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.
Stroke. 1998 Sep;29(9):1952-8.
Stroke; a journal of cerebral circulation
Tatlisumak T, Takano K, Carano RA, Miller LP, Foster AC, Fisher M. (1998). Delayed treatment with an adenosine kinase inhibitor, GP683, attenuates infarct size in rats with temporary middle cerebral artery occlusion. Neurology Publications. Retrieved from https://escholarship.umassmed.edu/neuro_pp/35