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.

Elevated Adenosine Induces Placental DNA Hypomethylation Independent of A2B Receptor Signaling in Preeclampsia

“…[20][21][22][23] More recent mouse studies showed that increased intracellular adenosine, resulting from genetic deletion of adenosine kinase, reverses elevated global DNA hypermethylation in specific neuronal cells of mouse models of epileptic disease. 24 Although early human studies showed that adenosine levels are increased in maternal and fetal circulation and placentas of patients with preeclampsia and that increased placental adenosine causes preeclampsia features in pregnant mice, 19,35,36 the possibility that elevated placental adenosine contributes to placental DNA hypomethylation associated with preeclampsia remained undetermined before our current studies. Here, taking advantage of our newly developed preeclampsia animal models genetically engineered to allow adenosine to accumulate in the mouse placentas, 19 we demonstrated that genetic deletion of placental ADA leads to increased placental adenosine, placental DNA hypomethylation, and preeclampsia symptoms in pregnant mice.…”

“…For this reason, elevated adenosine is associated with DNA hypomethylation. [20][21][22][23][24] However, the function of elevated placental adenosine in DNA hypomethylation in preeclampsia remains unknown largely because of the lack of in vivo experimental models. Here, we report the use of 2 independent preeclampsia models, both characterized by elevated placental adenosine 19 that led us to discover that elevated placental adenosine contributes to the placental DNA hypomethylation in preeclampsia.…”

Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

“…The acute or initiating phase (lasting 2-3 h) is characterized by an acute surge in adenosine associated with a transient downregulation of astrocytic adenosine kinase (ADK), which commands the cellular uptake of the nucleoside from the extracellular milieu. Besides controlling neuronal excitability, high levels of adenosine can transiently reduce epigenetic DNA methylation, which precipitates epileptogenesis by favoring the transcription and expression of initiating genes [57]. In humans, the following weeks or months are critical for epileptogenesis as inflammatory processes are activated leading to microglial and astroglial activation (reviewed in [58,59]).…”

Adenosine kinase deficiency: expanding the clinical spectrum and evaluating therapeutic options

“…including epigenetic DNA methylation. ADK inhibitors and deficiency of ADK were shown to induce hypomethylation of DNA via biochemical interference with the transmethylation pathway in mice (Williams-Karnesky et al 2013). As may be expected from the importance of this pathway, autosomal-recessive ADK deficiency comprises a complex inborn error of metabolism with a severe clinical phenotype.…”