Journal Mobile Options
Table of Contents
Vol. 27, No. 2-4, 2005
Issue release date: March–August 2005
Dev Neurosci 2005;27:127–133

Strain Variability, Injury Distribution, and Seizure Onset in a Mouse Model of Stroke in the Immature Brain

Comi A.M. · Johnston M.V. · Wilson M.A.
Departments of aNeurology, bPediatrics, and cNeuroscience, Johns Hopkins University School of Medicine, and eKennedy Krieger Research Institute, Baltimore, Md., USA

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Neonatal stroke is an important cause of neurologic morbidity and cerebral palsy. Recently, we have determined that in postnatal day 12 CD1 mice unilateral carotid ligation alone results in seizures and brain injury. We have shown that, in this model, seizure scores correlate with brain injury scores. We have applied this model to another strain of mice to assess strain-related differences in vulnerability to seizures and brain injury after unilateral carotid ligation. Under isoflurane anesthesia, unilateral right-sided carotid ligation was performed in postnatal day 12 C3HeB/FeJ mice followed by a 4-hour period of observation in a 35°C incubator. Seizure scores and brain jury scores were assigned and compared to scores in mice receiving sham surgery. Timing of seizure onset and regional distribution of brain injury were compared in the CD1 and C3HeB/FeJ mice. Unilateral carotid ligation in postnatal day 12 C3HeB/FeJ mice resulted in seizure behavior and brain injury in some animals, with similar time to seizure onset and regional injury distribution, but affected a significantly smaller percentage of C3HeB/FeJ pups than that observed in postnatal day 12 CD1 mice, indicating strain-related vulnerability in this model.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Hagberg B, Hagberg G, Beckung E, Uvebrant P: Changing panorama of cerebral palsy in Sweden. 8. Prevalence and origin in the birth year period 1991–1994. Acta Paediatr 2001;90:271–277.
  2. Ashwal S, Russman BS, Blasco PA, Miller G, Sandler A, Shevell M, et al: Practice parameter: Diagnostic assessment of the child with cerebral palsy: Report of the quality standards subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2004;62:851–863.
  3. Lynch JK, Nelson KB: Epidemiology of perinatal stroke. Curr Opin Pediatr 2001;13:499–505.
  4. Lynch JK, Hirtz DG, deVeber G, Nelson KB: Report of the National Institute of Neurological Disorders and Stroke workshop on perinatal and childhood stroke. Pediatrics 2002;109:116–123.
  5. Nelson RM, Lambert DG, Richard GA, Hainsworth AH: Pharmacology of ischemia-induced glutamate efflux from rat cerebral cortex in vitro. Brain Res 2003;964:1–8.
  6. Johnston MV, Trescher WH, Ishida A, Nakajima W: Neurobiology of hypoxic-ischemic injury in the developing brain. Pediatr Res 2001;49:735–741.
  7. Wieloch T: Molecular mechanisms of ischemic brain damage; in Edvinsson L, Krause DN (eds): Cerebral Blood Flow and Metabolism. Philadelphia, Lippincott Williams and Wilkins, 2002, pp 423–451.
  8. Vannucci RC, Connor JR, Mauger DT, Palmer C, Smith MB, Towfighi J, et al: Rat model of perinatal hypoxic-ischemic brain damage. J Neurosci Res 1999;55:158–163.
  9. Hoehn M, Nicolay K, Franke C, van der SB: Application of magnetic resonance to animal models of cerebral ischemia. J Magn Reson Imaging 2001;14:491–509.
  10. Leker RR, Constantini S: Experimental models in focal cerebral ischemia: Are we there yet? Acta Neurochir Suppl 2002;83:55–59.
  11. Ginsberg MD, Busto R: Rodent models of cerebral ischemia. Stroke 1989;20:1627–1642.
  12. Towfighi J, Mauger D, Vannucci RC, Vannucci SJ: Influence of age on the cerebral lesions in an immature rat model of cerebral hypoxia-ischemia: A light microscopic study. Brain Res Dev Brain Res 1997;100:149–160.
  13. Liu XH, Kwon D, Schielke GP, Yang GY, Silverstein FS, Barks JD: Mice deficient in interleukin-1 converting enzyme are resistant to neonatal hypoxic-ischemic brain damage. J Cereb Blood Flow Metab 1999;19:1099–1108.
  14. Gibson ME, Han BH, Choi J, Knudson CM, Korsmeyer SJ, Parsadanian M, et al: BAX contributes to apoptotic-like death following neonatal hypoxia-ischemia: Evidence for distinct apoptosis pathways. Mol Med 2001;7:644–655.
  15. Skoff RP, Bessert DA, Barks JD, Song D, Cerghet M, Silverstein FS: Hypoxic-ischemic injury results in acute disruption of myelin gene expression and death of oligodendroglial precursors in neonatal mice. Int J Dev Neurosci 2001;19:197–208.
