals but not in the 250 ng ADO/d animals). Bottom row: high magnification images that illustrate extensive sprouting of mossy fiber axons in animals 21 weeks after KA (white arrow). M, molecular layer; G, granular layer; H, hilus. Original magnification, ×5 (top row); ×10 (middle row); ×40 (bottom row). Scale bars: 500 μm. (B) Quantitative analysis of Timm staining shows that transient ADO delivery significantly reduced mossy fiber sprouting compared with that in animals 21 seconds after KA (sham) within the 3-month time span between weeks 9 and 21. Data represent group average Timm score in hippocampus and are displayed as mean ± SEM. *P < 0.05; **P < 0.01. n = 3 for all groups.