The effect of granulocyte-colony stimulating factor in global cerebral ischemia in rats.
Granulocyte-colony stimulating factor (G-CSF) is an endogenous peptide hormone of the hematopoietic system that has entered Phase I/II clinical trials for treatment of ischemic stroke. Severe intraoperative hypotension can lead to global cerebral ischemia and apoptotic neuron loss within the hippocampus. We tested G-CSF in a rat model of global cerebral ischemia. Global cerebral ischemia was induced in male Sprague-Dawley rats (280-330 g) with the 2-vessel occlusion model (hemorrhagic hypotension to a mean arterial pressure of 30-35 mm Hg and bilateral common carotid artery occlusion for 8 min). Three groups of animals were used: global ischemia without treatment (GI, n=49), global ischemia with G-CSF treatment (GI+G-CSF, n=42), and sham surgery (Sham, n=26). Rats in the treatment group received G-CSF (50 mug/kg, subcutaneously) 12 h before surgery, on the day of surgery, and on postoperative Day 1 and were euthanized on Days 2, 3, and 14. Mild hyperglycemia was observed in all groups. T-maze testing for spontaneous alternation demonstrated initial improvement in the G-CSF treatment group but no long-term benefit. Measurement of daily body weight demonstrated an initial trend toward improvement in the G-CSF group. Quantitative Nissl histology of the hippocampus demonstrated equivalent outcomes on Days 3 and 14, which was supported by quantitative TUNEL stain. Immunohistochemistry and Western blot demonstrated an initial increase in phosphorylated-AKT in the GI+G-CSF group on Day 2. We conclude that G-CSF treatment is associated with transient early improvement in neurobehavioral outcomes after global ischemia complicated by mild hyperglycemia, but no long-term protection.
Matchett
Gerald A
GA
Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
Calinisan
Jason B
JB
Matchett
Genoveve C
GC
Martin
Robert D
RD
Zhang
John H
JH
D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002452:Cell Count; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D016179:Granulocyte Colony-Stimulating Factor