Skip to main content

Advertisement

SpringerLink
Log in

The Role of Oxidative Stress in the Progression of Secondary Brain Injury Following Germinal Matrix Hemorrhage

  • Review
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

Abstract

Germinal matrix hemorrhage (GMH) can be a fatal condition responsible for the death of 1.7% of all neonates in the USA. The majority of GMH survivors develop long-term sequalae with debilitating comorbidities. Higher grade GMH is associated with higher mortality rates and higher prevalence of comorbidities. The pathophysiology of GMH can be broken down into two main titles: faulty hemodynamic autoregulation and structural weakness at the level of tissues and cells. Prematurity is the most significant risk factor for GMH, and it predisposes to both major pathophysiological mechanisms of the condition. Secondary brain injury is an important determinant of survival and comorbidities following GMH. Mechanisms of brain injury secondary to GMH include apoptosis, necrosis, neuroinflammation, and oxidative stress. This review will have a special focus on the mechanisms of oxidative stress following GMH, including but not limited to inflammation, mitochondrial reactive oxygen species, glutamate toxicity, and hemoglobin metabolic products. In addition, this review will explore treatment options of GMH, especially targeted therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

Bcl-2/Bax:

B cell lymphoma protein 2/Bcl-2-associated X

H2O2 :

Hydrogen peroxide

IVH:

Intraventricular hemorrhage

NADPH:

Nicotinamide adenine dinucleotide phosphate

NLRP3:

Nucleotide-binding domain-like receptor protein 3

NMDA:

N-methyl-d-aspartate

NMDAR:

NMDA receptors

NO:

Nitric oxide

NOS:

Neuronal nitric oxide synthase

NOX:

NADPH oxidase

ONOO- :

Peroxynitrite

O2 - :

Superoxide

PPARγ:

Proliferator-activated receptor-gamma

ROS:

Reactive oxygen species

TH:

Therapeutic hypothermia

Wnt:

Wingless/integrated

OH:

Hydroxyl radical

References

  1. Ballabh P, Braun A, Nedergaard M. The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis. 2004;16:1–13. https://doi.org/10.1016/j.nbd.2003.12.016.

    Article  CAS  PubMed  Google Scholar 

  2. Brouwer AJ, Groenendaal F, Benders MJ, de Vries LS. Early and late complications of germinal matrix-intraventricular haemorrhage in the preterm infant: what is new? Neonatology. 2014;106:296–303. https://doi.org/10.1159/000365127.

    Article  CAS  PubMed  Google Scholar 

  3. Mukerji A, Shah V, Shah PS. Periventricular/intraventricular hemorrhage and neurodevelopmental outcomes: a meta-analysis. Pediatrics. 2015;136:1132–43. https://doi.org/10.1542/peds.2015-0944.

    Article  PubMed  Google Scholar 

  4. O'Shea TM, Allred EN, Kuban KC, Hirtz D, Specter B, Durfee S, Paneth N, Leviton A. Intraventricular hemorrhage and developmental outcomes at 24 months of age in extremely preterm infants. J Child Neurol. 2012;27:22–9. https://doi.org/10.1177/0883073811424462.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Song J, Nilsson G, Xu Y, Zelco A, Rocha-Ferreira E, Wang Y, Zhang X, Zhang S, Ek J, Hagberg H, et al. Temporal brain transcriptome analysis reveals key pathological events after germinal matrix hemorrhage in neonatal rats. J Cereb Blood Flow Metab. 2022;42:1632–49. https://doi.org/10.1177/0271678x221098811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tan AP, Svrckova P, Cowan F, Chong WK, Mankad K. Intracranial hemorrhage in neonates: a review of etiologies, patterns and predicted clinical outcomes. Eur J Paediatr Neurol. 2018;22:690–717. https://doi.org/10.1016/j.ejpn.2018.04.008.

    Article  PubMed  Google Scholar 

  7. Klebe D, McBride D, Krafft PR, Flores JJ, Tang J, Zhang JH. Posthemorrhagic hydrocephalus development after germinal matrix hemorrhage: established mechanisms and proposed pathways. J Neurosci Res. 2020;98:105–20. https://doi.org/10.1002/jnr.24394.

    Article  CAS  PubMed  Google Scholar 

  8. Ballabh P, Braun A, Nedergaard M. Anatomic analysis of blood vessels in germinal matrix, cerebral cortex, and white matter in developing infants. Pediatr Res. 2004;56:117–24. https://doi.org/10.1203/01.Pdr.0000130472.30874.Ff.

    Article  PubMed  Google Scholar 

  9. Ballabh P, Xu H, Hu F, Braun A, Smith K, Rivera A, Lou N, Ungvari Z, Goldman SA, Csiszar A, et al. Angiogenic inhibition reduces germinal matrix hemorrhage. Nat Med. 2007;13:477–85. https://doi.org/10.1038/nm1558.

    Article  CAS  PubMed  Google Scholar 

  10. Ballabh P. Pathogenesis and prevention of intraventricular hemorrhage. Clin Perinatol. 2014;41:47–67. https://doi.org/10.1016/j.clp.2013.09.007.

