Abstract
Hydrogen (H2) has been reported to neutralize toxic reactive oxygen species. Oxidative stress is an important mechanism of neuronal damage after perinatal asphyxia. We examined whether 2.1% H2-supplemented room air (H2-RA) ventilation would preserve cerebrovascular reactivity (CR) and brain morphology after asphyxia/reventilation (A/R) in newborn pigs. Anesthetized, ventilated piglets were assigned to one of the following groups: A/R with RA or H2-RA ventilation (A/R-RA and A/R-H2-RA; n = 8 and 7, respectively) and respective time control groups (n = 9 and 7). Asphyxia was induced by suspending ventilation for 10 min, followed by reventilation with the respective gases for 4 h. After euthanasia, the brains were processed for neuropathological examination. Pial arteriolar diameter changes to graded hypercapnia (5–10% CO2 inhalation), and NMDA (10−4 M) were determined using the closed cranial window/intravital microscopy before and 1 h after asphyxia. Neuropathology revealed that H2-RA ventilation significantly reduced neuronal injury induced by A/R in virtually all examined brain regions including the cerebral cortex, the hippocampus, basal ganglia, cerebellum, and the brainstem. Furthermore, H2-RA ventilation significantly increased CR to hypercapnia after A/R (% vasodilation was 23 ± 4% versus 41 ± 9%, p < 0.05). H2-RA ventilation did not affect reactive oxygen species-dependent CR to NMDA. In summary, H2-RA could be a promising approach to reduce the neurologic deficits after perinatal asphyxia.
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Abbreviations
- A/R:
-
asphyxia/reventilation
- aCSF:
-
artificial cerebrospinal fluid
- CoBF:
-
cortical blood flow
- CR:
-
cerebrovascular reactivity
- H2-RA:
-
hydrogen-supplemented room air
- MABP:
-
mean arterial blood pressure
- PAD:
-
pial arteriolar diameter
- RA:
-
room air
- ROS:
-
reactive oxygen species
References
Bryce J, Boschi-Pinto C, Shibuya K, Black RE 2005 WHO estimates of the causes of death in children. Lancet 365: 1147–1152
Degos V, Loron G, Mantz J, Gressens P 2008 Neuroprotective strategies for the neonatal brain. Anesth Analg 106: 1670–1680
Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, Kapellou O, Levene M, Marlow N, Porter E, Thoresen M, Whitelaw A, Brocklehurst P 2009 Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 361: 1349–1358
Rutherford M, Ramenghi LA, Edwards AD, Brocklehurst P, Halliday H, Levene M, Strohm B, Thoresen M, Whitelaw A, Azzopardi D 2010 Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial. Lancet Neurol 9: 39–45
Vento M, Asensi M, Sastre J, Garcia-Sala F, Pallardo FV, Vina J 2001 Resuscitation with room air instead of 100% oxygen prevents oxidative stress in moderately asphyxiated term neonates. Pediatrics 107: 642–647
Buonocore G, Perrone S, Longini M, Vezzosi P, Marzocchi B, Paffetti P, Bracci R 2002 Oxidative stress in preterm neonates at birth and on the seventh day of life. Pediatr Res 52: 46–49
Saugstad OD 2005 Room air resuscitation-two decades of neonatal research. Early Hum Dev 81: 111–116
Solberg R, Andresen JH, Escrig R, Vento M, Saugstad OD 2007 Resuscitation of hypoxic newborn piglets with oxygen induces a dose-dependent increase in markers of oxidation. Pediatr Res 62: 559–563
Kumar VH, Patel A, Swartz DD, Wang H, Wynn KA, Nielsen LC, Ryan RM 2010 Exposure to supplemental oxygen and its effects on oxidative stress and antioxidant enzyme activity in term newborn lambs. Pediatr Res 67: 66–71
Munkeby BH, Borke WB, Bjornland K, Sikkeland LI, Borge GI, Halvorsen B, Saugstad OD 2004 Resuscitation with 100% O2 increases cerebral injury in hypoxemic piglets. Pediatr Res 56: 783–790
Temesvári P, Karg E, Bodi I, Nemeth I, Pinter S, Lazics K, Domoki F, Bari F 2001 Impaired early neurologic outcome in newborn piglets reoxygenated with 100% oxygen compared with room air after pneumothorax-induced asphyxia. Pediatr Res 49: 812–819
Domoki F, Zimmermann A, Cserni G, Bori R, Temesvari P, Bari F 2006 Reventilation with room air or 100% oxygen after asphyxia differentially affects cerebral neuropathology in newborn pigs. Acta Paediatr 95: 1109–1115
Davis PG, Tan A, O'Donnell CP, Schulze A 2004 Resuscitation of newborn infants with 100% oxygen or air: a systematic review and meta-analysis. Lancet 364: 1329–1333
Saugstad OD, Ramji S, Vento M 2005 Resuscitation of depressed newborn infants with ambient air or pure oxygen: a meta-analysis. Biol Neonate 87: 27–34
