AccScience Publishing / ITPS / Volume 9 / Issue 3 / DOI: 10.36922/ITPS025510059
Submit to ITPS
Cite this article
2
Download
40
Views
Related Info Links
Google Scholar
More by Authors Links
Sandesh Kumar Pattanaik
Journal Browser
Volume | Year
Issue
Search
News and Announcements
View All
MINI-REVIEW

Role of arginase in hypoxic–ischemic brain injury in infants: An update

Sandesh Kumar Pattanaik1* ,  Diptirani Rath1
Show Less
1 Department of Pharmacology, School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan Deemed to Be University, Bhubaneswar, Odisha , India
INNOSC Theranostics and Pharmacological Sciences 2026, 9(3), 025510059 https://doi.org/10.36922/ITPS025510059
Received: 19 December 2025 | Revised: 10 April 2026 | Accepted: 19 May 2026 | Published online: 27 October 2026
© 2026 by the Aithor(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Download PDF
XML
Cite
Abstract

Hypoxic–ischemic (HI) brain injury is a major cause of neurological impairment in newborns worldwide and can lead to severe short- and long-term neurodevelopmental dysfunction. Adult neuroprotective interventions, on the other hand, may have a major influence on children’s developing nervous systems. The detailed aetiology of HI in the developing brain needs to be discovered to establish new pathways for successful therapies. The exact mechanism of newborn HI brain damage is still not completely known. However, mitochondria play a huge part not only because of their central position in metabolism, but also because certain enzymes are involved in the mitochondrial urea cycle. Arginase is responsible for two key physiological functions: the production of proline and polyamines, and the detoxification of ammonium ions. The arginase enzyme catalyses the final phase of the urea cycle by removing extra nitrogen from the amino acid. The release of nitrogen is a key feature of both neuronal and vascular cell signalling and is crucial for ensuring adequate blood supply to the central nervous system. In this mini-review, arginine and ornithine were used to evaluate their roles in regulating arginase activity under HI conditions.

Keywords
Neonatal hypoxia–ischemia
Arginase
Nitric oxide
Proline
Polyamines
Funding
This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest
The authors declare that they have no conflicts of interest regarding this paper.
References
  1. Lawn JE, Cousens S ZJ. Lancet neonatal survival steering team. 4 million neonatal deaths: When? Where? Why? 2005;365:891-900. doi: 10.1016/S0140-6736(05)71048-5
  2. Millar LJ, Shi L, Hoerder-Suabedissen A, Molnár Z. Neonatal hypoxia ischaemia: Mechanisms, models, and therapeutic challenges. Front Cell Neurosci. 2017;11. doi: 10.3389/fncel.2017.00078
  3. Krystofova J, Pathipati P, Russ J, Sheldon A, Ferriero D. The Arginase Pathway in Neonatal Brain Hypoxia-Ischemia. Dev Neurosci. 2019;40(5-6):437-450. doi: 10.1159/000496467
  4. Rawanduzy CA, Earl E, Mayer G, Lucke-Wold B. Pediatric Stroke: A Review of Common Etiologies and Management Strategies. Biomedicines. 2022;11(1):2. doi: 10.3390/biomedicines11010002
