Delayed treatment with an adenosine kinase inhibitor, GP683, attenuates infarct size in rats with temporary middle cerebral artery occlusion.

Abstract

BACKGROUND AND PURPOSE:

Brain ischemia is associated with a marked increase in extracellular adenosine levels. This results in activation of cell surface adenosine receptors and some degree of neuroprotection. Adenosine kinase is a key enzyme controlling adenosine metabolism. Inhibition of this enzyme enhances the levels of endogenous brain adenosine already elevated as a result of the ischemic episode. We studied a novel adenosine kinase inhibitor (AKI), GP683, in a rat focal ischemia model.

METHODS:

Four groups of 10 adult Sprague-Dawley rats were exposed to 90 minutes of temporary middle cerebral artery (MCA) occlusion. Animals were injected intraperitoneally with vehicle, 0.5 mg/kg, 1.0 mg/kg, or 2.0 mg/kg of GP683 30, 150, and 270 minutes after the induction of ischemia by a researcher blinded to treatment group. The animals were euthanatized 24 hours after MCA occlusion, and brains were stained with 2,3,5-triphenyltetrazolium chloride. We measured brain temperatures in a separate group of 6 rats before and after administration of 1.0 mg/kg GP683.

RESULTS:

All treated groups showed a reduction in infarct volumes, but a significant effect was observed only in the 1.0 mg/kg-dose group (44% reduction, P=0.0077). Body weight, physiological parameters, neurological scores, and mortality did not differ among the 4 groups. No apparent behavioral side effects were observed. Brain temperatures did not change after drug injection.

CONCLUSIONS:

Our results indicate that the use of AKIs offers therapeutic potential and may represent a novel approach to the treatment of acute brain ischemia. The therapeutic effect observed was not caused by a decrease in brain temperature.

• Authors: T Tatlisumak, K Takano, R A Carano, L P Miller, A C Foster, M Fisher
• Journal: Stroke (Stroke) Vol. 29 Issue 9 Pg. 1952-8 (Sep 1998) ISSN: 0039-2499 [Print] United States
• PMID: 9731623 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GP 683
• Neuroprotective Agents
• Pyrimidines
• Adenosine Kinase

Topics

• Adenosine Kinase (antagonists & inhibitors)
• Animals
• Arterial Occlusive Diseases (drug therapy, pathology)
• Body Temperature
• Brain (blood supply, enzymology)
• Cerebral Infarction (drug therapy, pathology)
• Disease Models, Animal
• Ischemic Attack, Transient (drug therapy, pathology)
• Male
• Neuroprotective Agents (pharmacology)
• Pyrimidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Time Factors