Role of adenosine in the antiepileptic effects of deep brain stimulation.

Maisa F Miranda,Beatriz O Amorim,Carlos E Macedo,Maria Josã© S Fernandes,Sergio Tufik,Mayra C Aarã£O,Josã© N Nobrega,Ana Paula Madureira,Antã´Nio-Carlos G De Almeida,Luiz E Mello,Luciene Covolan,Clement Hamani,Monica L Andersen,Antã´Nio M Rodrigues

doi:10.3389/fncel.2014.00312

Abstract

Despite the effectiveness of anterior thalamic nucleus (AN) deep brain stimulation (DBS) for the treatment of epilepsy, mechanisms responsible for the antiepileptic effects of this therapy remain elusive. As adenosine modulates neuronal excitability and seizure activity in animal models, we hypothesized that this nucleoside could be one of the substrates involved in the effects of AN DBS. We applied 5 days of stimulation to rats rendered chronically epileptic by pilocarpine injections and recorded epileptiform activity in hippocampal slices. We found that slices from animals given DBS had reduced hippocampal excitability and were less susceptible to develop ictal activity. In live animals, AN DBS significantly increased adenosine levels in the hippocampus as measured by microdialysis. The reduced excitability of DBS in vitro was completely abolished in animals pre-treated with A1 receptor antagonists and was strongly potentiated by A1 receptor agonists. We conclude that some of the antiepileptic effects of DBS may be mediated by adenosine.

Highlights

Deep brain stimulation (DBS) involves the delivery of current to the brain parenchyma though implanted electrodes
anterior thalamic nucleus (AN)-DBS INDUCES ADENOSINE RELEASE IN HIPPOCAMPUS As shown in Figure 1, AN DBS increased hippocampal levels of adenosine in both epileptic and non-epileptic animals (DBS main effect F(1,12) = 527.59, p < 0.0001). This increase was significantly higher in pilocarpine injections (Pilo) + DBS rats compared to Pilo + Sham animals (Figure 1A)
ANTIEPILEPTIC EFFECTS OF AN DBS IN VITRO We have previously found that animals receiving DBS for 5 days had a significant decrease in hippocampal excitability measured in vitro with electrophysiology (Covolan et al, 2014)

Summary

Introduction

Deep brain stimulation (DBS) involves the delivery of current to the brain parenchyma though implanted electrodes. We have recently shown that AN DBS reduced the frequency of spontaneous recurrent seizures in chronic epileptic animals (Covolan et al, 2014). Animals receiving stimulation had a significant decrease in hippocampal excitability. This proved to be a more reliable measure of the effectiveness of DBS than frequency of seizures, due to the variability in seizure rate that occurs across animals and in the same animals over time (Covolan et al, 2014)

Methods

Results

Conclusion