    Article  PubMed  Google Scholar 

  11. Raybaud C, Ahmad T, Rastegar N, Shroff M, Al Nassar M. The premature brain: developmental and lesional anatomy. Neuroradiology. 2013;55(Suppl 2):23–40. https://doi.org/10.1007/s00234-013-1231-0.

    Article  PubMed  Google Scholar 

  12. Takashima S, Tanaka K. Microangiography and vascular permeability of the subependymal matrix in the premature infant. Can J Neurol Sci. 1978;5:45–50.

    Article  CAS  PubMed  Google Scholar 

  13. Cuestas E, Bas J, Pautasso J. Sex differences in intraventricular hemorrhage rates among very low birth weight newborns. Gend Med. 2009;6:376–82. https://doi.org/10.1016/j.genm.2009.06.001.

    Article  PubMed  Google Scholar 

  14. Rosenkrantz TS, Hussain Z, Fitch RH. Sex differences in brain injury and repair in newborn infants: clinical evidence and biological mechanisms. Front Pediatr. 2019;7:211. https://doi.org/10.3389/fped.2019.00211.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Baenziger O, Jaggi JL, Mueller AC, Morales CG, Lipp HP, Lipp AE, Duc G, Bucher HU. Cerebral blood flow in preterm infants affected by sex, mechanical ventilation, and intrauterine growth. Pediatr Neurol. 1994;11:319–24. https://doi.org/10.1016/0887-8994(94)90009-4.

    Article  CAS  PubMed  Google Scholar 

  16. Ballabh P. Intraventricular hemorrhage in premature infants: mechanism of disease. Pediatr Res. 2010;67:1–8. https://doi.org/10.1203/PDR.0b013e3181c1b176.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Parodi A, Govaert P, Horsch S, Bravo MC, Ramenghi LA, Agut T, Alarcon A, Arena R, Bartocci M, Bravo M, et al. Cranial ultrasound findings in preterm germinal matrix haemorrhage, sequelae and outcome. Pediatr Res. 2020;87:13–24. https://doi.org/10.1038/s41390-020-0780-2.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ballabh P, de Vries LS. White matter injury in infants with intraventricular haemorrhage: mechanisms and therapies. Nat Rev Neurol. 2021;17:199–214. https://doi.org/10.1038/s41582-020-00447-8.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Garton T, Hua Y, Xiang J, Xi G, Keep RF. Challenges for intraventricular hemorrhage research and emerging therapeutic targets. Expert Opin Ther Targets. 2017;21:1111–22. https://doi.org/10.1080/14728222.2017.1397628.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Hanley DF. Intraventricular hemorrhage: severity factor and treatment target in spontaneous intracerebral hemorrhage. Stroke. 2009;40:1533–8. https://doi.org/10.1161/strokeaha.108.535419.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Romantsik O, Bruschettini M, Ley D. Intraventricular hemorrhage and white matter injury in preclinical and clinical studies. Neoreviews. 2019;20:e636–52. https://doi.org/10.1542/neo.20-11-e636.

    Article  PubMed  Google Scholar 

  22. Sadrzadeh SM, Graf E, Panter SS, Hallaway PE, Eaton JW. Hemoglobin. A biologic fenton reagent. J Biol Chem. 1984;259:14354–6.

    Article  CAS  PubMed  Google Scholar 

  23. Czerska M, Mikołajewska K, Zieliński M, Gromadzińska J, Wąsowicz W. Today's oxidative stress markers. Med Pr. 2015;66:393–405. https://doi.org/10.13075/mp.5893.00137.

    Article  PubMed  Google Scholar 

  24. Hu X, Tao C, Gan Q, Zheng J, Li H, You C. Oxidative stress in intracerebral hemorrhage: sources, mechanisms, and therapeutic targets. Oxid Med Cell Longev. 2016;2016:3215391. https://doi.org/10.1155/2016/3215391.

    Article  CAS  PubMed  Google Scholar 

  25. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev. 2014;94:909–50. https://doi.org/10.1152/physrev.00026.2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39:44–84. https://doi.org/10.1016/j.biocel.2006.07.001.

    Article  CAS  PubMed  Google Scholar 

  27. Martini S, Castellini L, Parladori R, Paoletti V, Aceti A, Corvaglia L. Free radicals and neonatal brain injury: from underlying pathophysiology to antioxidant treatment perspectives. Antioxidants (Basel). 2021;10 https://doi.org/10.3390/antiox10122012.

  28. Orellana-Urzúa S, Claps G, Rodrigo R. Improvement of a novel proposal for antioxidant treatment against brain damage occurring in ischemic stroke patients. CNS Neurol Disord Drug Targets. 2021;20:3–21. https://doi.org/10.2174/1871527319666200910153431.

    Article  CAS  PubMed  Google Scholar 

  29. Dani C, Cecchi A, Bertini G. Role of oxidative stress as physiopathologic factor in the preterm infant. Minerva Pediatr. 2004;56:381–94.

