The effect of granulocyte-colony stimulating factor in global cerebral ischemia in rats

Abstract

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 μg/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.