title: Guanosine protects against reperfusion injury in rat brains after ischemic stroke.
abstract: After ischemic stroke, early thrombolytic therapy to reestablish tissue perfusion improves outcome but triggers a cascade of deleterious cellular and molecular events. Using a collaborative approach, our groups examined the effects of guanosine (Guo) in response to ischemic reperfusion injury in vitro and in vivo. In a transient middle cerebral artery occlusion (MCAO) in rats, Guo significantly reduced infarct volume in a dose-dependent manner when given systemically either immediately before or 30 min, but not 60 min, after the onset of the 5.5-hr reperfusion period. In a separate experiment, Guo significantly reduced infarct volume after 24 hr of reperfusion when administered 5 min before reperfusion. Western blot analysis did not reveal any significant changes either in endoplasmic reticulum (ER) stress proteins (GRP 78 and 94) or HSP 70 or in levels of m-calpain. In vitro oxygen and glucose deprivation (OGD) significantly increased production of both reactive oxygen species (ROS) and interleukin-8 (IL-8) in the primary astrocytes. Guo did not alter ROS or IL-8 production when given to the astrocytes before OGD. However, Guo when added to the cells prior to or 30 min after reperfusion significantly reduced IL-8 release but not ROS formation. Our study revealed a dose- and time-dependent protective effect of Guo on reperfusion injury in vitro and vivo. The mechanisms by which Guo exerts its effect are independent of unfolded proteins in ER or the level of intracellular calcium or ROS formation. However, the effect may be induced, at least partially, by inhibiting IL-8, a marker of reperfusion-triggered proinflammatory events.
authors.affiliation: Department of Biomedical Science, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Connell
authors.forename: Patrizia
authors.initials: P
authors.lastname: Di Iorio
authors.forename: Iqbal
authors.initials: I
authors.lastname: Sayeed
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ballerini
authors.forename: Monique C
authors.initials: MC
authors.lastname: Saleh
authors.forename: Patricia
authors.initials: P
authors.lastname: Giuliani
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Saleh
authors.forename: Michel P
authors.initials: MP
authors.lastname: Rathbone
authors.forename: Caixin
authors.initials: C
authors.lastname: Su
authors.forename: Shucui
authors.initials: S
authors.lastname: Jiang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000172:deficiency; D006151:Guanosine / Q000008:administration & dosage*; D006360:Heat-Shock Proteins / Q000378:metabolism; D000860:Hypoxia; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015424:Reperfusion / Q000009:adverse effects; D015427:Reperfusion Injury / Q000150:complications / Q000517:prevention & control*; D013997:Time Factors
chemical_list: D006360:Heat-Shock Proteins; D016209:Interleukin-8; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D006151:Guanosine; D005947:Glucose