  5. Singh R, Turner RC, Nguyen L, Motwani K, Swatek M, Lucke-Wold BP. Pediatric Traumatic Brain Injury and Autism: Elucidating Shared Mechanisms. Behav Neurol. 2016;2016:1-14. doi: 10.1155/2016/8781725
  6. Clemente GS, Waarde A Van, Antunes F, Dömling A. Arginase as a Potential Biomarker of Disease Progression : A Molecular Imaging Perspective. Int J Mol Sci. 21(15):5291. doi: 10.3390/ijms21155291
  7. Di Costanzo L, Sabio G, Mora A, et al. Crystal structure of human arginase I at 1.29-Å resolution and exploration of inhibition in the immune response. Proc Natl Acad Sci USA. 2005;102(37):13058-13063. doi: 10.1073/pnas.0504027102
  8. Cama E, Colleluori DM, Emig FA, et al. Human arginase II: Crystal structure and physiological role in male and female sexual arousal. Biochemistry. 2003;42(28):8445-8451. doi: 10.1021/bi034340j
  9. Gotoh T, Araki M, Mori M. Chromosomal localization of the human arginase II gene and tissue distribution of its mRNA. Biochem Biophys Res Commun. 1997;233(2):487-491. doi: 10.1006/bbrc.1997.6473
  10. Caldwell RW, Rodriguez PC, Toque HA, Narayanan SP, Caldwell RB. Arginase: A Multifaceted Enzyme Important in Health andDisease. Physiol Rev. 2018;98(2):641-665. doi: 10.1152/physrev.00037.2016
  11. Choi S, Park C, Ahn M, Lee JH, Shin T. Immunohistochemical study of arginase 1 and 2 in various tissues of rats. Acta Histochem. 2012;114(5):487-494. doi: 10.1016/j.acthis.2011.09.002
  12. Vockley JG, Jenkinson CP, Shukla H, Kern RM, Grody WW, Cederbaum SD. Cloning and characterization of the human type II arginase gene. Genomics. 1996;38(2):118-123. doi: 10.1006/geno.1996.0606
  13. Yu H, Iyer RK, Kern RM, Rodriguez WI, Grody WW, Cederbaum SD. Expression of arginase isozymes in mouse brain. J Neurosci Res. 2001;66(3):406-422. doi: 10.1002/jnr.1233
  14. Shank RP, LeM. Campbell G. Ornithine as a precursor of glutamate and GABA: Uptake and metabolism by neuronal and glial enriched cellular material. J Neurosci Res. 1983;9(1):47-57. doi: 10.1002/jnr.490090107
  15. Vodovotz Y, Bogdan C, Paik J, Xie QW, Nathan C. Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor γ. J Exp Med. 1993;178(2):605-613. doi: 10.1084/jem.178.2.605
  16. Xie QW, Nathan C. Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon-gamma and bacterial lipopolysaccharide. Trans Assoc Am Physicians. 1993;106:1-12. doi: 10.1084/jem.177.6.1779
  17. Xie QW, Kashiwabara Y, Nathan C. Role of transcription factor NF-κB/Rel in induction of nitric oxide synthase. J Biol Chem. 1994;269(7):4705-4708. doi: 10.1016/s0021-9258(17)37600-7
  18. Que LG, George SE, Gotoh T, Mori M, Huang YCT. Effects of arginase isoforms on NO production by nNOS. Nitric Oxide. 2002;6(1):1-8. doi: 10.1006/niox.2001.0355
  19. Wang HG, Lu FM, Jin I, et al. Presynaptic and postsynaptic roles of NO, cGK, and RhoA in long-lasting potentiation and aggregation of synaptic proteins. Neuron. 2005;45(3):389-403. doi: 10.1016/j.neuron.2005.01.011
  20. Li H, Meininger CJ, Hawker JR, et al. Regulatory role of arginase I and II in nitric oxide, polyamine, and proline syntheses in endothelial cells. Am J Physiol Endocrinol Metab. 2001;280(1 43-1). doi: 10.1152/ajpendo.2001.280.1.e75