    CAS  PubMed  Google Scholar 

  30. Marseglia L, D'Angelo G, Manti S, Arrigo T, Barberi I, Reiter RJ, Gitto E. Oxidative stress-mediated aging during the fetal and perinatal periods. Oxid Med Cell Longev. 2014;2014:358375. https://doi.org/10.1155/2014/358375.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ozsurekci Y, Aykac K. Oxidative stress related diseases in newborns. Oxid Med Cell Longev. 2016;2016:2768365. https://doi.org/10.1155/2016/2768365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dawes W. Secondary brain injury following neonatal intraventricular hemorrhage: the role of the ciliated ependyma. Front Pediatr. 2022;10:887606. https://doi.org/10.3389/fped.2022.887606.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Zhang Y, Khan S, Liu Y, Wu G, Yong VW, Xue M. Oxidative stress following intracerebral hemorrhage: from molecular mechanisms to therapeutic targets. Front Immunol. 2022;13:847246. https://doi.org/10.3389/fimmu.2022.847246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Goulding DS, Vogel RC, Gensel JC, Morganti JM, Stromberg AJ, Miller BA. Acute brain inflammation, white matter oxidative stress, and myelin deficiency in a model of neonatal intraventricular hemorrhage. J Neurosurg Pediatr. 2020;26:613–23. https://doi.org/10.3171/2020.5.Peds20124.

    Article  PubMed  Google Scholar 

  35. Leijser LM, de Vries LS. Preterm brain injury: germinal matrix-intraventricular hemorrhage and post-hemorrhagic ventricular dilatation. Handb Clin Neurol. 2019;162:173–99. https://doi.org/10.1016/b978-0-444-64029-1.00008-4.

    Article  PubMed  Google Scholar 

  36. Niemczyk E, Majczak A, Hallmann A, Kedzior J, Woźniak M, Wakabayashi T. A possible involvement of plasma membrane NAD(P)H oxidase in the switch mechanism of the cell death mode from apoptosis to necrosis in menadione-induced cell injury. Acta Biochim Pol. 2004;51:1015–22.

    CAS  PubMed  Google Scholar 

  37. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25:486–541. https://doi.org/10.1038/s41418-017-0012-4.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Li L, Yun D, Zhang Y, Tao Y, Tan Q, Qiao F, Luo B, Liu Y, Fan R, Xian J, et al. A cannabinoid receptor 2 agonist reduces blood-brain barrier damage via induction of MKP-1 after intracerebral hemorrhage in rats. Brain Res. 2018;1697:113–23. https://doi.org/10.1016/j.brainres.2018.06.006.

    Article  CAS  PubMed  Google Scholar 

  39. Yang C, Hawkins KE, Doré S, Candelario-Jalil E. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. Am J Physiol Cell Physiol. 2019;316:C135–53. https://doi.org/10.1152/ajpcell.00136.2018.

    Article  CAS  PubMed  Google Scholar 

  40. Panfoli I, Candiano G, Malova M, De Angelis L, Cardiello V, Buonocore G, Ramenghi LA. Oxidative stress as a primary risk factor for brain damage in preterm newborns. Front Pediatr. 2018;6:369. https://doi.org/10.3389/fped.2018.00369.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Saugstad OD. Hypoxanthine as an indicator of hypoxia: its role in health and disease through free radical production. Pediatr Res. 1988;23:143–50. https://doi.org/10.1203/00006450-198802000-00001.

    Article  CAS  PubMed  Google Scholar 

  42. Liu Y, Wei J, Chang M, Liu Z, Li D, Hu S, Hu L. Proteomic analysis of endothelial progenitor cells exposed to oxidative stress. Int J Mol Med. 2013;32:607–14. https://doi.org/10.3892/ijmm.2013.1419.

    Article  CAS  PubMed  Google Scholar 

  43. Zia MT, Csiszar A, Labinskyy N, Hu F, Vinukonda G, LaGamma EF, Ungvari Z, Ballabh P. Oxidative-nitrosative stress in a rabbit pup model of germinal matrix hemorrhage: role of NAD(P)H oxidase. Stroke. 2009;40:2191–8. https://doi.org/10.1161/strokeaha.108.544759.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Zhang R, Brennan ML, Shen Z, MacPherson JC, Schmitt D, Molenda CE, Hazen SL. Myeloperoxidase functions as a major enzymatic catalyst for initiation of lipid peroxidation at sites of inflammation. J Biol Chem. 2002;277:46116–22. https://doi.org/10.1074/jbc.M209124200.

    Article  CAS  PubMed  Google Scholar 

  45. Kupsco A, Schlenk D. Oxidative stress, unfolded protein response, and apoptosis in developmental toxicity. Int Rev Cell Mol Biol. 2015;317:1–66. https://doi.org/10.1016/bs.ircmb.2015.02.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yao Z, Bai Q, Wang G. Mechanisms of oxidative stress and therapeutic targets following intracerebral hemorrhage. Oxid Med Cell Longev. 2021;2021:8815441. https://doi.org/10.1155/2021/8815441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ma Q, Chen S, Hu Q, Feng H, Zhang JH, Tang J. NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage. Ann Neurol. 2014;75:209–19. https://doi.org/10.1002/ana.24070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Iadecola C. Bright and dark sides of nitric oxide in ischemic brain injury. Trends Neurosci. 1997;20:132–9. https://doi.org/10.1016/s0166-2236(96)10074-6.

