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The Journal of Neuroscience, February 16, 2005, 25(7):1682-1690; doi:10.1523/JNEUROSCI.3127-04.2005

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Cellular/Molecular
Activation of Nuclear Factor-B via Endogenous Tumor Necrosis Factor Regulates Survival of Axotomized Adult Sensory Neurons

Paul Fernyhough,^1,2,3 Darrell R. Smith,¹ Jason Schapansky,² Randy Van Der Ploeg,^1,2 Natalie J. Gardiner,³ Christopher W. Tweed,³ Andreas Kontos,³ Lyle Freeman,³ Tertia D. Purves-Tyson,³ and Gordon W. Glazner^1,2

¹Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada R2H 2A6, ²Division of Neurodegenerative Disorders, St. Boniface Research Centre, Winnipeg, Manitoba, Canada R2H 2A6, and ³School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom

Embryonic dorsal root ganglion (DRG) neurons die after axonal damage in vivo, and cultured embryonic DRG neurons require exogenous neurotrophic factors that activate the neuroprotective transcription factor nuclear factor-B (NF-B) for survival. In contrast, adult DRG neurons survive permanent axotomy in vivo and in defined culture media devoid of exogenous neurotrophic factors in vitro. Peripheral axotomy in adult rats induces local accumulation of the cytokine tumor necrosis factor (TNF), a potent activator of NF-B activity. We tested the hypothesis that activation of NF-B stimulated by endogenous TNF was required for survival of axotomized adult sensory neurons. Peripheral axotomy of lumbar DRG neurons by sciatic nerve crush induced a very rapid (within 2 h) and significant elevation in NF-B-binding activity. This phenomenon was mimicked in cultured neurons in which there was substantial NF-B nuclear translocation and a significant rise in NF-B DNA-binding activity after plating. Inhibitors of NF-B (SN50 or NF-B decoy DNA) resulted in necrotic cell death of medium to large neurons (40 µm) within 24 h (60 and 75%, respectively), whereas inhibition of p38 and mitogen-activated protein/extracellular signal-regulated kinase did not effect survival. ELISA revealed that these cultures contained TNF, and exposure to an anti-TNF antibody inhibited NF-B DNA-binding activity by 35% and killed 40% of medium to large neurons within 24 h. The results show for the first time that cytokine-mediated activation of NF-B is a component of the signaling pathway responsible for maintenance of adult sensory neuron survival after axon damage.

Key words: denervation; dorsal root ganglion (DRG); necrosis; nerve; neuropathy; neurotrophic; sciatic; sensory neurons; transcription; trophic

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Received Aug 11, 2003; revised December 1, 2004; accepted December 2, 2004.

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