Effects of Allopurinol and Deferoxamine on Reperfusion Injury of the Brain in Newborn Piglets after Neonatal Hypoxia-Ischemia

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 ϭ 12), allopurinol (30 mg/kg/d, n ϭ 10), or deferoxamine (12.5 mg/kg/d, n ϭ 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. The neonatal brain appears to be vulnerable to oxidative stress after perinatal hypoxia-ischemia with reperfusion and reoxygenation due to excessive free radical production, relatively large amounts of NPBI production, and inadequate scavenging mechanisms to counteract these potentially neurotoxic events (1). During perinatal hypoxia-ischemia and upon reperfusion, a biochemical cascade occurs, including modification of the NMDA receptor-ion channel complex, leading to increased intracellular Ca 2ϩ and resulting in the conversion of xanthine dehydrogenase to xanthine oxidase (2). During the primary hypoxic-ischemic insult, ADP is degraded to hypoxanthine and then oxidated to xanthine and on to uric acid by xanthine oxidase upon reperfusion [for review, see Fellman and Raivio (3)]. During these reactions, superoxide and hydrogen peroxide are formed, which can be converted to the highly reactive hydroxyl radical through the Haber-Weiss reaction, catalyzed by ferrous iron (4). The reactive oxygen species Received October 28, 2002; accepted April 11, 2003

Nonprotein-Bound Iron and Plasma Protein Oxidative Stress at Birth

“…Oxidation of albumin can therefore be expected to decrease plasma antioxidant defenses and increase the likelihood of tissue damage due to OS in the newborn. This finding is extremely relevant to clinical practice suggesting a role for NPBI chelators in decreasing neonatal oxidative stress (38). …”

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

“…138 Additionally, in large animal models of hypoxic/ischemic injury in the immature brain, deferoxamine reduces free iron levels, preserves cerebral energy metabolism and electrical brain activity, and attenuates edema. 139,140 With such compelling evidence for the beneficial effects of iron chelation in varying types of brain injury, deferoxamine, or a similar compound, is a prime therapeutic candidate for the treatment of TBI in children.…”

Umbilical cord clamping in term piglets: A useful model to study perinatal asphyxia?

“…The various methods applied to induce hypoxia and/or ischemia include, among others, reduction of the fraction of inspired oxygen, either by placing newborn piglets in a hypoxia chamber with a reduced ambient oxygen tension [7] or by decreasing the inspiratory oxygen percentage in mechanically ventilated piglets [10]. The latter method has also been conducted with simultaneous occlusion of both carotid arteries [11,12].…”