  21. Cai D, Deng K, Mellado W, Lee J, Ratan RR, Filbin MT. Arginase I and polyamines act downstream from cyclic AMP in overcoming inhibition of axonal growth MAG and myelin in vitro. Neuron. 2002;35(4):711-719. doi: 10.1016/S0896-6273(02)00826-7
  22. Malaterre J, Strambi C, Aouane A, Strambi A, Rougon G, Cayre M. A novel role for polyamines in adult neurogenesis in rodent brain. Eur J Neurosci. 2004;20(2):317-330. doi: 10.1111/j.1460-9568.2004.03498.x
  23. Pernet V, Bourgeois P, Polo A Di. A role for polyamines in retinal ganglion cell excitotoxic death. J Neurochem. 2007;103(4):1481-1490. doi: 10.1111/j.1471-4159.2007.04843.x
  24. Grillo MA, Fossa T, Dianzani U. Arginase, ornithine decarboxylase and S-adenosylmethionine decarboxylase in chicken brain and retina. Int J Biochem. 1983;15(8):1081-1084. doi: 10.1016/0020-711X(83)90047-2
  25. Nakamura H, Saheki T, Nakagawa S. Differential cellular localization of enzymes of l-arginine metabolism in the rat brain. Brain Res. 1990;530(1):108-112. doi: 10.1016/0006-8993(90)90664-W
  26. Peters D, Berger J, Langnaese K, et al. Arginase and Arginine Decarboxylase - Where Do the Putative Gate Keepers of Polyamine Synthesis Reside in Rat Brain? PLoS ONE. 2013;8(6). doi: 10.1371/journal.pone.0066735
  27. Braissant O, Gotoh T, Loup M, Mori M, Bachmann C. L-arginine uptake, the citrulline-NO cycle and arginase II in the rat brain: An in situ hybridization study. Mol Brain Res. 1999;70(2):231-241. doi: 10.1016/S0169-328X(99)00151-5
  28. Lee J, Ryu H, Ferrante RJ, Morris SM, Ratan RR. Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox. Proc Natl Acad Sci USA. 2003;100(8):4843-4848. doi: 10.1073/pnas.0735876100
  29. Konarska L, Tomaszewski L. Studies on l-arginase in developing rat small instestine, brain, and kidney. Biochem Med Metab Biol. 1986;35(2):156-169. doi: 10.1016/0885-4505(86)90070-8
  30. Shimizu H, Kakimoto Y, Sano I. Changes in concentration of polyamines in the developing mouse brain. Nature. 1965;207(5002):1196-1197. doi: 10.1038/2071196a0
  31. Murthy MRV, Rappoport DA. Biochemistry of the developing rat brain VI. Preparation and properties of ribosomes. BBA Section Nucleic Acids And Protein Synthesis. 1965;95(1):132-145. doi: 10.1016/0005-2787(65)90218-2
  32. Ferriero DM. Neonatal Brain Injury. New Engl J Med. 2004;351(19):1985-1995. doi: 10.1056/nejmra041996
  33. Prieto CP, Krause BJ, Quezada C, Martin RS, Sobrevia L, Casanello P. Hypoxia-reduced nitric oxide synthase activity is partially explained by higher arginase-2 activity and cellular redistribution in human umbilical vein endothelium. Placenta. 2011;32(12):932-940. doi: 10.1016/j.placenta.2011.09.003
  34. Cowburn AS, Crosby A, Macías D, et al. HIF-2α–arginase axis is essential for the development of pulmonary hypertension. Proc Natl Acad Sci USA. 2016;113(31):8801-8806.doi: 10.1073/pnas.1602978113
  35. Martín-Aragón Baudel MAS, Rae MT, Darlison MG, Poole AV, Fraser JA. Preferential activation of HIF-2α adaptive signalling in neuronal-like cells in response to acute hypoxia. PLoS ONE. 2017;12(10). doi: 10.1371/journal.pone.0185664
  36. Jin Y, Jin Y, Chen B, Tipple TE, Nelin LD. Arginase II is a target of miR-17-5p and regulates miR-17-5p expression in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2014;307(2). doi: 10.1152/ajplung.00266.2013
