Purchase this article with an account.
P. A. Maher, A. Hanneken; Oxidant Mediated Inhibition of Ciliary Neurotrophic Factor (CNTF) Signaling in Retinal Ganglion Cells. Invest. Ophthalmol. Vis. Sci. 2007;48(13):643.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Ciliary neurotrophic factor (CNTF) is thought to play an important role in the endogenous neuroprotective system in the retina. However, recent reports have suggested that CNTF signaling in CNS-derived nerve cells could be affected by oxidative stress. The first goal of this research was to determine if oxidative stress could disrupt CNTF signaling in retinal ganglion cells and then to characterize the types of stress that were most damaging. Following characterization of the stress response, the next goal was to identify treatments that could prevent the loss of CNTF signaling in RGCs in response to oxidative stress.
Cultured retinal ganglion cells (RGC-5 cells) were treated with a variety of oxidants at different concentrations and for differing lengths of time prior to treatment of the cells with CNTF. CNTF was added to the cells and signaling through the CNTF receptor was monitored by immunoblotting with antibodies to the activated forms of downstream signaling molecules including STAT3. STAT3 nuclear translocation was also monitored by both immunoblotting of nuclear fractions and immunocytochemistry. Following the establishment of conditions that resulted in a significant diminution in the response to CNTF, a variety of compounds were tested for their ability to reduce the effects of specific oxidants on CNTF signaling. Several different treatment paradigms with the compounds were also evaluated.
Oxidants such as hydrogen peroxide and t-butyl peroxide cause a rapid decrease in basal and stimulated CNTF receptor signaling in RGC-5 cells. Other oxidants such as the mitochondrial complex I inhibitor rotenone and diethyl maleate, which depletes glutathione, showed a more delayed response. We have identified several compounds that can prevent the loss of CNTF signaling and are characterizing their specificity with respect to different oxidants and their mechanisms of action.
Specific oxidants can cause a decrease in CNTF signaling in RGC cells. This could impact the biological effects of neurotrophic agents which signal through the CNTF receptor. In addition, treatments that rely on the presentation of CNTF to the retina could be less effective than expected since cells exposed to oxidative stress will be much less responsive than their unexposed counterparts. Thus, agents which restore CNTF signaling in the presence of oxidative stress should be considered before administration of CNTF.
This PDF is available to Subscribers Only