Delayed treatment with an adenosine kinase inhibitor, GP683, attenuates infarct size in rats with temporary middle cerebral artery occlusion
Department of Neurology
Adenosine Kinase; Animals; Arterial Occlusive Diseases; Body Temperature; Brain; Cerebral Infarction; Disease Models, Animal; Ischemic Attack, Transient; Male; Neuroprotective Agents; Pyrimidines; Rats; Rats, Sprague-Dawley; Time Factors
Nervous System Diseases | Neurology
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.
Rights and Permissions
Citation: Stroke. 1998 Sep;29(9):1952-8.
Tatlisumak, Turgut; Takano, Kentaro; Carano, Richard A.D.; Miller, Leonard P.; Foster, Alan C.; and Fisher, Marc, "Delayed treatment with an adenosine kinase inhibitor, GP683, attenuates infarct size in rats with temporary middle cerebral artery occlusion" (1998). Neurology Publications and Presentations. Paper 35.