Abstract
Background: Germinal matrix hemorrhage (GMH) is a neurological disease of very low birth weight premature infants leading to post-hemorrhagic hydrocephalus, cerebral palsy, and mental retardation. Hydrogen (H2) is a potent antioxidant shown to selectively reverse cytotoxic oxygen-radical injury in the brain. This study investigated the therapeutic effect of hydrogen gas after neonatal GMH injury.
Methods: Neonatal rats underwent stereotaxic infusion of clostridial collagenase into the right germinal matrix brain region. Cognitive function was assessed at 3 weeks, and then sensorimotor function, cerebral, cardiac and splenic growths were measured 1 week thereafter.
Results: Hydrogen gas inhalation markedly suppressed mental retardation and cerebral palsy outcomes in rats at the juvenile developmental stage. The administration of H2 gas, early after neonatal GMH, also normalized the brain atrophy, splenomegaly and cardiac hypertrophy 1 month after injury.
Conclusion: This study supports the role of cytotoxic oxygen-radical injury in early neonatal GMH. Hydrogen gas inhalation is an effective strategy to help protect the infant brain from the post-hemorrhagic consequences of brain atrophy, mental retardation and cerebral palsy. Further studies are necessary to determine the mechanistic basis of these protective effects.
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References
Ballabh P (2010) Intraventricular hemorrhage in premature infants: mechanism of disease. Pediatr Res 67:1–8. doi:10.1203/PDR.0b013e3181c1b176
Kadri H, Mawla AA, Kazah J (2006) The incidence, timing, and predisposing factors of germinal matrix and intraventricular hemorrhage (GMH/IVH) in preterm neonates. Childs Nerv Syst 22:1086–1090. doi:10.1007/s00381-006-0050-6
Heron M, Sutton PD, Xu J, Ventura SJ, Strobino DM, Guyer B (2010) Annual summary of vital statistics: 2007. Pediatrics 125:4–15. doi:peds.2009-2416 [pii], 10.1542/peds.2009-2416
Ballabh P, Braun A, Nedergaard M (2004) The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 16:1–13. doi:10.1016/j.nbd.2003.12.016, S0969996103002833 [pii]
Murphy BP, Inder TE, Rooks V, Taylor GA, Anderson NJ, Mogridge N, Horwood LJ, Volpe JJ (2002) Posthaemorrhagic ventricular dilatation in the premature infant: natural history and predictors of outcome. Arch Dis Child Fetal Neonatal Ed 87:F37–F41
Balasubramaniam J, Del Bigio MR (2006) Animal models of germinal matrix hemorrhage. J Child Neurol 21:365–371
Peeling J, Del Bigio MR, Corbett D, Green AR, Jackson DM (2001) Efficacy of disodium 4-[(tert-butylimino)methyl]benzene-1, 3-disulfonate N-oxide (NXY-059), a free radical trapping agent, in a rat model of hemorrhagic stroke. Neuropharmacology 40:433–439. doi:S0028390800001702 [pii]
Peeling J, Yan HJ, Chen SG, Campbell M, Del Bigio MR (1998) Protective effects of free radical inhibitors in intracerebral hemorrhage in rat. Brain Res 795:63–70. doi:S0006-8993(98)00253-4 [pii]
Peeling J, Yan HJ, Corbett D, Xue M, Del Bigio MR (2001) Effect of FK-506 on inflammation and behavioral outcome following intracerebral hemorrhage in rat. Exp Neurol 167:341–347. doi:10.1006/exnr.2000.7564, S0014-4886(00)97564-2 [pii]
Nakamura T, Kuroda Y, Yamashita S, Zhang X, Miyamoto O, Tamiya T, Nagao S, Xi G, Keep RF, Itano T (2008) Edaravone attenuates brain edema and neurologic deficits in a rat model of acute intracerebral hemorrhage. Stroke 39:463–469. doi:STROKEAHA.107.486654 [pii], 10.1161/STROKEAHA.107.486654
