Effects of allopurinol and deferoxamine on reperfusion injury of the brain in newborn piglets after neonatal hypoxia-ischemia.
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.
Peeters-Scholte
Cacha
C
Department of Neonatology, Image Sciences Institute, University Medical Center, 3584 EA Utrecht, The Netherlands.
Braun
Kees
K
Koster
Johanna
J
Kops
Nicole
N
Blomgren
Klas
K
Buonocore
Giuseppe
G
van Buul-Offers
Sylvia
S
Hagberg
Henrik
H
Nicolay
Klaas
K
van Bel
Frank
F
Groenendaal
Floris
F
D000493:Allopurinol / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003676:Deferoxamine / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000378:metabolism / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D015427:Reperfusion Injury / Q000473:pathology*; D013552:Swine
D004791:Enzyme Inhibitors; D007502:Iron Chelating Agents; D000493:Allopurinol; D007501:Iron; D053148:Caspase 3; D020169:Caspases; D003676:Deferoxamine