Elsevier

Neuroscience

Volume 116, Issue 3, 17 February 2003, Pages 705-714
Neuroscience

Original contribution
Extracellular glutamate levels and neuropathology in cerebral white matter following repeated umbilical cord occlusion in the near term fetal sheep

https://doi.org/10.1016/S0306-4522(02)00756-XGet rights and content

Abstract

Umbilical cord occlusion causes fetal hypoxemia which can result in brain injury including damage to cerebral white matter. Excessive glutamate release may be involved in the damage process. This study examined the relation between extracellular glutamate levels in the cerebral white matter of the ovine fetus during and after intermittent umbilical cord occlusion and the degree of resultant fetal brain injury. Fetal sheep underwent surgery for chronic catheterisation and implantation of an intra-cerebral microdialysis probe at 130 days of gestation (term ∼147 days). Four days after surgery (day 1), seven fetuses were subjected to 5×2 min umbilical cord occlusions, and on the following day (day 2) they were subjected to either 4 or 5×4 min umbilical cord occlusions; seven fetuses served as controls. Microdialysis samples were collected before, during and after the umbilical cord occlusions to determine extracellular glutamate levels in the cerebral white matter. Fetal blood gas status was measured and the fetal electrocorticogram was recorded continuously. During the periods of umbilical cord occlusions on both days 1 and 2, fetal arterial oxygen saturation, arterial partial pressure of oxygen and arterial pH decreased (P<0.05) while arterial partial pressure of carbon dioxide increased (P<0.05). All fetuses showed episodes of isoelectric electrocortical activity during umbilical cord occlusions on both days 1 and 2. In fetuses with patent microdialysis probes there were marked increases of glutamate efflux in the cerebral white matter following umbilical cord occlusion. Fetal brains were removed at autopsy on day 5 and subjected to histological assessment. Brain damage was observed in all fetuses exposed to cord occlusion, particularly in the periventricular white matter, with the most extensive damage occurring in the fetuses with the greatest increases in glutamate levels. We conclude that, in the unanesthetised fetus in utero, glutamatergic processes are associated with umbilical cord occlusion-induced brain damage in the cerebral white matter.

Section snippets

Experimental procedures

This study was approved by the Animal Care Committees of the Lawson Research Institute and the University of Western Ontario, in accordance with the guidelines of the Canadian Council on Animal Care.

Results

Results are presented for 14 (7 UCO, 7 controls) of the 20 fetuses. Of the other six animals, two controls had to be euthanized due to poor maternal condition and one fetus died in association with placental bleeding. One UCO fetus developed unexplained metabolic acidemia on day 1 and died. Two of the four fetuses which had 5×4 min UCO on day 2 died from metabolic acidosis following UCO; this led to a change in the protocol to 4×4 min UCO on day 2 for 5 of the UCO animals reported here.

Discussion

This is the first study to describe a correlation between levels of glutamate in the cerebral white matter and the extent of white matter damage in chronically catheterised, unanaesthetised fetuses in utero subjected to repeated UCOs. Fetal white matter damage ranged from extensive injury including severe periventricular necrosis to more diffuse subcortical damage, including reduced myelination, increased apoptosis and an increase in lectin-positive microglia/macrophages. Most significantly we

Conclusion

We have shown for the first time that repeated UCO in the late-gestation, unanaesthetised ovine fetus in utero results in both an increased glutamate efflux in the cerebral white matter and brain damage, with the higher levels of glutamate efflux being associated with more extensive white matter injury. Changes in extracellular glutamate levels must be interpreted with caution at this time as a greater increase in glutamate may reflect a more severe insult as well as reflecting the potential

Acknowledgements

This work was supported by grants from the Medical Research Council of Canada and the National Health and Medical Research Council of Australia. We wish to thank Jac Homan, Susan White, Jhodie Duncan and Mardi Sait for their excellent assistance. We also thank Dr. Bryan Richardson for his interest in these studies.

References (49)

  • J.L. Henderson et al.

    Chronic hypoxemia causes extracellular glutamate concentration to increase in the cerebral cortex of the near-term fetal sheep

    Brain Res Dev Brain Res

    (1998)
  • T. Ikeda et al.

    Physiologic and histologic changes in near-term fetal lambs exposed to asphyxia by partial umbilical cord occlusion

    Am J Obstet Gynecol

    (1998)
  • E.C. Mallard et al.

    Transient umbilical cord occlusion causes hippocampal damage in the fetal sheep

    Am J Obstet Gynecol

    (1992)
  • E.C. Mallard et al.

    Repeated asphyxia causes loss of striatal projection neurons in the fetal sheep brain

    Neurosci

    (1995)
  • L.I. Mann

    Pregnancy events and brain damage

    Am J Obstet Gynecol

    (1986)
  • A. McRae et al.

    Microglia activation after neonatal hypoxic-ischemia

    Dev Brain Res

    (1995)
  • J. Ohyu et al.

    Early axonal and glial pathology in fetal sheep brains with leukomalacia induced by repeated umbilical cord occlusion

    Brain Dev

    (1999)
  • R. Osak et al.

    Nuchal cord evident at birth impacts on fetal size relative to that of the placenta

    Early Hum Dev

    (1997)
  • P.G. Osborne et al.

    In vivo characterisation of extracellular dopamine, GABA and acetylcholine from the dorsolateral striatum of awake freely moving rats by chronic microdialysis

    J Neurosci Methods

    (1991)
  • S. Rees et al.

    The vulnerability of the fetal sheep brain to hypoxemia at mid-gestation

    Dev Brain Res

    (1997)
  • M.N. Woodroofe et al.

    Detection of interleukin-1 and interleukin-6 in adult rat brain, following mechanical injury, by in vivo microdialysisEvidence of a role for microglia in cytokine production

    J Neuroimmunol

    (1991)
  • A.H. Wyllie et al.

    Cell deathThe significance of apoptosis

    Int Rev Cytol

    (1980)
  • S.A. Back et al.

    Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion

    J Neurosci

    (1998)
  • H. Benveniste et al.

    Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis

    J Neurochem

    (1984)
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