Wagner KR, Sharp FR, Ardizzone TD, Lu A, Clark JF (2003) Heme and iron metabolism: role in cerebral hemorrhage. J Cereb Blood Flow Metab 23:629–652. doi:10.1097/01.WCB.0000073905. 87928.6D
Wu J, Hua Y, Keep RF, Nakamura T, Hoff JT, Xi G (2003) Iron and iron-handling proteins in the brain after intracerebral hemorrhage. Stroke 34:2964–2969. doi:10.1161/01.STR.0000103140.52838.45, 01.STR.0000103140.52838.45 [pii]
Xi G, Keep RF, Hoff JT (2006) Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 5:53–63. doi:S1474-4422(05)70283-0 [pii], 10.1016/S1474-4422(05)70283-0
Xi G, Wagner KR, Keep RF, Hua Y, de Courten-Myers GM, Broderick JP, Brott TG, Hoff JT (1998) Role of blood clot formation on early edema development after experimental intracerebral hemorrhage. Stroke 29:2580–2586
Nakamura T, Keep RF, Hua Y, Hoff JT, Xi G (2005) Oxidative DNA injury after experimental intracerebral hemorrhage. Brain Res 1039:30–36. doi:S0006-8993(05)00104-6 [pii], 10.1016/j.brainres. 2005.01.036
Lee KR, Colon GP, Betz AL, Keep RF, Kim S, Hoff JT (1996) Edema from intracerebral hemorrhage: the role of thrombin. J Neurosurg 84:91–96
Xi G, Keep RF, Hoff JT (1998) Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J Neurosurg 89:991–996
Huang FP, Xi G, Keep RF, Hua Y, Nemoianu A, Hoff JT (2002) Brain edema after experimental intracerebral hemorrhage: role of hemoglobin degradation products. J Neurosurg 96:287–293
Nakamura T, Keep RF, Hua Y, Nagao S, Hoff JT, Xi G (2006) Iron-induced oxidative brain injury after experimental intracerebral hemorrhage. Acta Neurochir Suppl 96:194–198
Zhao X, Sun G, Zhang J, Strong R, Song W, Gonzales N, Grotta JC, Aronowski J (2007) Hematoma resolution as a target for intracerebral hemorrhage treatment: role for peroxisome proliferator-activated receptor gamma in microglia/macrophages. Ann Neurol 61:352–362. doi:10.1002/ana.21097
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. doi:nm1577 [pii], 10.1038/nm1577
Hughes RN (2004) The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory. Neurosci Biobehav Rev 28:497–505. doi:S0149-7634(04)00073-9 [pii], 10.1016/j.neubiorev.2004.06.006
Fathali N, Ostrowski RP, Lekic T, Jadhav V, Tong W, Tang J, Zhang JH (2010) Cyclooxygenase-2 inhibition provides lasting protection against neonatal hypoxic-ischemic brain injury. Crit Care Med 38:572–578. doi:10.1097/CCM.0b013e3181cb1158
Zhou Y, Fathali N, Lekic T, Tang J, Zhang JH (2009) Glibenclamide improves neurological function in neonatal hypoxia-ischemia in rats. Brain Res 1270:131–139. doi:S0006-8993(09)00520-4 [pii], 10.1016/j.brainres.2009.03.010
Lekic T, Hartman R, Rojas H, Manaenko A, Chen W, Ayer R, Tang J, Zhang JH (2010) Protective effect of melatonin upon neuropathology, striatal function, and memory ability after intracerebral hemorrhage in rats. J Neurotrauma 27:627–637. doi:10.1089/neu.2009.1163
Hartman R, Lekic T, Rojas H, Tang J, Zhang JH (2009) Assessing functional outcomes following intracerebral hemorrhage in rats. Brain Res 1280:148–157. doi:S0006-8993(09)00957-3 [pii], 10.1016/j.brainres.2009.05.038
Andine P, Thordstein M, Kjellmer I, Nordborg C, Thiringer K, Wennberg E, Hagberg H (1990) Evaluation of brain damage in a rat model of neonatal hypoxic-ischemia. J Neurosci Methods 35:253–260
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Lekic, T. et al. (2011). Protective Effect of Hydrogen Gas Therapy After Germinal Matrix Hemorrhage in Neonatal Rats. In: Zhang, J., Colohan, A. (eds) Intracerebral Hemorrhage Research. Acta Neurochirurgica Supplementum, vol 111. Springer, Vienna. https://doi.org/10.1007/978-3-7091-0693-8_40
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