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

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 +/- 1.5 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, alpha, beta-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.
AuthorsG Zhang, P H Franklin, T F Murray
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 264 Issue 3 Pg. 1415-24 (Mar 1993) ISSN: 0022-3565 [Print] United States
PMID8450475 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Adenosine Deaminase Inhibitors
  • Receptors, Purinergic
  • alpha,beta-methyleneadenosine 5'-diphosphate
  • Pentostatin
  • bicuculline methiodide
  • Thioinosine
  • Adenosine Diphosphate
  • 8-(4-sulfophenyl)theophylline
  • Theophylline
  • Adenosine Kinase
  • 4-nitrobenzylthioinosine
  • Adenosine
  • Bicuculline
Topics
  • Adenosine (physiology)
  • Adenosine Deaminase Inhibitors
  • Adenosine Diphosphate (analogs & derivatives, pharmacology)
  • Adenosine Kinase (antagonists & inhibitors)
  • Animals
  • Bicuculline (analogs & derivatives, pharmacology)
  • Cerebral Cortex (physiology)
  • Male
  • Pentostatin (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Purinergic (drug effects, physiology)
  • Seizures (prevention & control)
  • Theophylline (analogs & derivatives, pharmacology)
  • Thioinosine (analogs & derivatives, pharmacology)

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