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 Previous Article
Journal of Neuroscience, Vol 10, 1035-1041, Copyright © 1990 by Society for Neuroscience
Excitatory amino acid release and free radical formation may cooperate in the genesis of ischemia-induced neuronal damage
DE Pellegrini-Giampietro, G Cherici, M Alesiani, V Carla and F Moroni
Dipartimento di Farmacologia Preclinica e Clinica, Mario Aiazzi Mancini, Universita di Firenze, Italy.
Excessive stimulation of excitatory amino acid (EAA) receptors and abnormal
production of oxygen-derived free radicals have repeatedly been implicated
in the series of events linking brain hypoxia or ischemia to neuronal
death. We report here that in rat hippocampal slices the KCl-stimulated
output of labeled D-3H aspartate or of endogenous aspartate and glutamate
significantly increased under in vitro simulated hypoxic, hypoglycemic, or
ischemic conditions. In particular, when the slices were incubated for 10
min at 32 degrees C under "ischemic" conditions (namely, lack of oxygen and
glucose), endogenous aspartate and glutamate in the supernatant increased
by 10 and 20 times, respectively. Since radical scavengers (D-mannitol),
drugs reducing free radical formation (indomethacin, corticosteroid), or
enzymes able to metabolize them (catalase and superoxide dismutase)
significantly reduced this output, it was supposed that free radicals
caused EAA release. A direct demonstration of this concept was obtained by
showing a significant release of EAA after incubation of hippocampal slices
with enzymes and substrates known to cause the formation of free radicals,
such as xanthine plus xanthine oxidase or arachidonic acid plus
prostaglandin synthase. Neither ischemia nor the enzymatic reactions
leading to free radical production increased the activity of the
cytoplasmic enzyme lactate dehydrogenase in the incubation medium, thus
ruling out a nonspecific cellular lysis. It appears therefore that during
ischemic states, brain production of reactive molecules (free radicals)
causes an increased output of EAA. This may trigger a series of events
which could help to explain the delayed loss of neurons after a transient
ischemic period.
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