The effects of neurotrophic factors on enteric ganglion cells in vitro

Korsak, Kris (2003). The effects of neurotrophic factors on enteric ganglion cells in vitro. PhD thesis The Open University.



The effects of neurotrophic factors on enteric ganglion cells were studied using variety of techniques. NT-3 was found to have protective effects on enteric neurons exposed to hydrogen peroxide. The second neurotrophic factor tested, GDNF, did not exhibit a similar, protective effect. Investigation of the effects of these factors on the levels of catalase and SOD Cu/Zn revealed that NT-3 does not affect levels of either enzyme after 12 and 36 hour incubation. In contrast to NT-3, GDNF was able to increase the levels of both enzymes, although this effect was observed only at the 36 hour time point. To investigate the mechanism of NT-3 induced protective effects, the signalling pathways initiated by NT-3 were also studied. PI-3K, an enzyme known to play a role in the survival responses initiated by trophic factors in many cell types was blocked using a specific inhibitor, LY294002. As a result, a dramatic decrease in cell numbers was observed in control as well as NT-3 and GDNF treated cultures. Inhibition of PI-3K also nullified the effects of trophic factors on the cells. Subsequently, the effects of NT-3 and combined NT-3/LY294002 treatment on the activity of several signalling proteins were examined. Control cultures showed steady, easily detectable levels of phosphorylated Akt, as well as total protein levels of bcl-2 and c-fos, which were independent of signalling initiated by addition of exogenous NT-3. In contrast, phosphorylation of MEK and ERK proteins was dependent upon exogenous NT-3. LY294002 treatment severely reduced the amount of phosphorylated Akt present in the cells. Additionally, the presence of phosphorylated MEK and ERK was observed at the point of NT-3 treatment, suggesting that in was independent of exogenous NT-3. Total protein levels of bcl-2 and c-fos proteins in the LY294002 treated cultures were elevated compared to controls.

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