Time window of fibroblast growth factor-18-mediated neuroprotection after occlusion of the middle cerebral artery in rats.
To assess the time window for fibroblast growth factor-18 (FGF18)-mediated neuroprotection, FGF18 was administered by intravenous infusion at various times after transient occlusion of the middle cerebral artery (MCAO) in rats. Vehicle or FGF18 (100 microg x kg(-1) x h(-1)) was infused at 0.25, 0.5, 1.0, 2.0, 4.0, or 8.0 hours after MCAO with infarct volumes and behavioral deficits measured at 24.0 hours after MCAO. A separate group of animals received the infusions 24 hours after MCAO with endpoints measured at 48 hours after MCAO. Infusion of FGF18 reduced infarct volumes and improved scores in tests of reference and working memory, motor ability, and exploratory behavior. FGF18 was most efficacious when infused within 2 hours after MCAO. Significant reductions in infarct volumes and reductions in deficits of reference memory and motor activity were also observed with FGF18 infused 24 hours after MCAO. Measurements taken at infusion times before 2 hours after MCAO showed that regional cerebral blood flow was increased by FGF18. Administration of vehicle or FGF18 had no significant effect on mean arterial blood pressure, heart rate, brain temperature, blood pH, Pco2, or Po2. These results demonstrate that FGF18 is an effective neuroprotective agent when administered early after transient MCAO in rats. Efficacy observed with infusions at later times suggests an expanded time window for FGF18-mediated neuroprotection.
Ellsworth
Jeff L
JL
ZymoGenetics, Inc., Seattle, Washington 98102, USA. jefe@zgi.com
Garcia
Richard
R
Yu
Jin
J
Kindy
Mark S
MS
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002560:Cerebrovascular Circulation; D004926:Escherichia coli / Q000378:metabolism; D005106:Exploratory Behavior / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000494:pharmacology*; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000517:prevention & control / Q000523:psychology; D007262:Infusions, Intravenous; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000502:physiology; D020768:Middle Cerebral Artery / Q000502:physiology*; D009043:Motor Activity / Q000502:physiology; D018696:Neuroprotective Agents; D011597:Psychomotor Performance / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology
D018696:Neuroprotective Agents; D011994:Recombinant Proteins; C113569:fibroblast growth factor 18; D005346:Fibroblast Growth Factors