  37. Chen B, Xue J, Meng X, Slutzky JL, Calvert AE, Chicoine LG. Resveratrol prevents hypoxia-induced arginase II expression and proliferation of human pulmonary artery smooth muscle cells via Akt-dependent signaling. Am J Physiol Lung Cell Mol Physiol. 2014;307(4):L317-L325. doi: 10.1152/ajplung.00285.2013
  38. Toby IT, Chicoine LG, Cui H, Chen B, Nelin LD. Hypoxia-induced proliferation of human pulmonary microvascular endothelial cells depends on epidermal growth factor receptor tyrosine kinase activation. Am J Physiol Lung Cell Mol Physiol. 2010;298(4). doi: 10.1152/ajplung.00122.2009
  39. Nelin LD, Chicoine LC, Reber KM, English BK, Young TL, Liu Y. Cytokine-induced endothelial arginase expression is dependent on epidermal growth factor receptor. Am J Respir Cell Mol Biol. 2005;33(4):394-401. doi: 10.1165/rcmb.2005-0039OC
  40. White HA, Jin Y, Chicoine LG, Chen B, Nelin LD. Hypoxia stimulates ERK via EGFR activation in human pulmonary microvascular endothelial cells. FASEB J. 2016;30:980. doi: 10.1152/ajplung.00267.2016
  41. Arteaga O, Álvarez A, Revuelta M, Santaolalla F, Urtasun A, Hilario E. Role of antioxidants in neonatal hypoxic–ischemic brain injury: New therapeutic approaches. Int J Mol Sci. 2017;18(2). doi: 10.3390/ijms18020265
  42. Wei LH, Jacobs AT, Morris SM, Ignarro LJ. IL-4 and IL-13 upregulate arginase I expression by cAMP and JAK/STAT6 pathways in vascular smooth muscle cells. Am J Physiol Cell Physiol. 2000;279(1 48-1). doi: 10.1152/ajpcell.2000.279.1.c248
  43. Zimmermann N, King NE, Laporte J, et al. Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis. J Clin Investig. 2003;111(12):1863-1874. doi: 10.1172/JCI200317912
  44. Cho WK, Lee CM, Kang MJ, et al. IL-13 receptor α2-arginase 2 pathway mediates IL-13-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2013;304(2): L112-L124.doi: 10.1152/ajplung.00101.2012
  45. Hesse M, Modolell M, La Flamme AC, et al. Differential Regulation of Nitric Oxide Synthase-2 and Arginase-1 by Type 1/Type 2 Cytokines In Vivo: Granulomatous Pathology Is Shaped by the Pattern of l-Arginine Metabolism. J Immunol. 2001;167(11):6533-6544. doi: 10.4049/jimmunol.167.11.6533
  46. Wang WW, Jenkinson CP, Griscavage JM, et al. Co-induction of arginase and nitric oxide synthase in murine macrophages activated by lipopolysaccharide. Biochem Biophys Res Commun. 1995;210(3):1009-1016. doi: 10.1006/bbrc.1995.1757
  47. Modolell M, Corraliza IM, Link F, Soler G, Eichmann K. Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow‐derived macrophages by TH 1 and TH 2 cytokines. Eur J Immunol. 1995;25(4):1101-1104. doi: 10.1002/eji.1830250436
  48. Xu L, Hilliard B, Carmody RJ, et al. Arginase and autoimmune inflammation in the central nervous system. Immunology. 2003;110(1):141-148. doi: 10.1046/j.1365-2567.2003.01713.x
  49. Ljubisavljevic S, Stojanovic I, Pavlovic R, et al. Modulation of nitric oxide synthase by arginase and methylated arginines during the acute phase of experimental multiple sclerosis. J Neurol Sci. 2012;318(1-2):106-111. doi: 10.1016/j.jns.2012.03.015
  50. Giles DA, Washnock-Schmid JM, Duncker PC, et al. Myeloid cell plasticity in the evolution of central nervous system autoimmunity. Ann Neurol. 2018;83(1):131-141. doi: 10.1002/ana.25128
