Manipulation of endogenous adenosine in the rat prepiriform cortex modulates seizure susceptibility

G. Zhang, P. H. Franklin, Thomas F. Murray

Research output: Contribution to journalArticle

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Abstract

A1 adenosine receptors in the rat prepiriform cortex play an important role in the inhibition of bicuculline methiodide-induced convulsions. In the present study we evaluated manipulation of endogenous adenosine in this brain area as a strategy to effect seizure suppression. All compounds evaluated were unilaterally microinjected into the rat prepiriform cortex. Administration of exogenous adenosine afforded a dose-dependent protection (ED50 = 48.1 ± 8.4 nmol) against bicuculline methiodide-induced seizures, and these anticonvulsant effects were significantly potentiated by treatment with an adenosine kinase inhibitor, 5'-amino-5'-deoxyadenosine; by the adenosine transport blockers, dilazep or nitrobenzylthioinosine 5'- monophosphate; and by an adenosine deaminase inhibitor, 2'-deoxycoformycin. When administered alone, 5'-amino-5'-deoxyadenosine, 5'-iodotubercidin and dilazep were found to be highly efficacious as anticonvulsants with respective ED50 values of 2.6 ± 0.8, 4.0 ± 2.7 and 5.6 ± 1.6 nmol. In contrast, 2'-deoxycoformycin was both less potent and less efficacious. These results suggest that accumulation of endogenous adenosine may contribute to seizure suppression, and that adenosine kinase and adenosine transport may play a pivotal role in the regulation of extracellular levels of adenosine in the central nervous system. The adenosine antagonist, 8-(p- sulfophenyl)theophylline, increased markedly the severity of bicuculline methiodide-induced seizures. Moreover, reduction of extracellular adenosine formation by a focal injection of an ecto-5'-nucleotidase inhibitor, α,β- methyleneadenosine diphosphate, produced generalized seizures (ED50 = 37.3 ± 22.7 nmol). Together the proconvulsant effect of an adenosine receptor antagonist and the convulsant action of an ecto-5'-nucleotidase inhibitor further support the role of endogenous adenosine as a tonically active antiepileptogenic substance in the rat prepiriform cortex.

Original languageEnglish
Pages (from-to)1415-1424
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume264
Issue number3
StatePublished - 1993
Externally publishedYes

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Adenosine
Seizures
Dilazep
Adenosine Kinase
Pentostatin
5'-Nucleotidase
Anticonvulsants
Adenosine Deaminase Inhibitors
Purinergic P1 Receptor Antagonists
Adenosine A1 Receptors
Piriform Cortex
Convulsants
Diphosphates
Central Nervous System
Injections
Brain
bicuculline methiodide

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Manipulation of endogenous adenosine in the rat prepiriform cortex modulates seizure susceptibility. / Zhang, G.; Franklin, P. H.; Murray, Thomas F.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 264, No. 3, 1993, p. 1415-1424.

Research output: Contribution to journalArticle

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abstract = "A1 adenosine receptors in the rat prepiriform cortex play an important role in the inhibition of bicuculline methiodide-induced convulsions. In the present study we evaluated manipulation of endogenous adenosine in this brain area as a strategy to effect seizure suppression. All compounds evaluated were unilaterally microinjected into the rat prepiriform cortex. Administration of exogenous adenosine afforded a dose-dependent protection (ED50 = 48.1 ± 8.4 nmol) against bicuculline methiodide-induced seizures, and these anticonvulsant effects were significantly potentiated by treatment with an adenosine kinase inhibitor, 5'-amino-5'-deoxyadenosine; by the adenosine transport blockers, dilazep or nitrobenzylthioinosine 5'- monophosphate; and by an adenosine deaminase inhibitor, 2'-deoxycoformycin. When administered alone, 5'-amino-5'-deoxyadenosine, 5'-iodotubercidin and dilazep were found to be highly efficacious as anticonvulsants with respective ED50 values of 2.6 ± 0.8, 4.0 ± 2.7 and 5.6 ± 1.6 nmol. In contrast, 2'-deoxycoformycin was both less potent and less efficacious. These results suggest that accumulation of endogenous adenosine may contribute to seizure suppression, and that adenosine kinase and adenosine transport may play a pivotal role in the regulation of extracellular levels of adenosine in the central nervous system. The adenosine antagonist, 8-(p- sulfophenyl)theophylline, increased markedly the severity of bicuculline methiodide-induced seizures. Moreover, reduction of extracellular adenosine formation by a focal injection of an ecto-5'-nucleotidase inhibitor, α,β- methyleneadenosine diphosphate, produced generalized seizures (ED50 = 37.3 ± 22.7 nmol). Together the proconvulsant effect of an adenosine receptor antagonist and the convulsant action of an ecto-5'-nucleotidase inhibitor further support the role of endogenous adenosine as a tonically active antiepileptogenic substance in the rat prepiriform cortex.",
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