    Article  CAS  PubMed  Google Scholar 

  49. Goulay R, Naveau M, Gaberel T, Vivien D, Parcq J. Optimized tPA: a non-neurotoxic fibrinolytic agent for the drainage of intracerebral hemorrhages. J Cereb Blood Flow Metab. 2018;38:1180–9. https://doi.org/10.1177/0271678x17719180.

    Article  CAS  PubMed  Google Scholar 

  50. Wang Z, Chen Z, Yang J, Yang Z, Yin J, Duan X, Shen H, Li H, Wang Z, Chen G. Treatment of secondary brain injury by perturbing postsynaptic density protein-95-NMDA receptor interaction after intracerebral hemorrhage in rats. J Cereb Blood Flow Metab. 2019;39:1588–601. https://doi.org/10.1177/0271678x18762637.

    Article  CAS  PubMed  Google Scholar 

  51. Qu J, Chen W, Hu R, Feng H. The injury and therapy of reactive oxygen species in intracerebral hemorrhage looking at mitochondria. Oxid Med Cell Longev. 2016;2016:2592935. https://doi.org/10.1155/2016/2592935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hanafy KA, Gomes JA, Selim M. Rationale and current evidence for testing iron chelators for treating stroke. Curr Cardiol Rep. 2019;21:20. https://doi.org/10.1007/s11886-019-1106-z.

    Article  PubMed  Google Scholar 

  53. Li J, Cao F, Yin H-L, Huang Z-J, Lin Z-T, Mao N, Sun B, Wang G. Ferroptosis: past, present and future. Cell Death & Dis. 2020;11:88. https://doi.org/10.1038/s41419-020-2298-2.

    Article  Google Scholar 

  54. Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 2016;26:165–76. https://doi.org/10.1016/j.tcb.2015.10.014.

    Article  CAS  PubMed  Google Scholar 

  55. Wan J, Ren H, Wang J. Iron toxicity, lipid peroxidation and ferroptosis after intracerebral haemorrhage. Stroke Vasc Neurol. 2019;4:93. https://doi.org/10.1136/svn-2018-000205.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Douglas-Escobar M, Weiss MD. Hypoxic-ischemic encephalopathy: a review for the clinician. JAMA Pediatr. 2015;169:397–403. https://doi.org/10.1001/jamapediatrics.2014.3269.

    Article  PubMed  Google Scholar 

  57. Martinello K, Hart AR, Yap S, Mitra S, Robertson NJ. Management and investigation of neonatal encephalopathy: 2017 update. Arch Dis Child Fetal Neonatal Ed. 2017;102:F346–58. https://doi.org/10.1136/archdischild-2015-309639.

    Article  PubMed  Google Scholar 

  58. Edwards AD, Yue X, Squier MV, Thoresen M, Cady EB, Penrice J, Cooper CE, Wyatt JS, Reynolds EO, Mehmet H. Specific inhibition of apoptosis after cerebral hypoxia-ischaemia by moderate post-insult hypothermia. Biochem Biophys Res Commun. 1995;217:1193–9. https://doi.org/10.1006/bbrc.1995.2895.

    Article  CAS  PubMed  Google Scholar 

  59. Thoresen M, Penrice J, Lorek A, Cady EB, Wylezinska M, Kirkbride V, Cooper CE, Brown GC, Edwards AD, Wyatt JS, et al. Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res. 1995;37:667–70. https://doi.org/10.1203/00006450-199505000-00019.

    Article  CAS  PubMed  Google Scholar 

  60. Schumacker PT, Rowland J, Saltz S, Nelson DP, Wood LD. Effects of hyperthermia and hypothermia on oxygen extraction by tissues during hypovolemia. J Appl Physiol. 1987;63:1246–52. https://doi.org/10.1152/jappl.1987.63.3.1246.

    Article  CAS  PubMed  Google Scholar 

  61. Thoresen M, Wyatt J. Keeping a cool head, post-hypoxic hypothermia--an old idea revisited. Acta Paediatr. 1997;86:1029–33. https://doi.org/10.1111/j.1651-2227.1997.tb14799.x.

    Article  CAS  PubMed  Google Scholar 

  62. Reiter RJ, Tan DX, Osuna C, Gitto E. Actions of melatonin in the reduction of oxidative stress. A review. J Biomed Sci. 2000;7:444–58. https://doi.org/10.1007/bf02253360.

    Article  CAS  PubMed  Google Scholar 

  63. Wang Z, Zhou F, Dou Y, Tian X, Liu C, Li H, Shen H, Chen G. Melatonin alleviates intracerebral hemorrhage-induced secondary brain injury in rats via suppressing apoptosis, inflammation, oxidative stress, DNA damage, and mitochondria injury. Transl Stroke Res. 2018;9:74–91. https://doi.org/10.1007/s12975-017-0559-x.

    Article  CAS  PubMed  Google Scholar 

  64. Martini S, Austin T, Aceti A, Faldella G, Corvaglia L. Free radicals and neonatal encephalopathy: mechanisms of injury, biomarkers, and antioxidant treatment perspectives. Pediatr Res. 2020;87:823–33. https://doi.org/10.1038/s41390-019-0639-6.

