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 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 injected (50 mg/Kg) twice daily for 3 days starting on Day 1 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 DG and 28 +/- 5% in the SVZ survived to 3 weeks. Compared with vehicle control, the EGF + FGF-2 infusion significantly increased the post-ischemic 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 infusion caused a significantly higher number of neuronal nuclear protein-BrdUrd 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 double-positive staining in either region.


CONCLUSIONS
Specific growth factor infusion enhances post-ischemic progenitor 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.
Türeyen
Kudret
K
Department of, Neurological Surgery, University of Wisconsin, Madison, Wisconsin 53792-3232, USA.
Vemuganti
Raghu
R
Bowen
Kellie K
KK
Sailor
Kurt A
KA
Dempsey
Robert J
RJ
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage / Q000494:pharmacology*; D007276:Injections, Intraventricular; D002546:Ischemic Attack, Transient / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D020768:Middle Cerebral Artery; D009474:Neurons / Q000473:pathology*; D010641:Phenotype; D051381:Rats; D011918:Rats, Inbred SHR; D013234:Stem Cells / Q000473:pathology*
D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor