Pieces of the Puzzle: Preliminary Evidence that Nuclear Factor-KB and Nerve Growth Factor Play a Role in Thalidomide-induced Peripheral Neuropathy
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Authors
Higgins, Carly N.
Issue Date
2003
Type
Thesis
Language
en_US
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Abstract
Thalidomide is best known for its role in causing severe birth defects such as limb
growth retardation and phocomelia in developing embryos. Little research was performed
following the thalidomide tragedy of the late 1950s, and its teratogenic mechanisms remained
a mystery. In the past ten years, however, there has been renewed interest in thalidomide as
it has proved to be therapeutic for a variety of disease states. Unfortunately, long-term
thalidomide users often develop irreversible peripheral neuropathy. Thalidomide is known to
induce oxidative stress and recent research has shown that nuclear factor-kappa B (NF-kB), a
redox-sensitive transcription factor involved in limb outgrowth, is modulated by this induced
oxidative stress. The effects of these changes on limb bud outgrowth have been
demonstrated and we believe that these mechanisms may be connected with the lesser-known
mechanism of thalidomide-induced peripheral neuropathy. Primary rat embryonic dorsal
root ganglia (DRG) cultures (gestation day 12) were treated with 100 µM thalidomide and
then evaluated using immunohistochetnistry. Observation of NF-kB showed an upregulation
of the transcription factor's activation and translocation in the neurons of 5-day-old cultures,
but not 14-day-old cultures, after thalidomide treatment. This indicates a connection between
thalidomide and NF-kB redox regulation in DRG, and raises many new interesting questions
regarding the effects of cell age and cell type on this phenomenon. Nerve growth factor's
(NGF) response to thalidomide treatment in DRG was also evaluated in this experiment. We
provide preliminary evidence that thalidomide induces upregulation and secretion of NGF by
astrocytes and subsequent binding to neuronal cells. It is not certain yet whether or not this
event is connected with the observed NF-kB activation, but we provide strong evidence that
NGF also plays an important role.
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v, 31 p.
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