Abstract
Striatal neurons are highly vulnerable to hypoxia-ischemia (HI) in term newborns. In a piglet model of HI, striatal neurons develop oxidative stress and organelle disruption by 3–6 h of recovery and ischemic cytopathology over 6–24 h of recovery. We tested the hypothesis that early treatment with the antioxidants EUK-134 (a manganese-salen derivative that acts as a scavenger of superoxide, hydrogen peroxide, nitric oxide or NO and peroxynitrite) or edaravone (MCI-186, a scavenger of hydroxyl radical and NO) protects striatal neurons from HI. Anesthetized newborn piglets were subjected to 40 min of hypoxia and 7 min of airway occlusion. At 30 min after resuscitation, the piglets received vehicle, EUK-134 or edaravone. Drug treatment did not affect arterial blood pressure, blood gases, blood glucose or rectal temperature. At 4 days of recovery, the density of viable neurons in the putamen of vehicle-treated piglets was 12 ± 6% (±SD) of sham-operated control density. Treatment with EUK-134 increased viability to 41 ± 17%, and treatment with edaravone increased viability to 39 ± 19%. In the caudate nucleus, neuronal viability was increased from 54 ± 11% in the vehicle group to 78 ± 15% in the EUK-134 group and to 73 ± 13% in the edaravone group. Antioxidant drug treatment accelerated recovery from neurologic deficits and decreased oxidative and nitrative damage to nucleic acids. Treatment with EUK-134 reduced the HI-induced formation of protein carbonyl groups and tyrosine nitration at 3 h of recovery. We conclude that systemic administration of antioxidant agents by 30 min after resuscitation from HI can reduce oxidative stress and salvage neurons in the highly vulnerable striatum in a large-animal model of neonatal HI. Therefore, oxidative stress is an important mechanism for this injury, and antioxidant therapy is a rational, mechanism-based approach to neuroprotection in the newborn brain.
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References
1.
Ferriero DM: Neonatal brain injury. N Engl J Med 2004;351:1985–1995.
[PubMed]
2.
Gonzalez FF, Ferriero DM: Therapeutics for neonatal brain injury. Pharmacol Ther 2008;120:43–53.
[PubMed]
3.
Ferriero DM: Oxidant mechanisms in neonatal hypoxia-ischemia. Dev Neurosci 2001;23:198–202.
[PubMed]
4.
Lafemina MJ, Sheldon RA, Ferriero DM: Acute hypoxia-ischemia results in hydrogen peroxide accumulation in neonatal but not adult mouse brain. Pediatr Res 2006;59:680–683.
[PubMed]
5.
Sheldon RA, Christen S, Ferriero DM: Genetic and pharmacologic manipulation of oxidative stress after neonatal hypoxia-ischemia. Int J Dev Neurosci 2008;26:87–92.
[PubMed]
6.
Blomgren K, Hagberg H: Free radicals, mitochondria, and hypoxia-ischemia in the developing brain. Free Radic Biol Med 2006;40:388–397.
[PubMed]
7.
Doverhag C, Keller M, Karlsson A, Hedtjarn M, Nilsson U, Kapeller E, Sarkozy G, Klimaschewski L, Humpel C, Hagberg H, Simbruner G, Gressens P, Savman K: Pharmacological and genetic inhibition of NADPH oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice. Neurobiol Dis 2008;31:133–144.
[PubMed]
8.
Palmer C, Vannucci RC, Towfighi J: Reduction of perinatal hypoxic-ischemic brain damage with allopurinol. Pediatr Res 1990;27:332–336.
[PubMed]
9.
Palmer C, Towfighi J, Roberts RL, Heitjan DF: Allopurinol administered after inducing hypoxia-ischemia reduces brain injury in 7-day-old rats. Pediatr Res 1993;33:405–411.
[PubMed]
10.
Palmer C, Roberts RL, Bero C: Deferoxamine posttreatment reduces ischemic brain injury in neonatal rats. Stroke 1994;25:1039–1045.
[PubMed]
11.
Bågenholm R, Andiné P, Hagberg H: Effects of the 21-amino steroid tirilazad mesylate (U-74006F) on brain damage and edema after perinatal hypoxia-ischemia in the rat. Pediatr Res 1996;40:399–403.