    Article  CAS  PubMed  Google Scholar 

  65. Blanco S, Hernández R, Franchelli G, Ramos-Álvarez MM, Peinado M. Melatonin influences NO/NOS pathway and reduces oxidative and nitrosative stress in a model of hypoxic-ischemic brain damage. Nitric Oxide. 2017;62:32–43. https://doi.org/10.1016/j.niox.2016.12.001.

    Article  CAS  PubMed  Google Scholar 

  66. Matsuki N, Takanohashi A, Boffi FM, Inanami O, Kuwabara M, Ono K. Hydroxyl radical generation and lipid peroxidation in C2C12 myotube treated with iodoacetate and cyanide. Free Radic Res. 1999;31:1–8. https://doi.org/10.1080/10715769900300551.

    Article  CAS  PubMed  Google Scholar 

  67. Meng H, Li F, Hu R, Yuan Y, Gong G, Hu S, Feng H. Deferoxamine alleviates chronic hydrocephalus after intraventricular hemorrhage through iron chelation and Wnt1/Wnt3a inhibition. Brain Res. 2015;1602:44–52. https://doi.org/10.1016/j.brainres.2014.08.039.

    Article  CAS  PubMed  Google Scholar 

  68. Cisternas P, Vio CP, Inestrosa NC. Role of Wnt signaling in tissue fibrosis, lessons from skeletal muscle and kidney. Curr Mol Med. 2014;14:510–22. https://doi.org/10.2174/1566524014666140414210346.

    Article  CAS  PubMed  Google Scholar 

  69. Miao CG, Yang YY, He X, Huang C, Huang Y, Zhang L, Lv XW, Jin Y, Li J. Wnt signaling in liver fibrosis: progress, challenges and potential directions. Biochimie. 2013;95:2326–35. https://doi.org/10.1016/j.biochi.2013.09.003.

    Article  CAS  PubMed  Google Scholar 

  70. Klebe D, Krafft PR, Hoffmann C, Lekic T, Flores JJ, Rolland W, Zhang JH. Acute and delayed deferoxamine treatment attenuates long-term sequelae after germinal matrix hemorrhage in neonatal rats. Stroke. 2014;45:2475–9. https://doi.org/10.1161/strokeaha.114.005079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Guo J, Chen Q, Tang J, Zhang J, Tao Y, Li L, Zhu G, Feng H, Chen Z. Minocycline-induced attenuation of iron overload and brain injury after experimental germinal matrix hemorrhage. Brain Res. 2015;1594:115–24. https://doi.org/10.1016/j.brainres.2014.10.046.

    Article  CAS  PubMed  Google Scholar 

  72. Liu Y, Li Z, Khan S, Zhang R, Wei R, Zhang Y, Xue M, Yong VW. Neuroprotection of minocycline by inhibition of extracellular matrix metalloproteinase inducer expression following intracerebral hemorrhage in mice. Neurosci Lett. 2021;764:136297. https://doi.org/10.1016/j.neulet.2021.136297.

    Article  CAS  PubMed  Google Scholar 

  73. Li Z, Liu Y, Wei R, Khan S, Xue M, Yong VW. The combination of deferoxamine and minocycline strengthens neuroprotective effect on acute intracerebral hemorrhage in rats. Neurol Res. 2021;43:854–64. https://doi.org/10.1080/01616412.2021.1939487.

    Article  CAS  PubMed  Google Scholar 

  74. Flores JJ, Klebe D, Rolland WB, Lekic T, Krafft PR, Zhang JH. PPARγ-induced upregulation of CD36 enhances hematoma resolution and attenuates long-term neurological deficits after germinal matrix hemorrhage in neonatal rats. Neurobiol Dis. 2016;87:124–33. https://doi.org/10.1016/j.nbd.2015.12.015.

    Article  CAS  PubMed  Google Scholar 

  75. Zhao X, Sun G, Zhang J, Strong R, Song W, Gonzales N, Grotta JC, Aronowski J. Hematoma resolution as a target for intracerebral hemorrhage treatment: role for peroxisome proliferator-activated receptor gamma in microglia/macrophages. Ann Neurol. 2007;61:352–62. https://doi.org/10.1002/ana.21097.

    Article  CAS  PubMed  Google Scholar 

  76. Chen Q, Shi X, Tan Q, Feng Z, Wang Y, Yuan Q, Tao Y, Zhang J, Tan L, Zhu G, et al. Simvastatin promotes hematoma absorption and reduces hydrocephalus following intraventricular hemorrhage in part by upregulating CD36. Transl Stroke Res. 2017;8:362–73. https://doi.org/10.1007/s12975-017-0521-y.

    Article  CAS  PubMed  Google Scholar 

  77. Chen Z, Zhang J, Chen Q, Guo J, Zhu G, Feng H. Neuroprotective effects of edaravone after intraventricular hemorrhage in rats. Neuroreport. 2014;25:635–40. https://doi.org/10.1097/wnr.0000000000000050.

