Lopatář, Ján (2011) Regulation of cortical excitability and seizure activity by purines. PhD thesis, University of Warwick.

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Abstract

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.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QP Physiology R Medicine > RM Therapeutics. Pharmacology
Library of Congress Subject Headings (LCSH):	Adenosine, Epilepsy, Convulsions, Adenosine triphosphate -- Receptors, Anticonvulsants
Official Date:	December 2011
Dates:	Date Event December 2011 Submitted
Institution:	University of Warwick
Theses Department:	School of Life Sciences
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Frenguelli, Bruno G. ; Dale, Nicholas
Sponsors:	Epilepsy Research UK
Extent:	262 leaves : ill., charts
Language:	eng

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