Journal of Neuroscience, Vol 15, 7071-7078, Copyright © 1995 by Society for Neuroscience
An obligate role for oxygen in the early stages of glutamate-induced, delayed neuronal death
JM Dubinsky, BS Kristal and M Elizondo-Fournier
Department of Physiology, University of Texas Health Science Center, San Antonio 78284-7756, USA.
In vitro models of hypoxic/hypoglycemic injury reveal common mechanisms
with glutamate excitotoxicity, but glutamate-induced toxicity in the
absence of oxygen has never been directly addressed. Therefore, we assessed
neuronal survival and intracellular calcium concentrations ([Ca2+]i) in
neonatal hippocampal cultures in response to glutamate in the presence and
absence of oxygen. Twenty-four hours of hypoxia alone killed 40% of the
initial population, attributable to glutamate receptor-stimulated osmotic
lysis. A 5 min glutamate exposure in ambient air killed 80% of the initial
population by 24 hr later. When cultures were deprived of oxygen during and
for 2-24 hr after excitotoxin exposure, glutamate did not cause additional
neuronal death beyond that induced by oxygen depletion alone. Toxicities
caused by activation of NMDA, AMPA, or kainate receptors were each
ameliorated by oxygen depletion. In the absence of oxygen, glutamate evoked
normal increases in [Ca2+]i, indicating that glutamate receptors functioned
normally. The glutamate-induced increases in [Ca2+]i were not toxic in the
absence of oxygen. In a similar manner, oxygen-depletion prevented neuronal
killing by the calcium ionophore, ionomycin. Neuronal death produced by
hydrogen peroxide or iron sulfate was not ameliorated by oxygen removal.
These oxidants maximally produced only a slow increase in [Ca2+]i as the
plasma membrane permeability increased nonspecifically. Therefore,
oxygen-based reactions were an essential component of calcium-mediated,
delayed neuronal death.
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