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The Journal of Neuroscience, October 17, 2007, 27(42):11315-11326; doi:10.1523/JNEUROSCI.3590-07.2007

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Development/Plasticity/Repair
Rapid Activation of Antioxidant Defenses by Nerve Growth Factor Suppresses Reactive Oxygen Species during Neuronal Apoptosis: Evidence for a Role in Cytochrome c Redistribution

Rebecca A. Kirkland, Geraldine M. Saavedra, and James L. Franklin

Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, Athens, Georgia 30602

Correspondence should be addressed to James L. Franklin, Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, 357 Wilson Pharmacy, Athens, GA 30602. Email: jfrankli{at}rx.uga.edu

Depriving mouse sympathetic neurons of nerve growth factor (NGF) causes their apoptotic death. A Bax-dependent increase of mitochondrial-derived reactive oxygen species (ROS) begins in these cells soon after NGF withdrawal. We investigated the effects on these ROS of adding NGF to cultures of NGF-deprived neurons. ROS levels were monitored with the fluorescent, redox-sensitive dyes CM-H₂DCFDA and MitoSOX Red. The intensity of the former dye increases when it is oxidized by H₂O₂ and free radicals downstream of H₂O₂. MitoSOX Red is relatively insensitive to oxidation by H₂O₂ but is sensitive to oxidation by superoxide (O₂^.–). Withdrawing NGF increased CM-H₂DCFDA intensity, indicating elevated H₂O₂-associated ROS. Re-exposure of cells deprived of NGF to NGF resulted in rapid suppression of these ROS. Neurons deprived of NGF also had increased MitoSOX Red intensities. Readdition of NGF had no effect on MitoSOX Red fluorescence. The suppression of CM-H₂DCFDA-detected ROS by NGF was caused by a rapid activation of glutathione redox cycling. The most likely explanation for these findings is that mitochondria increased O₂^.– production after NGF withdrawal. The O₂^.– was converted to H₂O₂ by dismutation, and the H₂O₂ was detoxified by accelerated glutathione redox cycling. Our previous work shows that H₂O₂ induces cytochrome c to be released from mitochondria in NGF-supported sympathetic neurons, whereas antioxidants that detoxify H₂O₂ block cytochrome c redistribution in NGF-deprived neurons. Readdition of NGF also immediately inhibits cytochrome c release. We present evidence that this inhibition is mediated by the rapid activation of glutathione redox cycling by NGF.

Key words: apoptosis; reactive oxygen; mitochondria; nerve growth factor; cell death; glutathione

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Received Feb. 27, 2007; revised Aug. 7, 2007; accepted Aug. 30, 2007.

Correspondence should be addressed to James L. Franklin, Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, 357 Wilson Pharmacy, Athens, GA 30602. Email: jfrankli{at}rx.uga.edu

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