[PubMed]
12.
Wang X, Svedin P, Nie C, Lapatto R, Zhu C, Gustavsson M, Sandberg M, Karlsson JO, Romero R, Hagberg H, Mallard C: N-acetylcysteine reduces lipopolysaccharide-sensitized hypoxic-ischemic brain injury. Ann Neurol 2007;61:263–271.
[PubMed]
13.
Ikeda T, Xia YX, Kaneko M, Sameshima H, Ikenoue T: Effect of the free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186), on hypoxia-ischemia-induced brain injury in neonatal rats. Neurosci Lett 2002;329:33–36.
[PubMed]
14.
Noor JI, Ikeda T, Ueda Y, Ikenoue T: A free radical scavenger, edaravone, inhibits lipid peroxidation and the production of nitric oxide in hypoxic-ischemic brain damage of neonatal rats. Am J Obstet Gynecol 2005;193:1703–1708.
[PubMed]
15.
Noor JI, Ikeda T, Mishima K, Aoo N, Ohta S, Egashira N, Iwasaki K, Fujiwara M, Ikenoue T: Short-term administration of a new free radical scavenger, edaravone, is more effective than its long-term administration for the treatment of neonatal hypoxic-ischemic encephalopathy. Stroke 2005;36:2468–2474.
[PubMed]
16.
Noor JI, Ueda Y, Ikeda T, Ikenoue T: Edaravone inhibits lipid peroxidation in neonatal hypoxic-ischemic rats: an in vivo microdialysis study. Neurosci Lett 2007;414:5–9.
[PubMed]
17.
Zhu C, Wang X, Huang Z, Qiu L, Xu F, Vahsen N, Nilsson M, Eriksson PS, Hagberg H, Culmsee C, Plesnila N, Kroemer G, Blomgren K: Apoptosis-inducing factor is a major contributor to neuronal loss induced by neonatal cerebral hypoxia-ischemia. Cell Death Differ 2007;14:775–784.
[PubMed]
18.
Martin LJ, Brambrink A, Koehler RC, Traystman RJ: Primary sensory and forebrain motor systems in the newborn brain are preferentially damaged by hypoxia-ischemia. J Comp Neurol 1997;377:262–285.
[PubMed]
19.
Miller SP, Ramaswamy V, Michelson D, Barkovich AJ, Holshouser B, Wycliffe N, Glidden DV, Deming D, Partridge JC, Wu YW, Ashwal S, Ferriero DM: Patterns of brain injury in term neonatal encephalopathy. J Pediatr 2005;146:453–460.
[PubMed]
20.
Rutherford MA, Azzopardi D, Whitelaw A, Cowan F, Renowden S, Edwards AD, Thoresen M: Mild hypothermia and the distribution of cerebral lesions in neonates with hypoxic-ischemic encephalopathy. Pediatrics 2005;116:1001–1006.
[PubMed]
21.
Martin LJ, Brambrink AM, Price AC, Kaiser A, Agnew DM, Ichord RN, Traystman RJ: Neuronal death in newborn striatum after hypoxia-ischemia is necrosis and evolves with oxidative stress. Neurobiol Dis 2000;7:169–191.
[PubMed]
22.
Mueller-Burke D, Koehler RC, Martin LJ: Rapid NMDA receptor phosphorylation and oxidative stress precede striatal neurodegeneration after hypoxic ischemia in newborn piglets and are attenuated with hypothermia. Int J Dev Neurosci 2008;26:67–76.
[PubMed]
23.
Yang ZJ, Torbey M, Li X, Bernardy J, Golden WC, Martin LJ, Koehler RC: Dopamine receptor modulation of hypoxic-ischemic neuronal injury in striatum of newborn piglets. J Cereb Blood Flow Metab 2007;27:1339–1351.
[PubMed]
24.
Yang ZJ, Carter EL, Torbey MT, Martin LJ, Koehler RC: Sigma receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine modulates neu- ronal nitric oxide synthase/postsynaptic density-95 coupling mechanisms and protects against neonatal ischemic degeneration of striatal neurons. Exp Neurol 2010;221:166–174.
[PubMed]
25.