  51. Suwanpradid J, Rojas M, Behzadian MA, Caldwell RW, Caldwell RB. Arginase 2 deficiency prevents oxidative stress and limits hyperoxia-induced retinal vascular degeneration. PLoS ONE. 2014;9(11). doi: 10.1371/journal.pone.0110604
  52. Bhardwaj R, Suzuki A, Leland P, Joshi BH, Puri RK. Identification of a novel role of IL-13Rα2 in human Glioblastoma multiforme: interleukin-13 mediates signal transduction through AP-1 pathway. J Transl Med. 2018;16(1):369. doi: 10.1186/s12967-018-1746-6
  53. Stevenson L, Matesanz N, Colhoun L, et al. Reduced nitro-oxidative stress and neural cell death suggests a protective role for microglial cells in TNFα-/- mice in ischemic retinopathy. Invest Ophthalmol Vis Sci. 2010;51(6):3291-3299. doi: 10.1167/iovs.09-4344
  54. Baker BJ, Akhtar LN, Benveniste EN. SOCS1 and SOCS3 in the control of CNS immunity. Trends Immunol. 2009;30(8):392-400. doi: 10.1016/j.it.2009.07.001
  55. Qin H, Yeh WI, De Sarno P, et al. Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3 (STAT3/SOCS3) axis in myeloid cells regulates neuroinflammation. Proc Natl Acad Sci USA. 2012;109(13):5004-5009. doi: 10.1073/pnas.1117218109
  56. Whyte CS, Bishop ET, Rückerl D, et al. Suppressor of cytokine signaling (SOCS)1 is a key determinant of differential macrophage activation and function. J Leukoc Biol. 2011;90(5):845-854. doi: 10.1189/jlb.1110644
  57. Schmok E, Dar MA, Behrends J, et al. Suppressor of cytokine signaling 3 in macrophages prevents exacerbated Interleukin-6-Dependent Arginase-1 activity and early permissiveness to experimental tuberculosis. Front Immunol. 2017;8. doi: 10.3389/fimmu.2017.01537
  58. Bansal V, Syres K, Harbrecht BG, Ochoa JB. Effect of prostoglandins in arginase I expression. J Surg Res. 2003;114(2):288. doi: 10.1016/j.jss.2003.08.057
  59. Zhou, Xiaolai, Björn Spittau, Kerstin Krieglstein. TGFβ signalling plays an important role in IL4-induced alternative activation of microglia. J Neuroinflammation. 2012;9(9):210. doi: 10.1186/1742-2094-9-210
  60. Narayanan SP, Suwanpradid J, Saul A, et al. Arginase 2 deletion reduces neuro-glial injury and improves retinal function in a model of retinopathy of prematurity. PloS ONE. 2011:e22460. doi: 10.1371/journal.pone.0022460
  61. Lacchini R, Muniz JJ, Nobre YTDA, Cologna AJ, Martins ACP, Tanus-Santos JE. Relationship between Arginase 1 and Arginase 2 levels and genetic polymorphisms with erectile dysfunction. Nitric Oxide. 2015;51:36-42. doi: 10.1016/j.niox.2015.10.003
  62. Lange PS, Langley B, Lu P, Ratan RR. Novel roles for arginase in cell survival, regeneration, and translation in the central nervous system. J Nutr. 2004;134(10):2812S-2817S. doi: 10.1093/jn/134.10.2812s
  63. Lucas R, Fulton D, Caldwell RW, Romero MJ. Arginase in the vascular endothelium: Friend or foe? Front Immunol. 2014;5. doi: 10.3389/fimmu.2014.00589
  64. Shin W, Berkowitz DE, Ryoo S. Increased arginase II activity contributes to endothelial dysfunction through endothelial nitric oxide synthase uncoupling in aged mice. Exp Mol Med. 2012;44(10):594-602. doi: 10.3858/emm.2012.44.10.068
