Pieces of the Puzzle: Preliminary Evidence that Nuclear Factor-KB and Nerve Growth Factor Play a Role in Thalidomide-induced Peripheral Neuropathy
Higgins, Carly N.
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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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