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Journal of Neuroscience, Vol 9, 2809-2818, Copyright © 1989 by Society for Neuroscience
Sensitivity of the developing rat brain to hypobaric/ischemic damage parallels sensitivity to N-methyl-aspartate neurotoxicity
C Ikonomidou, JL Mosinger, KS Salles, J Labruyere and JW Olney
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110.
The endogenous excitotoxin, glutamate (Glu), acting at the N-methyl-
aspartate (NMA) subtype of Glu receptor, is thought to play a major role in
hypoxic/ischemic neuronal degeneration. In the present study, the
sensitivities of the developing rat CNS to hypoxic/ischemic neuronal
degeneration and to the neurotoxic action of NMA were compared at various
postnatal ages. In the hypoxic/ischemic experiments, ischemia was produced
by unilateral common carotid artery ligation and hypoxia by subjecting the
pups to a partial vacuum. Keeping the duration of the hypobaric episode
constant at 75 min for all age groups, we observed that the vulnerability
of the immature brain to hypobaric/ischemic damage increased during the
early neonatal period (days 2-4), reached a peak at day 6 and then
diminished progressively with increasing age. In the second part of the
study, NMA was microinjected unilaterally into the head of the caudate
nucleus at various postnatal ages (2-80 d). In the early neonatal period
(days 2- 6), injections of relatively small doses of NMA (6-15 nmol)
produced a dose-dependent widespread excitotoxic reaction throughout the
forebrain with peak sensitivity being observed on day 6. The cytotoxic
reaction to NMA was identical in appearance and time course to that induced
by hypobaric/ischemic methods. With increasing age, the excitotoxic
response to a given dose of NMA decreased progressively and the lesions
became more strictly confined to the injection site. Cell populations most
sensitive to NMA toxicity in the 2-10 d period closely correlated with
those most vulnerable to hypoxia/ischemia, and sensitivity to both types of
injury reached a peak at 6 d. These findings reinforce other evidence
linking an excitotoxic mechanism and the NMA subtype of Glu receptor to
hypoxic/ischemic brain damage and suggest that there may be a period during
development when NMA receptors are hypersensitive to excitotoxic
stimulation, thus rendering the neurons possessing such receptors
hypervulnerable to hypoxic/ischemic damage.
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