Available online at www.sciencedirect.com
Effect of cerebral hypothermia and asphyxia on the
subventricular zone and white matter tracts in preterm
Robert Daniel Barrett, Laura Bennet, Andrew Naylor, Sherly A. George,
Justin M. Dean, Alistair Jan Gunn
Department of Physiology, Faculty of Medicine and Health Science, The University of Auckland, Private Bag 92019,
Auckland 1023, New Zealand
Accepted 13 June 2012
Available online 2 July 2012
Prolonged, moderate cerebral hypothermia is consistently neuroprotective after experimental
hypoxia–ischemia. We have previously shown that hypothermia is also protective after
profound asphyxia in the preterm brain. However, there is a concern whether hypothermia
could suppress the proliferative response to injury in the white matter or subventricular zone
(SVZ). Preterm (0.7 gestation) fetal sheep received complete umbilical cord occlusion for 25 min
followed by cerebral hypothermia (extradural temperature reduced from 39.470.3 to
29.572.6 1C) from 90 min to 70 h after the end of occlusion or sham cooling. Occlusion-
normothermia was associated with no effect on CNPaseþ cells, but loss of O4þ oligodendro-
cytes, induction of cleaved caspase-3, and IB4þ microglia in the gyral and periventricular white
matter compared to sham-occlusion (p o 0.05), with a signiﬁcant increase in KI67þ cells in the
periventricular white matter (p o 0.05). Hypothermia was associated with signiﬁcant protection
of O4þ cells, with suppression of IB4þ microglia and KI67þ cells in the periventricular white
matter. There was no signiﬁcant change in astrocytes, microglia, KI67þ,orcaspase-3þ cells in
the SVZ after asphyxia. In conclusion, this study provides strong support for the selective
vulnerability of immature oligodendrocytes to a highly relevant insult in the fetal sheep.
Although white matter protection with cerebral hypothermia was associated with reduced
proliferation in the white matter tracts, it did not impair proliferation in the SVZ.
& 2012 Elsevier B.V. All rights reserved.
Preterm born infants have high rates of injury to the white
matter structures of the brain, with high rates of neurodevelop-
mental impairment including cerebral palsy (Committee on
Understanding Premature Birth and Assuring Healthy Out-
comes; Institute of Medicine, 2007). In modern preterm cohorts,
the predominant pattern of injury involves diffuse non-destruc-
tive lesions in the periventricular and adjacent white matter
regions. These diffuse lesions are characterized by oligodendro-
cyte (OL) cell death and deﬁcits in OL maturation (Buser et al.,
2012), resulting in disturbances in normal myelination.
Cerebral hypothermia is now an established treatment for
hypoxic–ischemic encephalopathy in term-born infants
0006-8993/$ - see front matter & 2012 Elsevier B.V. All rights reserved.
Abbreviations: GFAP, glial ﬁbrillary acidic protein; pre-OL, pre-oligodendrocyte; IB4, isolectin B4; SVZ, subventricular zone;
WM, white matter
Corresponding author. Fax: þ64 9 373 7499.
E-mail address: email@example.com (A.J. Gunn).
brain research 1469 (2012) 35–42