  16. Aden U, Halldner L, Lagercrantz H, Dalmau I, Ledent C, Fredholm BB: Aggravated brain damage after hypoxic ischemia in immature adenosine A2A knockout mice. Stroke 2003;34:739–744.
  17. Hagberg H, Wilson MA, Matsushita H, Zhu C, Lange M, Gustavsson M, et al: PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury. J Neurochem 2004;90:1068–1075.
  18. Donadio MF, Kozlowski PB, Kaplan H, Wisniewski HM, Majkowski J: Brain vasculature and induced ischemia in seizure-prone and non-seizure-prone gerbils. Brain Res 1982;234:263–273.
  19. Kelly S, McCulloch J, Horsburgh K: Minimal ischaemic neuronal damage and HSP70 expression in MF1 strain mice following bilateral common carotid artery occlusion. Brain Res 2001;914:185–195.
  20. Kim SB, Kang SA, Park JS, Lee JS, Hong CD: Effects of hypoxia on the extracellular matrix production of cultured rat mesangial cells. Nephron 1996;72:275–280.
  21. Kuan CY, Whitmarsh AJ, Yang DD, Liao G, Schloemer AJ, Dong C, et al: A critical role of neural-specific JNK3 for ischemic apoptosis. Proc Natl Acad Sci USA 2003;100:15184–15189.
  22. Mu D, Jiang X, Sheldon RA, Fox CK, Hamrick SE, Vexler ZS, et al: Regulation of hypoxia-inducible factor 1alpha and induction of vascular endothelial growth factor in a rat neonatal stroke model. Neurobiol Dis 2003;14:524–534.
  23. Comi AM, Weisz CJ, Highet BH, Johnston MV, Wilson MA: A new model of stroke and ischemic seizures in the immature mouse. Pediatr Neurol 2004;31:254–257.
  24. Morrison RS, Wenzel HJ, Kinoshita Y, Robbins CA, Donehower LA, Schwartzkroin PA: Loss of the p53 tumor suppressor gene protects neurons from kainate-induced cell death. J Neurosci 1996;16:1337–1345.
  25. Matsushita H, Johnston MV, Lange MS, Wilson MA: Protective effect of erythropoietin in neonatal hypoxic ischemia in mice. Neuroreport 2003;14:1757–1761.
  26. McKhann GM, Wenzel HJ, Robbins CA, Sosunov AA, Schwartzkroin PA: Mouse strain differences in kainic acid sensitivity, seizure behavior, mortality, and hippocampal pathology. Neuroscience 2003;122:551–561.
  27. Yang G, Kitagawa K, Matsushita K, Mabuchi T, Yagita Y, Yanagihara T, et al: C57BL/6 strain is most susceptible to cerebral ischemia following bilateral common carotid occlusion among seven mouse strains: Selective neuronal death in the murine transient forebrain ischemia. Brain Res 1997;752:209–218.
  28. Maeda K, Hata R, Hossmann KA: Regional metabolic disturbances and cerebrovascular anatomy after permanent middle cerebral artery occlusion in C57black/6 and SV129 mice. Neurobiol Dis 1999;6:101–108.
  29. Lightfoot JT, Turner MJ, Debate KA, Kleeberger SR: Interstrain variation in murine aerobic capacity. Med Sci Sports Exerc 2001;33:2053–2057.
  30. Majid A, He YY, Gidday JM, Kaplan SS, Gonzales ER, Park TS, et al: Differences in vulnerability to permanent focal cerebral ischemia among 3 common mouse strains. Stroke 2000;31:2707–2714.
  31. Wellons JC 3rd, Sheng H, Laskowitz DT, Burkhard MG, Pearlstein RD, Warner DS: A comparison of strain-related susceptibility in two murine recovery models of global cerebral ischemia. Brain Res 2000;868:14–21.
  32. Sheldon RA, Sedik C, Ferriero DM: Strain-related brain injury in neonatal mice subjected to hypoxia-ischemia. Brain Res 1998;810:114–122.
  33. Beckmann N: High resolution magnetic resonance angiography non-invasively reveals mouse strain differences in the cerebrovascular anatomy in vivo. Magn Reson Med 2000;44:252–258.
  34. Barone FC, Knudsen DJ, Nelson AH, Feuerstein GZ, Willette RN: Mouse strain differences in susceptibility to cerebral ischemia are related to cerebral vascular anatomy. J Cereb Blood Flow Metab 1993;13:683–692.
  35. Ferraro TN, Golden GT, Smith GG, DeMuth D, Buono RJ, Berrettini WH: Mouse strain variation in maximal electroshock seizure threshold. Brain Res 2002;936:82–86.
  36. Frankel WN, Taylor L, Beyer B, Tempel BL, White HS: Electroconvulsive thresholds of inbred mouse strains. Genomics 2001;74:306–312.
  37. Ryan MJ, Didion SP, Davis DR, Faraci FM, Sigmund CD: Endothelial dysfunction and blood pressure variability in selected inbred mouse strains. Arterioscler Thromb Vasc Biol 2002;22:42–48.
  38. Schwarcz A, Natt O, Watanabe T, Boretius S, Frahm J, Michaelis T: Localized proton MRS of cerebral metabolite profiles in different mouse strains. Magn Reson Med 2003;49:822–827.
  39. Lambertsen KL, Gregersen R, Finsen B: Microglial-macrophage synthesis of tumor necrosis factor after focal cerebral ischemia in mice is strain dependent. J Cereb Blood Flow Metab 2002;22:785–797.
  40. Skynner HA, Rosahl TW, Knowles MR, Salim K, Reid L, Cothliff R, et al: Alterations of stress related proteins in genetically altered mice revealed by two-dimensional differential in-gel electrophoresis analysis. Proteomics 2002;2:1018–1025.
  41. Schauwecker PE: Differences in ionotropic glutamate receptor subunit expression are not responsible for strain-dependent susceptibility to excitotoxin-induced injury. Brain Res Mol Brain Res 2003;112:70–81.
  42. Menard C, Valastro B, Martel MA, Martinoli MG, Massicotte G: Strain-related variations of AMPA receptor modulation by calcium-dependent mechanisms in the hippocampus: Contribution of lipoxygenase metabolites of arachidonic acid. Brain Res 2004;1010:134–143.
  43. Aso K, Scher MS, Barmada MA: Cerebral infarcts and seizures in the neonate. J Child Neurol 1990;5:224–228.
  44. deVeber G, Andrew M: Cerebral sinovenous thrombosis in children. N Engl J Med 2001;345:417–423.
  45. Delsing BJ, Catsman-Berrevoets CE, Appel IM: Early prognostic indicators of outcome in ischemic childhood stroke. Pediatr Neurol 2001;24:283–289.
  46. Sreenan C, Bhargava R, Robertson CM: Cerebral infarction in the term newborn: Clinical presentation and long-term outcome. J Pediatr 2000;137:351–355.
  47. Bentue-Ferrer D, Bellissant E, Decombe R, Allain H: Temporal profile of aminergic neurotransmitter release in striatal dialysates in rats with post-ischemic seizures. Exp Brain Res 1994;97:437–443.
  48. Krugers HJ, Kemper RH, Korf J, Ter Horst GJ, Knollema S: Metyrapone reduces rat brain damage and seizures after hypoxia-ischemia: An effect independent of modulation of plasma corticosterone levels? J Cereb Blood Flow Metab 1998;18:386–390.
  49. Holtzman D, Togliatti A, Khait I, Jensen F: Creatine increases survival and suppresses seizures in the hypoxic immature rat. Pediatr Res 1998;44:410–414.
  50. Cataltepe O, Vannucci RC, Heitjan DF, Towfighi J: Effect of status epilepticus on hypoxic-ischemic brain damage in the immature rat. Pediatr Res 1995;38:251–257.
  51. Wirrell EC, Armstrong EA, Osman LD, Yager JY: Prolonged seizures exacerbate perinatal hypoxic-ischemic brain damage. Pediatr Res 2001;50:445–454.
  52. Jensen FE, Holmes GL, Lombroso CT, Blume HK, Firkusny IR: Age-dependent changes in long-term seizure susceptibility and behavior after hypoxia in rats. Epilepsia 1992;33:971–980.
  53. Sanchez RM, Koh S, Rio C, Wang C, Lamperti ED, Sharma D, et al: Decreased glutamate receptor 2 expression and enhanced epileptogenesis in immature rat hippocampus after perinatal hypoxia-induced seizures. J Neurosci 2001;21:8154–8163.
  54. Nakajima W, Ishida A, Lange MS, Gabrielson KL, Wilson MA, Martin LJ, et al: Apoptosis has a prolonged role in the neurodegeneration after hypoxic ischemia in the newborn rat. J Neurosci 2000;20:7994–8004.
  55. Northington FJ, Ferriero DM, Flock DL, Martin LJ: Delayed neurodegeneration in neonatal rat thalamus after hypoxia-ischemia is apoptosis. J Neurosci 2001;21:1931–1938.
  56. Oppenheim RW, Flavell RA, Vinsant S, Prevette D, Kuan CY, Rakic P: Programmed cell death of developing mammalian neurons after genetic deletion of caspases. J Neurosci 2001;21:4752–4760.

Pay-per-View Options
Direct payment This item at the regular price: USD 9.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 8.00