Delayed treatment with an adenosine kinase inhibitor, GP683, attenuates infarct size in rats with temporary middle cerebral artery occlusion.
OBJECTIVE
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.
Tatlisumak
T
T
Department of Neurology, Helsinki University Central Hospital, Finland. turgut.tatlisumak@helsinki.fi
Takano
K
K
Carano
R A
RA
Miller
L P
LP
Foster
A C
AC
Fisher
M
M
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy* / Q000473:pathology; D001831:Body Temperature; D001921:Brain / Q000098:blood supply / Q000201:enzymology; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
C108064:GP 683; D018696:Neuroprotective Agents; D011743:Pyrimidines; D000248:Adenosine Kinase