Acta Neuropathologica

, Volume 118, Issue 3, pp 391–399 | Cite as

Nitrosative stress and inducible nitric oxide synthase expression in periventricular leukomalacia

  • Robin L. Haynes
  • Rebecca D. Folkerth
  • Felicia L. Trachtenberg
  • Joseph J. Volpe
  • Hannah C. Kinney
Original Paper


Periventricular leukomalacia (PVL) is a lesion of the immature cerebral white matter in the perinatal period and associated predominantly with prematurity and cerebral ischemia/reperfusion as well as inflammation due to maternofetal infection. It consists of focal necrosis in the periventricular region and diffuse gliosis with microglial activation and premyelinating oligodendrocyte (pre-OL) injury in the surrounding white matter. We previously showed nitrotyrosine in pre-OLs in PVL, suggesting involvement of nitrosative stress in this disorder. Here we hypothesize that inducible nitric oxide synthase (iNOS) expression is increased in PVL relative to controls. Using immunocytochemistry in human archival tissue, the density of iNOS-expressing cells was determined in the cerebral white matter of 15 PVL cases [29–51 postconceptional (PC) weeks] and 16 control cases (20–144 PC weeks). Using a standardization score of 0–3, the density of iNOS-positive cells was significantly increased in the diffuse component of PVL (score of 1.8 ± 0.3) cases compared to controls (score of 0.7 ± 0.3) (P = 0.01). Intense iNOS expression occurred in reactive astrocytes in acute through chronic stages and in activated microglia primarily in the acute stage, suggesting an early role for microglial iNOS in PVL’s pathogenesis. This study supports an important role for iNOS-induced nitrosative stress in the reactive/inflammatory component of PVL.


Nitrotyrosine Oxidative stress Astrocytes Microglia 



Analysis of covariance




Glial fibrillary acidic protein




Inducible nitric oxide synthase


Nitric oxide






Postmortem interval




Premyelinating oligodendrocyte


Periventricular leukomalacia



The authors thank Mr. Richard A. Belliveau for assistance in this study. This research was supported by grants from the National Institute of Neurological Diseases and Stroke (PO1-NS38475) (HCK, JJV), National Institute of Child Health and Development (Children’s Hospital Developmental Disabilities Research Center) (P30-HD18655), and the William Randolph Hearst Award.


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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Robin L. Haynes
    • 1
    • 3
  • Rebecca D. Folkerth
    • 1
    • 2
  • Felicia L. Trachtenberg
    • 4
  • Joseph J. Volpe
    • 3
    • 5
  • Hannah C. Kinney
    • 1
    • 3
  1. 1.Departments of PathologyChildren’s Hospital BostonBostonUSA
  2. 2.Brigham and Women’s HospitalBostonUSA
  3. 3.Harvard Medical SchoolBostonUSA
  4. 4.New England Research InstitutesWatertownUSA
  5. 5.Department of NeurologyChildren’s Hospital BostonBostonUSA

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