  65. Munder M. Arginase: An emerging key player in the mammalian immune system: REVIEW. Br J Pharmacol. 2009;158(3):638-651. doi: 10.1111/j.1476-5381.2009.00291.x
  66. Morris Jr SM. Recent advances in arginine metabolism: roles and regulation of the arginases. Br J Pharmacol. 2009;157(6):922-930. doi: 10.1111/j.1476-5381.2009.00278.x
  67. Huynh NN, Harris EE, Chin-Dusting JFP, Andrews KL. The vascular effects of different arginase inhibitors in rat i/ated aorta and mesenteric arteries. Br J Pharmacol. 2009;156(1):84-93. doi: 10.1111/j.1476-5381.2008.00036.x
  68. Chandra S, Romero MJ, Shatanawi A, Alkilany AM, Caldwell RB, Caldwell RW. Oxidative species increase arginase activity in endothelial cells through the RhoA/Rho kinase pathway. Br J Pharmacol. 2012;165(2):506-519. doi: 10.1111/j.1476-5381.2011.01584.x
  69. Kanyo ZF, Scolnick LR, Ash DE, Christianson DW. Structure of a unique binuclear manganese cluster in arginase. Nature. 1996;383(6600):554-557. doi: 10.1038/383554a0
  70. Cox JD, Kim NN, Traish AM, Christianson DW. Arginase–boronic acid complex highlights a physiological role in erectile function. Nat Struct Biol. 1999;6(11):1043-1047. doi: 10.1038/14929
  71. Baggio R, Emig FA, Christianson DW, Ash DE, Chakder S, Rattan S. Biochemical and functional profile of a newly developed potent and isozyme-selective arginase inhibitor. J Pharmacol Exp Ther. 1999;290(3):1409-1416. doi: 10.1016/S0022-3565(24)35048-7
  72. Berkowitz DE, White R, Li D, et al. Arginase Reciprocally Regulates Nitric Oxide Synthase Activity and Contributes to Endothelial Dysfunction in Aging Blood Vessels. Circulation. 2003;108(16):2000-2006. doi: 10.1161/01.CIR.0000092948.04444.C7
  73. Steppan J, Nyhan D, Berkowitz DE. Development of novel arginase inhibitors for therapy of endothelial dysfunction. Front Immunol. 2013;4. doi: 10.3389/fimmu.2013.00278
  74. Bivalacqua TJ, Burnett AL, Hellstrom WJG, Champion HC. Overexpression of arginase in the aged mouse penis impairs erectile function and decreases eNOS activity: Influence of in vivo gene therapy of anti-arginase. Am J Physiol Heart Circ Physiol. 2007;292(3). doi: 10.1152/ajpheart.00121.2005
  75. Vadivel A, Aschner JL, Rey-Parra GJ, et al. L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats. Pediatr Res. 2010;68(6):519-525. doi: 10.1203/PDR.0b013e3181f90278
  76. Ivanenkov YA, Chufarova N V. Small-molecule arginase inhibitors. Pharm Pat Anal. 2014;3(1):65-85. doi: 10.4155/PPA.13.75
  77. Yang M, Rangasamy D, Matthaei KI, et al. Inhibition of Arginase I Activity by RNA Interference Attenuates IL-13-Induced Airways Hyperresponsiveness. J Immunol. 2006;177(8):5595-5603. doi: 10.4049/jimmunol.177.8.5595
  78. Wu G, Morris SM. Arginine metabolism: Nitric oxide and beyond. Biochem J. 1998;336(1):1-17. doi: 10.1042/bj3360001
  79. Zaiman A, Fijalkowska I, Hassoun PM, Tuder RM. One hundred years of research in the pathogenesis of pulmonary hypertension. Am J Respir Cell Mol Biol. 2005;33(5):425-431. doi: 10.1165/rcmb.F307
Next article in this issue
Share
Back to top
INNOSC Theranostics and Pharmacological Sciences, Electronic ISSN: 2705-0823 Print ISSN: 2705-0734, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept