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Injury
Response in the Developing Nervous System
Over the past 14 years, my research has been focused on the pathobiology
of hypoxic-ischemic injury in the developing nervous system. This process
differs markedly from that in the mature nervous system and through a
series of investigations, both in vivo and in vitro, in animals and in
humans, we have documented those differences.
The immature brain is uniquely and exquisitely sensitive to oxidative
stress which accounts for the cell death seen after hypoxia-ischemia.
As in all neurological diseases, there are vulnerable regions of injury
and these regions are damaged in an age-dependent manner. For example,
in the premature brain, we see injury in the periventricular white matter
that reflect damage to the developing oligodendrocytes, but we also have
new data to suggest that subplate neurons are involved as well . In the
term baby, we see a different pattern of vulnerability, with damage to
the deep gray nuclei and this pattern of vulnerability can be used to
predict neurodevelopmental outcome later in life (see human studies below).
This pattern may be due to the unique distribution of a network of cells
with a rich supply of glutamate receptors that parallels the distribution
of a population of neurons containing neuronal nitric oxide synthase
that are uniquely spared after hypoxia-ischemia at this age Since these
cells are spared, they are available to signal relentlessly and release
the free radical nitric oxide and oxidatively challenge the newborn brain.
Selective destructive or targeted elimination of the nitric oxide synthase
neurons results in protection in animal models, although pharmacological
inhibition of the enzyme has not been satisfactory due to the non-selectivity
of the compounds and to the fact that there is some depression of enzymatic
activity immediately after the insult. We have also shown that hypoxic-ischemic
injury results in prolonged and delayed cell death both locally and in
remote regions after the insult.These data have important consequences
for future studies because they suggest that there is prolonged window
of opportunity for the administration of neuroprotective agents. We have
shown that therapies used for the adult nervous system must not be assumed
to work for the newborn brain. For example, overexpression of superoxide
dismutase had been successful in treating adult stroke in animal models,
but in the immature animal, this overexpression leads to more injury
because the neonatal animals have less antioxidant reserve . This was
the first example where therapy assumed to be neuroprotective for all
ages actually had deleterious effects in the immature brain. Subsequently,
other reports followed for other agents (Ikonomidou et al, Science 283,
1999).
Currently, we have two prospective human research studies ongoing to
delineate injury patterns and identify prognostic factors that will determine
neurodevelopmental outcome in babies with neonatal encephalopathy. We
have studied over 150 preterm (PREMRI – Premature Asphyxia Magnetic
Resonance Imaging) and 200 term (BAMRI –Brain Asphyxia Magnetic
Resonance Imaging) infants using state-of-the art magnetic resonance
(MR) imaging modalities such as spectroscopy, diffusion tensor imaging,
and perfusion mapping.
Selected Publications:
2001 Northington FJ, FERRIERO DM, Flock DL, Martin LJ. Delayed thalamic
neurodegeneration after hypoxia-ischemia in neonatal rat diencephalon
is programmed cell death. J. Neurosci 21:1931-1938.
2002 Parent JM, Vexler ZS, Gong C, Derugin N, FERRIERO DM. Focal cerebral
ischemia increases adult rat forebrain subventricular zone neuroblast
proliferation and induces neostriatal neurogenesis. Ann Neurol 52(6):802-813
2003 Manabat C, Han B, Wendland M, Derugin N, Fox C, Choi J, Holtzman
DM, FERRIERO DM, Vexler ZS. Reperfusion differentially induces caspase-3
activation in ischemic core and penumbra after stroke in immature brain.
Stroke: 34(1):207-13.
2003 McQuillen PS, Sheldon RA, Shatz CJ, FERRIERO DM. Selective vulnerability
of subplate neurons following early neonatal hypoxia ischemia. J Neurosci,
in press
Contact Information:
Email: ferrierod@neuropeds.ucsf.edu
Phone: 415/502-5820
Address: Box 0663, Room C 215
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
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