Anticonvulsant effect and neurotransmitter modulation of focal and systemic 2-chloroadenosine against the development of pilocarpine-induced seizures.
The present microdialysis study was aimed at evaluating the anticonvulsant effect of the adenosine A(1) receptor agonist 2-chloroadenosine (2-CADO) against pilocarpine-induced seizures in rats. The hippocampal neurotransmitter modulation on the action of 2-CADO and its possible activation of hippocampal adenosine A(2a) receptors was also assessed. Intrahippocampal perfusion of 2-CADO (100 microM) produced a sustained attenuation of baseline dopamine levels, while eliciting a delayed augmentation of both glutamate and GABA efflux. When co-perfused with pilocarpine (10 mM) or injected systemically (7.5 mg/kg), 2-CADO prevented the development of seizures as well as pilocarpine-evoked augmentation of the glutamate and dopamine levels. However, the delayed increase in glutamate overflow with intrahippocampal 2-CADO was still observed. Intraperitoneal injection of selective adenosine A(2a) receptor antagonist SCH 58261 reversed the 2-CADO-elicited attenuation of pilocarpine-induced increment in dopamine efflux and completely abolished the delayed augmentation of glutamate levels, irrespective of perfusion with pilocarpine. Intraperitoneal injection of 5 mg/kg 2-CADO mostly prevented the elevation of pilocarpine-induced glutamate efflux but could not confer adequate protection. We conclude that 2-CADO can prevent pilocarpine-induced seizures by both intrahippocampal perfusion and systemic administration. The attenuation of pilocarpine-induced dopamine efflux and the late elevations of glutamate are likely to be mediated by hippocampal A(2a) receptors. Inhibition of presynaptic glutamate release does not appear to be sufficient for the anticonvulsant action. Postsynaptic events could play a more important role.
Khan
G M
GM
Department of Pharmaceutical Chemistry and Drug Analysis, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
Smolders
I
I
Ebinger
G
G
Michotte
Y
Y
D015762:2-Chloroadenosine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D004569:Electroencephalography / Q000187:drug effects; D004594:Electrophysiology; D006624:Hippocampus / Q000502:physiology; D007267:Injections; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000378:metabolism / Q000502:physiology*; D010862:Pilocarpine / Q000494:pharmacology*; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology; D014230:Triazoles / Q000494:pharmacology
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D000927:Anticonvulsants; D018721:Muscarinic Agonists; D018377:Neurotransmitter Agents; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D014230:Triazoles; D010862:Pilocarpine; D015762:2-Chloroadenosine