Anticonvulsant effect of AMP by direct activation of adenosine A1 receptor.
Purinergic neurotransmission mediated by adenosine (Ado) type 1 receptors (A1Rs) plays pivotal roles in negative modulation of epileptic seizures, and Ado is thought to be a key endogenous anticonvulsant. Recent evidence, however, indicates that AMP, the metabolic precursor of Ado, also activate A1Rs. Here, we evaluated the antiepileptic effects of AMP adopting in vitro and in vivo models of epilepsy. We report that AMP reversed the increase in population spike (PS) amplitude and the decrease in PS latency induced by a Mg(2+)-free extracellular solution in CA1 neurons of mouse hippocampal slices. The AMP effects were inhibited by the A1R antagonist DPCPX, but not prevented by inhibiting conversion of AMP into Ado, indicating that AMP inhibited per se sustained hippocampal excitatory neurotransmission by directly activating A1Rs. AMP also reduced seizure severity and mortality in a model of audiogenic convulsion. Of note, the anticonvulsant effects of AMP were potentiated by preventing its conversion into Ado and inhibited by DPCPX. When tested in a model of kainate-induced seizure, AMP prolonged latency of convulsions but had no effects on seizure severity and mortality. Data provide the first evidence that AMP is an endogenous anticonvulsant acting at A1Rs.
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Italy. Electronic address: mirko.muzzi@unifi.it.
Mirko
M
Muzzi
Elisabetta
E
Coppi
Anna Maria
AM
Pugliese
Alberto
A
Chiarugi
D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009924:Organ Culture Techniques; D043682:Receptor, Adenosine A1 / Q000187:drug effects / Q000378:metabolism*; D014970:Xanthines / Q000494:pharmacology
D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D000927:Anticonvulsants; D043682:Receptor, Adenosine A1; D014970:Xanthines; D000249:Adenosine Monophosphate; C051360:1,3-dipropyl-8-cyclopentylxanthine
A1 receptors; AMP; Adenosine; Epilepsy