    Article  PubMed  Google Scholar 

  78. Lekic T, Manaenko A, Rolland W, Fathali N, Peterson M, Tang J, Zhang JH. Protective effect of hydrogen gas therapy after germinal matrix hemorrhage in neonatal rats. Acta Neurochir Suppl. 2011;111:237–41. https://doi.org/10.1007/978-3-7091-0693-8_40.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Manaenko A, Lekic T, Ma Q, Ostrowski RP, Zhang JH, Tang J. Hydrogen inhalation is neuroprotective and improves functional outcomes in mice after intracerebral hemorrhage. Acta Neurochir Suppl. 2011;111:179–83. https://doi.org/10.1007/978-3-7091-0693-8_30.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Cheng B, Ballabh P. Recovery of the brain after intraventricular hemorrhage. Semin Fetal Neonatal Med. 2022;27:101224. https://doi.org/10.1016/j.siny.2021.101224.

    Article  PubMed  Google Scholar 

  81. Dohare P, Zia MT, Ahmed E, Ahmed A, Yadala V, Schober AL, Ortega JA, Kayton R, Ungvari Z, Mongin AA, et al. AMPA-Kainate receptor inhibition promotes neurologic recovery in premature rabbits with intraventricular hemorrhage. J Neurosci. 2016;36:3363–77. https://doi.org/10.1523/jneurosci.4329-15.2016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Goddard J, Lewis RM, Alcala H, Zeller RS. Intraventricular hemorrhage--an animal model. Biol Neonate. 1980;37:39–52. https://doi.org/10.1159/000241254.

    Article  CAS  PubMed  Google Scholar 

  83. Wheeler AS, Sadri S, Gutsche BB, DeVore JS, David-Mian Z, Latyshevsky H. Intracranial hemorrhage following intravenous administration of sodium bicarbonate or saline solution in the newborn lamb asphyxiated in utero. Anesthesiology. 1979;51:517–21. https://doi.org/10.1097/00000542-197912000-00007.

    Article  CAS  PubMed  Google Scholar 

  84. Reynolds ML, Evans CA, Reynolds EO, Saunders NR, Durbin GM, Wigglesworth JS. Intracranial haemorrhage in the preterm sheep fetus. Early Hum Dev. 1979;3:163–86. https://doi.org/10.1016/0378-3782(79)90005-7.

    Article  CAS  PubMed  Google Scholar 

  85. Lekic T, Manaenko A, Rolland W, Tang J, Zhang JH. A novel preclinical model of germinal matrix hemorrhage using neonatal rats. Acta Neurochir Suppl. 2011;111:55–60. https://doi.org/10.1007/978-3-7091-0693-8_10.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Segado-Arenas A, Infante-Garcia C, Benavente-Fernandez I, Sanchez-Sotano D, Ramos-Rodriguez JJ, Alonso-Ojembarrena A, Lubian-Lopez S, Garcia-Alloza M. Cognitive impairment and brain and peripheral alterations in a murine model of intraventricular hemorrhage in the preterm newborn. Mol Neurobiol. 2018;55:4896–910. https://doi.org/10.1007/s12035-017-0693-1.

    Article  CAS  PubMed  Google Scholar 

  87. Mayfrank L, Kissler J, Raoofi R, Delsing P, Weis J, Küker W, Gilsbach JM. Ventricular dilatation in experimental intraventricular hemorrhage in pigs. Characterization of cerebrospinal fluid dynamics and the effects of fibrinolytic treatment. Stroke. 1997;28:141–8. https://doi.org/10.1161/01.str.28.1.141.

    Article  CAS  PubMed  Google Scholar 

  88. Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell. 2005;120:421–33. https://doi.org/10.1016/j.cell.2004.12.020.

    Article  CAS  PubMed  Google Scholar 

  89. Goritz C, Mauch DH, Pfrieger FW. Multiple mechanisms mediate cholesterol-induced synaptogenesis in a CNS neuron. Mol Cell Neurosci. 2005;29:190–201. https://doi.org/10.1016/j.mcn.2005.02.006.

    Article  CAS  PubMed  Google Scholar 

  90. Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein LJ. Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol. 2013;106-107:1–16. https://doi.org/10.1016/j.pneurobio.2013.04.001.

    Article  PubMed  Google Scholar 

  91. Atienza-Navarro I, Alves-Martinez P, Lubian-Lopez S, Garcia-Alloza M. Germinal matrix-intraventricular hemorrhage of the preterm newborn and preclinical models: inflammatory considerations. Int J Mol Sci. 2020;21 https://doi.org/10.3390/ijms21218343.

  92. McCarty JH, Monahan-Earley RA, Brown LF, Keller M, Gerhardt H, Rubin K, Shani M, Dvorak HF, Wolburg H, Bader BL, et al. Defective associations between blood vessels and brain parenchyma lead to cerebral hemorrhage in mice lacking alphav integrins. Mol Cell Biol. 2002;22:7667–77. https://doi.org/10.1128/mcb.22.21.7667-7677.2002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Gould DB, Phalan FC, Breedveld GJ, van Mil SE, Smith RS, Schimenti JC, Aguglia U, van der Knaap MS, Heutink P, John SW. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science. 2005;308:1167–71. https://doi.org/10.1126/science.1109418.

    Article  CAS  PubMed  Google Scholar 

  94. Yang D, Baumann JM, Sun YY, Tang M, Dunn RS, Akeson AL, Kernie SG, Kallapur S, Lindquist DM, Huang EJ, et al. Overexpression of vascular endothelial growth factor in the germinal matrix induces neurovascular proteases and intraventricular hemorrhage. Sci Transl Med. 2013;5:193ra190. https://doi.org/10.1126/scitranslmed.3005794.