Yoshida H, Yanai H, Namiki Y, Fukatsu-Sasaki K, Furutani N, Tada N: Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury. CNS Drug Rev 2006;12:9–20.
[PubMed]
26.
Edaravone Acute Brain Infarction Study Group: Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction: randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc Dis 2003;15:222–229.
[PubMed]
27.
Golden TR, Patel M: Catalytic antioxidants and neurodegeneration. Antioxid Redox Signal 2009;11:555–570.
[PubMed]
28.
Doctrow SR, Huffman K, Marcus CB, Tocco G, Malfroy E, Adinolfi CA, Kruk H, Baker K, Lazarowych N, Mascarenhas J, Malfroy B: Salen-manganese complexes as catalytic scavengers of hydrogen peroxide and cytoprotective agents: structure-activity relationship studies. J Med Chem 2002;45:4549–4558.
[PubMed]
29.
Pong K, Doctrow SR, Baudry M: Prevention of 1-methyl-4-phenylpyridinium- and 6-hydroxydopamine-induced nitration of tyrosine hydroxylase and neurotoxicity by EUK-134, a superoxide dismutase and catalase mimetic, in cultured dopaminergic neurons. Brain Res 2000;881:182–189.
[PubMed]
30.
Pong K, Doctrow SR, Huffman K, Adinolfi CA, Baudry M: Attenuation of staurosporine-induced apoptosis, oxidative stress, and mitochondrial dysfunction by synthetic superoxide dismutase and catalase mimetics, in cultured cortical neurons. Exp Neurol 2001;171:84–97.
[PubMed]
31.
Sharpe MA, Ollosson R, Stewart VC, Clark JB: Oxidation of nitric oxide by oxomanganese-salen complexes: a new mechanism for cellular protection by superoxide dismutase/catalase mimetics. Biochem J 2002;366:97–107.
[PubMed]
32.
Baker K, Marcus CB, Huffman K, Kruk H, Malfroy B, Doctrow SR: Synthetic combined superoxide dismutase/catalase mimetics are protective as a delayed treatment in a rat stroke model: a key role for reactive oxygen species in ischemic brain injury. J Pharmacol Exp Ther 1998;284:215–221.
[PubMed]
33.
Rong Y, Doctrow SR, Tocco G, Baudry M: EUK-134, a synthetic superoxide dismutase and catalase mimetic, prevents oxidative stress and attenuates kainate-induced neuropathology. Proc Natl Acad Sci USA 1999;96:9897–9902.
[PubMed]
34.
Shichinohe H, Kuroda S, Yasuda H, Ishikawa T, Iwai M, Horiuchi M, Iwasaki Y: Neuroprotective effects of the free radical scavenger edaravone (MCI-186) in mice permanent focal brain ischemia. Brain Res 2004;1029:200–206.
[PubMed]
35.
Zhang W, Sato K, Hayashi T, Omori N, Nagano I, Kato S, Horiuchi S, Abe K: Extension of ischemic therapeutic time window by a free radical scavenger, edaravone, reperfused with tPA in rat brain. Neurol Res 2004;26:342–348.
[PubMed]
36.
Agnew DM, Koehler RC, Guerguerian AM, Shaffner DH, Traystman RJ, Martin LJ, Ichord RN: Hypothermia for 24 hours after asphyxic cardiac arrest in piglets provides striatal neuroprotection that is sustained 10 days after rewarming. Pediatr Res 2003;54:253–262.
[PubMed]
37.
Martin LJ, Brambrink AM, Lehmann C, Portera-Cailliau C, Koehler RC, Rothstein J, Traystman RJ: Hypoxia-ischemia causes abnormalities in glutamate transporters and death of astroglia and neurons in newborn striatum. Ann Neurol 1997;42:335–348.
[PubMed]
38.
Johnston MV: Selective vulnerability in the neonatal brain. Ann Neurol 1998;44:155–156.
[PubMed]
39.
Brambrink AM, Martin LJ, Hanley DF, Becker KJ, Koehler RC, Traystman RJ: Effects of the AMPA receptor antagonist NBQX on outcome of newborn pigs after asphyxic cardiac arrest. J Cereb Blood Flow Metab 1999;19:927–938.
[PubMed]
40.
