The effects of adenosine A3 receptor stimulation on seizures in mice.
We have previously shown that acute preischemic adenosine A3 receptor stimulation results in an increased postischemic damage, while chronic stimulation of this receptor diminishes it. Since several pathophysiological phenomena are common for both ischemia and seizures, we have explored the effect of acute and chronic administration of the adenosine A3 receptor selective agonist IB-MECA (N6-(3-iodobenzyl) adenosine-5'-N-methylcarboxamide) prior to seizures induced by N-methyl-D-aspartate (NMDA), pentamethylenetetrazole, or electric shock. At 100 micrograms/kg, acutely injected IB-MECA was protective in chemically but not electrically induced seizures. In chronic administration of IB-MECA, significant protection against chemically induced seizures was obtained in all studied measures, i.e., seizure latency, neurological impairment, and survival. Although threshold voltage was unchanged in electrically induced seizures, a chronic regimen of IB-MECA significantly reduced postepileptic mortality. Since the combination of an arteriole-constricting compound 48/80 and hypotension-inducing clonidine injected prior to NMDA results in a significant protection against seizures, and since acute stimulation of adenosine A3 receptor causes both arteriolar constriction and severe hypotension, there is a possibility that the protection obtained by the acutely administered drug may result from inadequate delivery of chemoconvulsants to the brain. It is, however, unknown whether the protective effect of chronically administered IB-MECA is related to the effect of the drug on blood flow, neuronal mechanisms, or both.
Von Lubitz
D K
DK
NIH/NIDDK, Molecular Recognition Section, Bethesda, MD 20892, USA.
Carter
M F
MF
Deutsch
S I
SI
Lin
R C
RC
Mastropaolo
J
J
Meshulam
Y
Y
Jacobson
K A
KA
D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D003000:Clonidine / Q000633:toxicity; D004347:Drug Interactions; D004597:Electroshock; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000633:toxicity; D010433:Pentylenetetrazole / Q000633:toxicity; D058906:Purinergic P1 Receptor Agonists; D012640:Seizures / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*; D003189:p-Methoxy-N-methylphenethylamine / Q000633:toxicity
D058906:Purinergic P1 Receptor Agonists; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D003189:p-Methoxy-N-methylphenethylamine; D016202:N-Methylaspartate; D000241:Adenosine; D003000:Clonidine; D010433:Pentylenetetrazole