From the Departments of Neurology, Helsinki University Central Hospital
(T.T.), Helsinki, Finland; The Medical Center of Central
Massachusetts–Memorial (T.T., K.T., M.F.), and the University of
Massachusetts Medical School (T.T., K.T., M.F.), Worcester, Mass; the
Department of Biomedical Engineering (R.A.D.C.), Worcester Polytechnic
Institute, Worcester, Mass; and Metabasis Therapeutics Inc (L.P.M., A.C.F.),
San Diego, Calif
Correspondence to Dr Turgut Tatlisumak, Department of Neurology, Helsinki University Central Hospital, Haartmaninkatu 4, FIN-00290 Helsinki, Finland. E-mail turgut.tatlisumak{at}helsinki.fi
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.
Department
of Neurology and Mallinckrodt Institute of Radiology,
Washington University School of Medicine,
St Louis, Missouri
{texf}
© 1998 American Heart Association, Inc.
Original Contributions
Delayed Treatment With an Adenosine Kinase Inhibitor, GP683, Attenuates Infarct Size in Rats With Temporary Middle Cerebral Artery Occlusion
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