Bone Marrow Cell Transplantation Time-Dependently Abolishes Efficacy of Granulocyte Colony-Stimulating Factor After Stroke in Hypertensive Rats

• Published in: Stroke (1970) 2014-08, Vol.45 (8), p.2431-2437
• Main Authors: Pösel, Claudia, Scheibe, Johanna, Kranz, Alexander, Bothe, Viktoria, Quente, Elfi, Fröhlich, Wenke, Lange, Franziska, Schäbitz, Wolf-Rüdiger, Minnerup, Jens, Boltze, Johannes, Wagner, Daniel-Christoph
• Format: Article
• Language: English
• Subjects: Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Bone Marrow Transplantation; Brain - physiopathology; Cardiology. Vascular system; Combined Modality Therapy; Granulocyte Colony-Stimulating Factor - therapeutic use; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - physiopathology; Infarction, Middle Cerebral Artery - surgery; Infarction, Middle Cerebral Artery - therapy; Male; Medical sciences; Nervous system (semeiology, syndromes); Neurology; Neutrophils; Rats; Rats, Inbred SHR; Recovery of Function - physiology; Stroke - drug therapy; Stroke - physiopathology; Stroke - surgery; Stroke - therapy; Time Factors; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/STROKEAHA.113.004460

BACKGROUND AND PURPOSE—We aimed to determine a possible synergistic effect of granulocyte colony-stimulating factor (G-CSF) and bone marrow–derived mononuclear cells (BM MNC) after stroke in spontaneously hypertensive rats. METHODS—Male spontaneously hypertensive rats were subjected to middle cerebral artery occlusion and randomly assigned to daily injection of 50 μg/kg G-CSF for 5 days starting 1 hour after stroke (groups 1, 2, and 3) with additional intravenous transplantation of 1.5×10E7 BM MNC per kilogram at 6 hours (group 2) or 48 hours (group 3) after stroke, or control treatment (group 4). Circulating leukocyte counts and functional deficits, infarct volume, and brain edema were repeatedly assessed in the first week and first month. RESULTS—G-CSF treatment led to a significant neutrophilia, to a reversal of postischemic depression of circulating leukocytes, and to a significantly improved functional recovery without affecting the infarct volume or brain edema. BM MNC cotransplantation was neutral after 6 hours, but reversed the functional effect of G-CSF after 48 hours. Short-term investigation of combined G-CSF and BM MNC treatment at 48 hours indicated splenic accumulation of granulocytes and transplanted cells, accompanied by a significant rise of granulocytes in the circulation and the ischemic brain. CONCLUSIONS—G-CSF improved functional recovery in spontaneously hypertensive rats, but this effect was abolished by cotransplantation of BM MNC after 48 hours. In the spleen, transplanted cells may hinder the clearance of granulocytes that were massively increased by G-CSF. Increased circulation and infiltration of granulocytes into the ischemic brain may be detrimental for stroke outcome.