ILCOR 2006 The International Liaison Committee on Resuscitation (ILCOR) consensus on science with treatment recommendations for pediatric and neonatal patients: neonatal resuscitation. Pediatrics 117: e978–e988
Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama Y, Asoh S, Ohta S 2007 Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med 13: 688–694
Cai J, Kang Z, Liu K, Liu W, Li R, Zhang JH, Luo X, Sun X 2009 Neuroprotective effects of hydrogen saline in neonatal hypoxia-ischemia rat model. Brain Res 1256: 129–137
Cai J, Kang Z, Liu WW, Luo X, Qiang S, Zhang JH, Ohta S, Sun X, Xu W, Tao H, Li R 2008 Hydrogen therapy reduces apoptosis in neonatal hypoxia-ischemia rat model. Neurosci Lett 441: 167–172
Fu Y, Ito M, Fujita Y, Ito M, Ichihara M, Masuda A, Suzuki Y, Maesawa S, Kajita Y, Hirayama M, Ohsawa I, Ohta S, Ohno K 2009 Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson's disease. Neurosci Lett 453: 81–85
Domoki F, Perciaccante JV, Shimizu K, Puskar M, Busija DW, Bari F 2002 N-methyl-D-aspartate-induced vasodilation is mediated by endothelium-independent nitric oxide release in piglets. Am J Physiol Heart Circ Physiol 282: H1404–H1409
Ferriero DM 2004 Neonatal brain injury. N Engl J Med 351: 1985–1995
Benders MJ, Bos AF, Rademaker CM, Rijken M, Torrance HL, Groenendaal F, van Bel F 2006 Early postnatal allopurinol does not improve short term outcome after severe birth asphyxia. Arch Dis Child Fetal Neonatal Ed 91: F163–F165
Torrance HL, Benders MJ, Derks JB, Rademaker CM, Bos AF, Van Den Berg P, Longini M, Buonocore G, Venegas M, Baquero H, Visser GH, Van Bel F 2009 Maternal allopurinol during fetal hypoxia lowers cord blood levels of the brain injury marker S-100B. Pediatrics 124: 350–357
Sauer H, Wartenberg M, Hescheler J 2001 Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cell Physiol Biochem 11: 173–186
Busija DW, Leffler CW 1989 Dilator effects of amino acid neurotransmitters on piglet pial arterioles. Am J Physiol 257: H1200–H1203
Busija DW, Bari F, Domoki F, Louis T 2007 Mechanisms involved in the cerebrovascular dilator effects of N-methyl-d-aspartate in cerebral cortex. Brain Res Rev 56: 89–100
Meng W, Tobin JR, Busija DW 1995 Glutamate-induced cerebral vasodilation is mediated by nitric oxide through N-methyl-D-aspartate receptors. Stroke 26: 857–862, discussion 863
Busija DW, Meng W, Bari F, McGough PS, Errico RA, Tobin JR, Louis TM 1996 Effects of ischemia on cerebrovascular responses to N-methyl-D-aspartate in piglets. Am J Physiol 270: H1225–H1230
Busija DW, Wei M 1993 Altered cerebrovascular responsiveness to N-methyl-D-aspartate after asphyxia in piglets. Am J Physiol 265: H389–H394
Leffler CW, Mirro R, Shanklin DR, Armstead WM, Shibata M 1994 Light/dye microvascular injury selectively eliminates hypercapnia-induced pial arteriolar dilation in newborn pigs. Am J Physiol 266: H623–H630
Hobbs C, Thoresen M, Tucker A, Aquilina K, Chakkarapani E, Dingley J 2008 Xenon and hypothermia combine additively, offering long-term functional and histopathologic neuroprotection after neonatal hypoxia/ischemia. Stroke 39: 1307–1313
Thoresen M, Hobbs CE, Wood T, Chakkarapani E, Dingley J 2009 Cooling combined with immediate or delayed xenon inhalation provides equivalent long-term neuroprotection after neonatal hypoxia-ischemia. J Cereb Blood Flow Metab 29: 707–714
Pan Y, Zhang H, VanDeripe DR, Cruz-Flores S, Panneton WM 2007 Heliox and oxygen reduce infarct volume in a rat model of focal ischemia. Exp Neurol 205: 587–590
David HN, Haelewyn B, Chazalviel L, Lecocq M, Degoulet M, Risso JJ, Abraini JH 2009 Post-ischemic helium provides neuroprotection in rats subjected to middle cerebral artery occlusion-induced ischemia by producing hypothermia. J Cereb Blood Flow Metab 29: 1159–1165
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This study was supported by grants from the National Scientific Research Fund of Hungary (OTKA, K68976, K63401). F.D. was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences.
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Domoki, F., Oláh, O., Zimmermann, A. et al. Hydrogen is Neuroprotective and Preserves Cerebrovascular Reactivity in Asphyxiated Newborn Pigs. Pediatr Res 68, 387–392 (2010). https://doi.org/10.1203/PDR.0b013e3181f2e81c
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DOI: https://doi.org/10.1203/PDR.0b013e3181f2e81c
