Hypoxia-inducible factor 1alpha and erythropoietin upregulation with deferoxamine salvage after neonatal stroke.
Treatment with deferoxamine (DFO) is protective against focal ischemia with global hypoxia when given as a preconditioning stimulus in neonatal rodents. DFO acts as an iron chelator and may stabilize HIF1alpha. Therefore, we hypothesized that DFO would protect against pure ischemia-reperfusion injury when given after the insult and that the protection would be associated with expression of hypoxia-inducible factor 1alpha (HIF1alpha) and downstream target genes such as erythropoietin (Epo). To test these hypotheses, we performed middle cerebral artery (MCA) occlusion in postnatal day 10 (P10) rats for 1.5 h followed by treatment with DFO or vehicle upon reperfusion. Preserved brain volumes were measured with cresyl violet staining 1 week after the insult. HIF1alpha and Epo expression were determined by Western blot and immunocytochemical analyses at different time points after injury. We found that DFO treatment preserved brain volumes when compared to vehicle (P < 0.05). In DFO-treated ischemic cortices, HIF1alpha expression peaked early, while Epo expression was seen in two phases and in different cell populations. Epo immunoreactivity colocalized with neuronal markers at 8 h but with astrocytic markers at 1 week. These results suggest that DFO is protective when administered after neonatal ischemic stroke and that this protection may be like that afforded by preconditioning through the upregulation of similar downstream pathways.
Mu
Dezhi
D
Department of Neurology, University of California San Francisco, San Francisco, CA 94143-0663, USA.
Chang
Yun Sil
YS
Vexler
Zinaida S
ZS
Ferriero
Donna M
DM
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D003676:Deferoxamine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000378:metabolism*; D005455:Fluorescent Antibody Technique / Q000379:methods; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000627:therapeutic use; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D005904:Glial Fibrillary Acidic Protein; D007502:Iron Chelating Agents; D004921:Erythropoietin; D010751:Phosphopyruvate Hydratase; D003676:Deferoxamine