adenosine-kinase and Arterial-Occlusive-Diseases

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.. 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.. 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.. 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.

Topics: 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

Endogenous adenosine released locally during cerebral ischemia is neuroprotective, and agents which decrease adenosine inactivation may potentiate its protective effects. The effects of 5'-deoxy-5-iodotubercidin (5'd-5IT), an inhibitor of the adenosine-catabolizing enzyme, adenosine kinase, were studied in male Wistar rats subjected to 2 h of transient middle cerebral artery occlusion. 5'd-5IT or the vehicle (10% DMSO in saline) was administered i.p. 30 min before, and 2 h and 6 h after the induction of middle cerebral artery occlusion. The infarct volume was determine using 2,3,5-triphenyltetrazolium chloride staining 48 h after middle cerebral artery occlusion. The infarct volume was significantly reduced in rats treated with 1.85 mg/kg x 3 (57% reduction, P < 0.001) or 1.0 mg/kg x 3 (34% reduction, P < 0.05), but not 0.3 mg/kg x 3 5'd-5IT compared to vehicle-treated rats. The reduction of infarct volume was accompanied by a significant improvement in behavioral measures of neurological deficit. These data further support a role of adenosine in neuroprotection and suggest that adenosine kinase inhibition may be a useful approach to the treatment of focal cerebral ischemia.

Topics: Adenosine Kinase; Animals; Arterial Occlusive Diseases; Body Temperature; Body Weight; Brain; Cerebral Infarction; Enzyme Inhibitors; Ischemic Attack, Transient; Male; Neuroprotective Agents; Rats; Rats, Wistar; Tubercidin