    Article  CAS  Google Scholar 

  95. Dohare P, Cheng B, Ahmed E, Yadala V, Singla P, Thomas S, Kayton R, Ungvari Z, Ballabh P. Glycogen synthase kinase-3β inhibition enhances myelination in preterm newborns with intraventricular hemorrhage, but not recombinant Wnt3A. Neurobiol Dis. 2018;118:22–39. https://doi.org/10.1016/j.nbd.2018.06.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Fischer EG, Lorenzo AV, Landis WJ, Welch K, Ofori-Kwakye SK, Dorval B, Hodgens KJ, Kerr CS. Vasculature to the germinal matrix in rabbit pups. J Neurosurg. 1986;64:650–6. https://doi.org/10.3171/jns.1986.64.4.0650.

    Article  CAS  PubMed  Google Scholar 

  97. Georgiadis P, Xu H, Chua C, Hu F, Collins L, Huynh C, Lagamma EF, Ballabh P. Characterization of acute brain injuries and neurobehavioral profiles in a rabbit model of germinal matrix hemorrhage. Stroke. 2008;39:3378–88. https://doi.org/10.1161/strokeaha.107.510883.

    Article  CAS  PubMed  Google Scholar 

  98. Cherian SS, Love S, Silver IA, Porter HJ, Whitelaw AG, Thoresen M. Posthemorrhagic ventricular dilation in the neonate: development and characterization of a rat model. J Neuropathol Exp Neurol. 2003;62:292–303. https://doi.org/10.1093/jnen/62.3.292.

    Article  PubMed  Google Scholar 

  99. Strahle JM, Garton T, Bazzi AA, Kilaru H, Garton HJ, Maher CO, Muraszko KM, Keep RF, Xi G. Role of hemoglobin and iron in hydrocephalus after neonatal intraventricular hemorrhage. Neurosurgery. 2014;75:696–705; discussion 706,. https://doi.org/10.1227/neu.0000000000000524.

    Article  PubMed  Google Scholar 

  100. Li P, Zhao G, Ding Y, Wang T, Flores J, Ocak U, Wu P, Zhang T, Mo J, Zhang JH, et al. Rh-IFN-α attenuates neuroinflammation and improves neurological function by inhibiting NF-κB through JAK1-STAT1/TRAF3 pathway in an experimental GMH rat model. Brain Behav Immun. 2019;79:174–85. https://doi.org/10.1016/j.bbi.2019.01.028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Tao Y, Li L, Jiang B, Feng Z, Yang L, Tang J, Chen Q, Zhang J, Tan Q, Feng H, et al. Cannabinoid receptor-2 stimulation suppresses neuroinflammation by regulating microglial M1/M2 polarization through the cAMP/PKA pathway in an experimental GMH rat model. Brain Behav Immun. 2016;58:118–29. https://doi.org/10.1016/j.bbi.2016.05.020.

    Article  CAS  PubMed  Google Scholar 

  102. Lorenzo AV, Welch K. Preterm rabbit model of intraventricular hemorrhage. J Neurosurg. 1986;64:688–9. https://doi.org/10.3171/jns.1986.64.4.0688.

    Article  CAS  PubMed  Google Scholar 

  103. Lorenzo AV, Welch K, Conner S. Spontaneous germinal matrix and intraventricular hemorrhage in prematurely born rabbits. J Neurosurg. 1982;56:404–10. https://doi.org/10.3171/jns.1982.56.3.0404.

    Article  CAS  PubMed  Google Scholar 

  104. Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke. 2011;42:1781–6. https://doi.org/10.1161/strokeaha.110.596718.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Sanai N, Nguyen T, Ihrie RA, Mirzadeh Z, Tsai HH, Wong M, Gupta N, Berger MS, Huang E, Garcia-Verdugo JM, et al. Corridors of migrating neurons in the human brain and their decline during infancy. Nature. 2011;478:382–6. https://doi.org/10.1038/nature10487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Salmaso N, Jablonska B, Scafidi J, Vaccarino FM, Gallo V. Neurobiology of premature brain injury. Nat Neurosci. 2014;17:341–6. https://doi.org/10.1038/nn.3604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Selim M, Foster LD, Moy CS, Xi G, Hill MD, Morgenstern LB, Greenberg SM, James ML, Singh V, Clark WM, et al. Deferoxamine mesylate in patients with intracerebral haemorrhage (i-DEF): a multicentre, randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol. 2019;18:428–38. https://doi.org/10.1016/s1474-4422(19)30069-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wei C, Wang J, Foster LD, Yeatts SD, Moy C, Mocco J, Selim M, Palesch Y, Griffin J, Perlmutter A, et al. Effect of deferoxamine on outcome according to baseline hematoma volume: a post hoc analysis of the i-DEF trial. Stroke. 2022;53:1149–56. https://doi.org/10.1161/STROKEAHA.121.035421.

    Article  CAS  PubMed  Google Scholar 

  109. Ohlsson A, Roberts RS, Schmidt B, Davis P, Moddeman D, Saigal S, Solimano A, Vincer M, Wright L. Male/female differences in indomethacin effects in preterm infants. J Pediatr. 2005;147:860–2. https://doi.org/10.1016/j.jpeds.2005.07.032.

