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Title: Regulation of cortical excitability and seizure activity by purines
Author: Lopatář, Ján
ISNI:       0000 0004 2724 0274
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2011
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The purine nucleoside adenosine is considered an important endogenous anticonvulsant, which exerts its actions via adenosine receptors. Adenosine can be released per se, or as ATP, which is then broken down to adenosine via the action of extracellularly located ectonucleotidases. ATP is a signalling molecule in its own right, which can activate ionotropic P2X and metabotropic P2Y receptors. While the role of adenosine and its receptors in epilepsy is well established, little data is known about the role of the P2 receptors. The aim of this work was threefold: (i) to what extent the P2 receptors modulate seizure-like activity in vitro, (ii) to detect the release of ATP and/or adenosine during seizure-like activity, and (iii) to establish the cellular source of the purines released. To do so, I used two NMDA receptor dependent models of electrically (high-frequency stimulation in Mg2+-free medium)- or chemically (6 mM K+ in Mg2+-free medium)- induced seizure-like events (SLE), and a model of bursting based on the activation of group I metabotropic glutamate receptors (GI mGluR). In my NMDA receptor-dependent models, I show that some P2 receptors partially aggravate SLEs, but their contribution is dwarfed compared to the powerful action of the adenosine A1 receptors. Accordingly, the minimal contribution of P2 receptors was reflected in my inability to detect ATP using microelectrode biosensors, despite my attempts to boost the amount of extracellular ATP using two ecto-ATPase inhibitors. GI mGluR-dependent bursting was partially blocked by the P2Y1 receptor antagonist MRS2179. Biosensor data revealed small, CA3 regionspecific ATP release. In contrast, larger quantities of adenosine were detected in all models used. Work with mice modified to express different levels of adenosine kinase (ADK) revealed that ADK plays an important role in regulating the amount of extracellular adenosine and seizure parameters. Furthermore, dn SNARE mice, in which astrocytic vesicular release of purines is selectively blocked, showed small amounts of SLE-related adenosine produced. My data suggest that P2 receptors partially contribute to seizure activity. Furthermore, I have confirmed the strong anticonvulsive action of adenosine, which is likely released from astrocytes, and tightly regulated by ADK. Thus, work contained in this thesis will hopefully contribute to the on-going attempts to establish adenosine-based epilepsy therapies.
Supervisor: Not available Sponsor: Epilepsy Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP Physiology ; RM Therapeutics. Pharmacology