EGF and FGF-2 infusion increases post-ischemic neural progenitor cell proliferation in the adult rat brain

OBJECTIVE: Epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2) play 1 a critical role in neurogenesis. In the present study, we evaluated the additive effect of administering these two factors on post-ischemic progenitor cell proliferation, survival, and phenotypic maturation in the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ) in the adult rat brain after transient middle cerebral artery occlusion. METHODS: A combination of EGF+FGF-2 (each 1.44 ng/d) was continuously administered into the lateral ventricles for 3 days, 5-bromodeoxyuridine (BrdUrd) was 1 injected (50 mg/Kg) twice daily for days starting on Day I of reperfusion, and cohorts of rats were sacrificed on Day 5 and Day 21 of reperfusion. RESULTS: Compared with sham controls, ischemic rats showed a significantly higher number of newly proliferated cells in both the DG (by 766 +/- 37%, P < 0.05) and the SVZ (by 650 +/- 43%, P < 0.05). Of the progenitor cells proliferated on Day 5 after ischemia, 41 +/- 6% in the DIG and 28 +/- 5% in the SVZ survived to 3 weeks. Compared with vehicle control, the EGF + FGF-2 infusion significantly increased the postischemic progenitor cell proliferation (by 319 +/- 40%, P < 0.05 in the DG and by 366 +/- 32%, P < 0.05 in the SVZ) and survival (by 40 +/- 12%, P < 0.05 in the DG and by 522 +/- 47%, P < 0.05 in the SVZ) studied at 5 and 21 days, respectively. Furthermore, of the newly proliferated cells survived to 3 weeks after ischemia, EGF + FGF-2 caused a significantly higher number of neuronal nuclear protein-BrdUrd infusion double-positive mature neurons in the DG (46 +/- 9%, P < 0.05) compared with vehicle control. Neuronal nuclear protein and BrdUrd double-positive mature neurons were also found in the DG. Glial fibrillary acidic protein-positive astrocytes did not show 1 double-positive staining in either region. CONCLUSION: Specific growth factor infusion enhances post-ischemic progenitor 1 cell proliferation by 5 days of reperfusion and neuronal maturation by 21 days of reperfusion in both the DG and SVZ in the adult rat brain.