Buonocore G, Groenendaal F: Anti-oxidant strategies. Semin Fetal Neonatal Med 2007;12:287–295.
[PubMed]
41.
Comellas AP, Dada LA, Lecuona E, Pesce LM, Chandel NS, Quesada N, Budinger GR, Strous GJ, Ciechanover A, Sznajder JI: Hypoxia-mediated degradation of Na,K-ATPase via mitochondrial reactive oxygen species and the ubiquitin-conjugating system. Circ Res 2006;98:1314–1322.
[PubMed]
42.
Samai M, Sharpe MA, Gard PR, Chatterjee PK: Comparison of the effects of the superoxide dismutase mimetics EUK-134 and tempol on paraquat-induced nephrotoxicity. Free Radic Biol Med 2007;43:528–534.
[PubMed]
43.
McLean C, Ferriero D: Mechanisms of hypoxic-ischemic injury in the term infant. Semin Perinatol 2004;28:425–432.
[PubMed]
44.
Martin LJ, Al-Abdulla NA, Brambrink AM, Kirsch JR, Sieber FE, Portera-Cailliau C: Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: a perspective on the contributions of apoptosis and necrosis. Brain Res Bull 1998;46:281–309.
[PubMed]
45.
Sarco DP, Becker J, Palmer C, Sheldon RA, Ferriero DM: The neuroprotective effect of deferoxamine in the hypoxic-ischemic immature mouse brain. Neurosci Lett 2000;282:113–116.
[PubMed]
46.
Peeters-Scholte C, Braun K, Koster J, Kops N, Blomgren K, Buonocore G, Buul-Offers S, Hagberg H, Nicolay K, van Bel F, Groenendaal F: Effects of allopurinol and deferoxamine on reperfusion injury of the brain in newborn piglets after neonatal hypoxia-ischemia. Pediatr Res 2003;54:516–522.
[PubMed]
47.
Benders MJ, Bos AF, Rademaker CM, Rijken M, Torrance HL, Groenendaal F, van Bel F: Early postnatal allopurinol does not improve short term outcome after severe birth asphyxia. Arch Dis Child Fetal Neonatal Ed 2006;91:F163–F165.
[PubMed]
48.
Rosenthal RA, Huffman KD, Fisette LW, Damphousse CA, Callaway WB, Malfroy B, Doctrow SR: Orally available Mn porphyrins with superoxide dismutase and catalase activities. J Biol Inorg Chem 2009;14:979–991.
[PubMed]
49.
Liang LP, Huang J, Fulton R, Day BJ, Patel M: An orally active catalytic metalloporphyrin protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in vivo. J Neurosci 2007;27:4326–4333.
[PubMed]
50.
Schleien CL, Koehler RC, Shaffner DH, Eberle B, Traystman RJ: Blood-brain barrier disruption after cardiopulmonary resuscitation in immature swine. Stroke 1991;22:477–483.
[PubMed]
51.
Mackensen GB, Patel M, Sheng H, Calvi CL, Batinic-Haberle I, Day BJ, Liang LP, Fridovich I, Crapo JD, Pearlstein RD, Warner DS: Neuroprotection from delayed postischemic administration of a metalloporphyrin catalytic antioxidant. J Neurosci 2001;21:4582–4592.
[PubMed]
52.
Sheng H, Yang W, Fukuda S, Tse HM, Paschen W, Johnson K, Batinic-Haberle I, Crapo JD, Pearlstein RD, Piganelli J, Warner DS: Long-term neuroprotection from a potent redox-modulating metalloporphyrin in the rat. Free Radic Biol Med 2009;47:917–923.
[PubMed]
53.
Toyokuni S: Reactive oxygen species-induced molecular damage and its application in pathology. Pathol Int 1999;49:91–102.
[PubMed]
54.
Groenendaal F, Lammers H, Smit D, Nikkels PG: Nitrotyrosine in brain tissue of neonates after perinatal asphyxia. Arch Dis Child Fetal Neonatal Ed 2006;91:F429–F433.
[PubMed]
55.
Groenendaal F, Vles J, Lammers H, de Vente J, Smit D, Nikkels PG: Nitrotyrosine in human neonatal spinal cord after perinatal asphyxia. Neonatology 2008;93:1–6.
[PubMed]
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