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Journal of Neuroscience, Vol 13, 3034-3040, Copyright © 1993 by Society for Neuroscience
Peptide growth factors protect against ischemia in culture by preventing nitric oxide toxicity
K Maiese, I Boniece, D DeMeo and JA Wagner
Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021.
Reduction or elimination of nitric oxide (NO) production in cortical
neurons by NO synthase (NOS) inhibitors during glutamate toxicity in vitro
or during focal cerebral ischemia in vivo can prevent neuronal cell death.
In contrast, growth factors can prevent neuronal degeneration induced by
treatment with glutamate or potassium cyanide. We have determined whether
NO mediates hippocampal cell death during anoxia in vitro and whether the
peptide growth factors basic fibroblast growth factor (bFGF) and epidermal
growth factor (EGF) can prevent hippocampal neuronal death during anoxia or
NO exposure. Both bFGF and EGF increased hippocampal neuronal survival from
about 35% in anoxic cultures to about 65% in treated cultures during an 8
hr period of anoxia. Inhibition of NOS by NG-monomethyl-L-arginine, a
competitive inhibitor of NOS, rescued 65-70% of the neurons that would
normally die during an 8 hr anoxic incubation, and this effect was reversed
by L- arginine, a precursor for NO. Thus, hippocampal neuronal death
following anoxia is, at least in part, mediated by NO. NO, generated by
either nitroprusside or 3-morpholino-sydnonimine, was toxic to hippocampal
neurons. Pretreatment of cultures with either bFGF (10 ng/ml) or EGF (10
ng/ml) prior to NO exposure increased survival from approximately 40% in
untreated cultures to 80% in treated cultures, yet the effect of combining
bFGF and EGF was not greater than treatment with either of the growth
factors alone. Knowledge that the growth factors bFGF and EGF are
neuroprotective against NO toxicity provides insights into the mechanisms
of ischemic neuronal death that may direct future therapeutic modalities
for cerebrovascular disease and neurodegenerative disorders.
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