After ischemic stroke, early intravenous thrombolytic therapy to reestablish tissue perfusion reduces neurological deficit and improves functional outcome.But the post-ischemic reperfusion may also trigger a cascade of deleterious cellular and molecular events.The reperfused issues undergo massive oxidative stress, including vascular damage that can result in hemorrhage into the brain tissue.The reperfusion cascade includes release of chemokines that recruit inflammatory cells;T-cells, macrophages and mast cells in brain that in turn release matrix metalloproteinases and other proteolytic enzymes, damaging the blood-brain barrier and the vessel walls triggering rupture.Additionally polymorphonuclear leucocytes enter the reperfused brain parenchyma, further increasing oxidative stress.The complications resulting from reperfusion injury, including brain hemorrhage, reduce the effectiveness of the thrombolytic therapy.This has led to a search for strategies to protect brain against such injuries.The purine nucleoside guanosine has been shown to exist extracellularly and, like the purine adenosine, to be an intercellular messenger demonstrating a plethora of both trophic and neuroprotective effects in vitro and in vivo.Interestingly, after focal stroke in rats guanosine is elevated within 2 hours and remains high for 7 days.These data led to investigation of the effect of exogenously administered guanosine in stroke models;protection against combined oxygen and glucose deprivation in vitro, against stroke in an ex-vivo model as well as in an in vivo rodent model of ischemic stroke.Guanosine also has anti-inflammatory effects in vivo (Jiang et al.2007), and cerebral reperfusion injury involves an inflammatory response.Therefore we questioned whether guanosine was neuroprotective against reperfusion injury following transient middle cerebral artery occlusion in rats.Guanosine administered intraperitoneally significantly reduced reperfusion injury in a dose-dependent manner.Guanosine is converted to uric acid, a scavenger of reactive oxygen species, raising the possibility that this was the mechanism by which guanosine produced its neuroprotective effects.Inosine, like guanosine, is converted to uric acid.But in contrast to guanosine, inosine was not neuroprotective.This makes it unlikely that the neuroprotective effects of guanosine are due to its conversion to uric acid.Guanosine was only neuroprotective when given in the first hour after reperfusion, indicating that if affected the early events in the reperfusion injury cascade.Moreover, guanosine does not exert its effects through induction of heat shock proteins.