Selective modulation of epileptic tissue by an adenosine A3
receptor-activating drug
Abstract
Background and Purpose Adenosine, through the A1 receptor (A1R), is an
endogenous anticonvulsant. Development of adenosine receptor agonists as
antiseizure medications has been hampered by their cardiac side effects.
A moderately A1R-selective agonist, MRS5474, has been reported to
suppress seizures without considerable cardiac action. Hypothesizing
that this drug could act through other than A1R and/or through a disease
specific mechanism, we assessed the effect of MRS5474 on the
hippocampus. Experimental Approach Excitatory synaptic currents, field
potentials, spontaneous activity, [3H]GABA uptake and GABAergic
currents were recorded from rodent or human hippocampal tissue.
Alterations in adenosine A3 receptor (A3R) density in human tissue were
assessed by Western Blot. Key Results MRS5474 (50-500nM) was devoid of
effect upon rodent excitatory synaptic signals in hippocampal slices,
except when hyperexcitability was previously induced in vivo or ex vivo.
This contrasted with the effect of other A1R agonists. MRS5474 inhibited
GAT-1 mediated GABA uptake, an action not blocked by an A1R antagonist
but blocked by an A3R antagonist and mimicked by an A3R agonist. A3R was
overexpressed in human hippocampal tissue samples from patients with
epilepsy that had focal resection from surgery. MRS5474 induced a
concentration-dependent potentiation of GABA-evoked currents in oocytes
micro-transplanted with human hippocampal membranes prepared from
epileptic hippocampal tissue but not from non-epileptic tissue, an
action blocked by an A3R antagonist. Conclusion and Implications We
identified a drug that activates A3R and has selective actions on
epileptic hippocampal tissue. This underscores A3R as a promising target
for the development of antiseizure medications.