    Article  CAS  PubMed  Google Scholar 

  110. Vohr BR, Allan WC, Westerveld M, Schneider KC, Katz KH, Makuch RW, Ment LR. School-age outcomes of very low birth weight infants in the indomethacin intraventricular hemorrhage prevention trial. Pediatrics. 2003;111:e340–6. https://doi.org/10.1542/peds.111.4.e340.

    Article  PubMed  Google Scholar 

  111. Dietz RM, Deng G, Orfila JE, Hui X, Traystman RJ, Herson PS. Therapeutic hypothermia protects against ischemia-induced impairment of synaptic plasticity following juvenile cardiac arrest in sex-dependent manner. Neuroscience. 2016;325:132–41. https://doi.org/10.1016/j.neuroscience.2016.03.052.

    Article  CAS  PubMed  Google Scholar 

  112. D'Angelo G, Chimenz R, Reiter RJ, Gitto E. Use of melatonin in oxidative stress related neonatal diseases. Antioxidants (Basel). 2020;9 https://doi.org/10.3390/antiox9060477.

  113. Elser HE, Holditch-Davis D, Brandon DH. Cerebral oxygenation monitoring: a strategy to detect IVH and PVL. Newborn Infant Nurs Rev. 2011;11:153–9. https://doi.org/10.1053/j.nainr.2011.07.007.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Variane GFT, Chock VY, Netto A, Pietrobom RFR, Van Meurs KP. Simultaneous near-infrared spectroscopy (NIRS) and amplitude-integrated electroencephalography (aEEG): dual use of brain monitoring techniques improves our understanding of physiology. Front Pediatr. 2020;7 https://doi.org/10.3389/fped.2019.00560.

  115. Roberts D, Brown J, Medley N, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2017;3:CD004454. https://doi.org/10.1002/14651858.CD004454.pub3.

    Article  PubMed  Google Scholar 

  116. Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev. 2009:CD004661. https://doi.org/10.1002/14651858.CD004661.pub3.

  117. Szymonowicz W, Yu VY, Walker A, Wilson F. Reduction in periventricular haemorrhage in preterm infants. Arch Dis Child. 1986;61:661–5. https://doi.org/10.1136/adc.61.7.661.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. de Bijl-Marcus K, Brouwer AJ, De Vries LS, Groenendaal F, Wezel-Meijler GV. Neonatal care bundles are associated with a reduction in the incidence of intraventricular haemorrhage in preterm infants: a multicentre cohort study. Arch Dis Child Fetal Neonatal Ed. 2020;105:419–24. https://doi.org/10.1136/archdischild-2018-316692.

    Article  PubMed  Google Scholar 

  119. Garvey AA, Kooi EMW, Smith A, Dempsey EM. Interpretation of cerebral oxygenation changes in the preterm infant. Children (Basel). 2018;5 https://doi.org/10.3390/children5070094.

  120. Kluckow M, Evans N. Low superior vena cava flow and intraventricular haemorrhage in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2000;82:F188–94. https://doi.org/10.1136/fn.82.3.f188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Sortica da Costa C, Cardim D, Molnar Z, Kelsall W, Ng I, Czosnyka M, Smielewski P, Austin T. Changes in hemodynamics, cerebral oxygenation and cerebrovascular reactivity during the early transitional circulation in preterm infants. Pediatr Res. 2019;86:247–53. https://doi.org/10.1038/s41390-019-0410-z.

    Article  PubMed  Google Scholar 

  122. Hansen ML, Pellicer A, Gluud C, Dempsey E, Mintzer J, Hyttel-Sørensen S, Heuchan AM, Hagmann C, Ergenekon E, Dimitriou G, et al. Cerebral near-infrared spectroscopy monitoring versus treatment as usual for extremely preterm infants: a protocol for the SafeBoosC randomised clinical phase III trial. Trials. 2019;20:811. https://doi.org/10.1186/s13063-019-3955-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

No funding or financial support was received for this study.

Author information

Authors and Affiliations

  1. Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon

    Mariam Nour Eldine & Hussein Noureldine

  2. School of Pharmacy, Lebanese American University, Byblos, Lebanon

    Maryam Alhousseini

  3. Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar

    Wared Nour-Eldine

  4. Department of Neurosurgery and Brain Repair, University of South Florida, Morsani College of Medicine, Tampa, Florida, USA

    Kunal V. Vakharia, Paul R. Krafft & Mohammad Hassan A. Noureldine

Authors
  1. Mariam Nour Eldine
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maryam Alhousseini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wared Nour-Eldine
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hussein Noureldine
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kunal V. Vakharia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paul R. Krafft
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mohammad Hassan A. Noureldine
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohammad Hassan A. Noureldine.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nour Eldine, M., Alhousseini, M., Nour-Eldine, W. et al. The Role of Oxidative Stress in the Progression of Secondary Brain Injury Following Germinal Matrix Hemorrhage. Transl. Stroke Res. 15, 647–658 (2024). https://doi.org/10.1007/s12975-023-01147-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-023-01147-3

Keywords

Search

Navigation