Abstract
The hypothesis was tested that treatment with allopurinol, a xanthine oxidase inhibitor, or deferoxamine, a chelator of nonprotein-bound iron, preserved cerebral energy metabolism, attenuated development of edema, and improved histologic outcome in the newborn piglet at 24 h after hypoxia-ischemia. Thirty-two newborn piglets were subjected to 1 h of hypoxia-ischemia by occluding both carotid arteries and reducing the fraction of inspired oxygen; five newborn piglets served as sham-operated controls. The depth of hypoxia-ischemia was controlled by phosphorous magnetic resonance spectroscopy. Upon reperfusion and reoxygenation, piglets received vehicle (n = 12), allopurinol (30 mg/kg/d, n = 10), or deferoxamine (12.5 mg/kg/d, n = 10). The cerebral energy status was determined with phosphorous magnetic resonance spectroscopy. The presence of vasogenic edema was assessed by T2-weighted magnetic resonance imaging. Brain cell injury was assessed with caspase-3 activity, histology, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end (TUNEL)-labeling. At 24 h after hypoxia-ischemia, the phosphocreatine/inorganic phosphate ratios were significantly decreased in vehicle-treated, but not in allopurinol- or deferoxamine-treated piglets. Water T2 values were significantly increased at 24 h after hypoxia-ischemia in cerebral cortex, thalamus, and striatum of vehicle-treated piglets, but not in allopurinol- and deferoxamine-treated piglets. No differences in caspase-3 activity, histologic outcome, or TUNEL-labeling were demonstrated between the three treatment groups. We suggest that allopurinol and deferoxamine may have an additional value in the treatment of perinatal hypoxia-ischemia with other neuroprotective agents or in combination with hypothermia.
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Abbreviations
- BE:
-
base excess
- Fio2:
-
fraction of inspired oxygen
- NPBI:
-
nonprotein-bound iron
- MABP:
-
mean arterial blood pressure
- MRI:
-
magnetic resonance imaging
- PCr:
-
phosphocreatine
- Pi:
-
inorganic phosphate
- 31P-MRS:
-
phosphorous magnetic resonance spectroscopy
- TUNEL:
-
terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling
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Acknowledgements
The authors thank Evelyn van den Tweel, Tomoaki Ioroi, and Nicole Hamers for their help with the experiments and the histology. We also thank the biotechnicians of the Central Laboratory Animal Institute of the Utrecht University for their enthusiastic help during the experiments; Robin de Graaf for designing the MR sequences; Changlian Zhu, from the Perinatal Center in Göteborg, Sweden, for assisting in the caspase-3 measurements; Tessa Ververs, of the pharmacological department of the University Medical Center, Utrecht, the Netherlands, for the determination of the allopurinol and oxypurinol concentrations; Cheraar Leusink for technical support during the animal experiments; and Gerard van Vliet for constructing the MR head coils. The MRVI software package was kindly provided by the participants of the EU Network programmes: Human Capital and Mobility, CHRX-CT94-0432 and Training and Mobility of Researchers, ERB-FMRX-CT970160.
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Supported by the Netherlands Organization for Scientific Research (NWO-AGIKO stipend 920–03–039) and the University Medical Center Utrecht (“Sterproject”). Oxford Instruments provided a cerebral function monitor, and Tyco Healthcare provided a Nellcor NPB-290 pulse oximeter.
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Peeters-Scholte, C., Braun, K., Koster, J. et al. Effects of Allopurinol and Deferoxamine on Reperfusion Injury of the Brain in Newborn Piglets after Neonatal Hypoxia-Ischemia. Pediatr Res 54, 516–522 (2003). https://doi.org/10.1203/01.PDR.0000081297.53793.C6
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DOI: https://doi.org/10.1203/01.PDR.0000081297.53793.C6
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