title: Combination of deferoxamine and erythropoietin: therapy for hypoxia-ischemia-induced brain injury in the neonatal rat?
abstract: Deferoxamine (DFO) and erythropoietin (EPO) have each been shown to provide neuroprotection in neonatal rodent models of brain injury. In view of the described anti-oxidative actions of DFO and the anti-apoptotic and anti-inflammatory effects of EPO, we hypothesized that the combination of DFO and EPO would increase neuroprotection after neonatal hypoxic-ischemic brain injury as compared to single DFO or EPO treatment. At postnatal day 7 rats underwent right common carotid artery occlusion followed by a 90-min exposure to 8% oxygen. Rats were treated intraperitoneally with DFO (200mg/kg), recombinant human EPO (1 kU/kg), a combination of DFO-EPO or vehicle at 0, 24 and 48 h after hypoxia-ischemia (HI) and were sacrificed at 72 h. DFO-EPO administration reduced the number of cleaved caspase 3-positive cells in the ipsilateral cerebral cortex. Early neuronal damage was assessed by staining for microtubuli-associated protein (MAP)-2. In our model 63+/-9% loss of ipsilateral MAP-2 was observed after HI, indicating extensive brain injury. DFO, EPO or DFO-EPO treatment did not improve neuronal integrity as defined by MAP-2. Cerebral white matter tracts were stained for myelin basic protein (MBP), a constituent of myelin. Hypoxia-ischemia strongly reduced MBP staining which suggests white matter damage. However, DFO, EPO and DFO-EPO treatment had no effect on the loss of MBP staining. Finally, HI-induced loss of striatal tyrosine hydroxylase staining was not attenuated by DFO, EPO or DFO-EPO. Although DFO-EPO treatment reduced the number of cleaved caspase 3(+) cells, treatment with DFO, EPO, or with the combination of DFO and EPO did not protect against gray or white matter damage in the experimental setting applied.
authors.affiliation: Laboratory for Psychoneuroimmunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Michael A
authors.initials: MA
authors.lastname: van der Kooij
authors.forename: Floris
authors.initials: F
authors.lastname: Groenendaal
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
authors.forename: Frank
authors.initials: F
authors.lastname: van Bel
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology; D020520:Brain Infarction / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D019610:Cytoprotection / Q000187:drug effects* / Q000502:physiology; D003676:Deferoxamine / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004338:Drug Combinations; D004357:Drug Synergism; D004921:Erythropoietin / Q000494:pharmacology* / Q000627:therapeutic use; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D004338:Drug Combinations; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D004676:Myelin Basic Protein; D004921:Erythropoietin; D053148:Caspase 3; D003676:Deferoxamine