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Title: Modulation of intracellular ATP influences seizure activity via the activity-dependent release of adenosine
Author: Hall, Jessicka
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2016
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A large number of patients with epilepsy have drug-resistant seizures. Therefore, there is a need for the development of new therapies. The purine nucleoside adenosine is an endogenous anticonvulsant that acts to supress neuronal excitability via adenosine A1 receptors. The aim of this thesis was to investigate whether manipulating ATP bioenergenetics and importantly adenosine levels had any effects on activity-dependent release of adenosine and seizure activity. ATP bioenergetics and adenosine levels were manipulated by pre-treating rat hippocampal slices with a combination of the sugar backbone of ATP (D-ribose) and the free purine base adenine (RibAde) and the phosphate buffer creatine. The role that the adenosine A2A receptor plays in relation to epileptiform activity was also investigated. Biosensors were used to measure the real-time release of adenosine. The K+ channel blocker 4-aminopyridine (4-AP; 50 μM) in Mg2+-free medium was the model used for inducing spontaneous bursting epileptiform activity. Additionally, homocysteine thiolactone (HTL) was used to “trap” intracellular adenosine to test if extracellular adenosine measured with biosensors, is released as adenosine per se and if this had any effects on seizure activity. I show that during bursting epileptiform activity, the amount of adenosine released is increased in RibAde slices compared to creatine and untreated (control) slices and increased the time between seizures compared to both creatine and control slices. No differences was found between creatine and control slices. My data also suggest that adenosine A2A receptors may partially contribute to seizure activity. HTL reduced adenosine release in a burst-dependent manner and also increased the frequency of seizures. HTL influenced the intensity of bursts in control but not RibAde-treated slices. This thesis provides evidence for the beneficial role of the ATP precursors ribose and adenine on reducing seizure activity and will hopefully contribute to ongoing attempts to establish adenosine-based epilepsy therapies.
Supervisor: Not available Sponsor: Biotechnology and Biological Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC Internal medicine