The Journal of Neuroscience, May 15, 2001, 21(10):3322-3331
Pyruvate Released by Astrocytes Protects Neurons from
Copper-Catalyzed Cysteine Neurotoxicity
Xue Feng
Wang and
Max S.
Cynader
Brain Research Centre and Department of Ophthalmology, University
of British Columbia and Vancouver Hospital & Health Sciences Centre,
Vancouver, British Columbia, Canada V5Z 3N9
We have found previously that astrocytes can provide cysteine to
neurons. However, cysteine has been reported to be neurotoxic although
it plays a pivotal role in regulating intracellular levels of
glutathione, the major cellular antioxidant. Here, we show that
cysteine toxicity is a result of hydroxyl radicals generated during
cysteine autoxidation. Transition metal ions are candidates to catalyze
this process. Copper substantially accelerates the autoxidation rate of
cysteine even at submicromolar levels, whereas iron and other
transition metal ions, including manganese, chromium, and zinc, are
less efficient. The autoxidation rate of cysteine in rat CSF is equal
to that observed in the presence of ~0.2 µM copper. In
tissue culture tests, we found that cysteine toxicity depends highly on
its autoxidation rate and on the total amount of cysteine being
oxidized, suggesting that the toxicity can be attributed to the free
radicals produced from cysteine autoxidation, but not to cysteine itself.
We have also explored the in vivo mechanisms that protect
against cysteine toxicity. Catalase and pyruvate were each found to
inhibit the production of hydroxyl radicals generated by cysteine autoxidation. In tissue culture, they both protected primary neurons against cysteine toxicity catalyzed by copper. This protection is
attributed to their ability to react with hydrogen peroxide, preventing
the formation of hydroxyl radicals. Pyruvate, but not catalase or
glutathione peroxidase, was detected in astrocyte-conditioned medium
and CSF. Our data therefore suggest that astrocytes can prevent
cysteine toxicity by releasing pyruvate.
Key words:
glia; glutathione; toxicity; oxidative stress; transition
metal; autoxidation; conditioned medium
Copyright © 2001 Society for Neuroscience 0270-6474/01/21103322-10$05.00/0
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