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Title: The influence of nicotinamide on the survival of retinal cells from insults caused by light and ischemia
Author: Ji, Dan
ISNI:       0000 0001 3590 5131
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2007
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Ganglion cell death in glaucoma is probably caused by insults that include ischemia and the influence of light to their many axonally located mitochondria. Experimental studies were conducted to determine whether light as impinging on the retina in situ (400-760 nm) affects cell function detrimentally in culture and retinal ganglion cells, in situ. Moreover, studies were carried out to deduce whether nicotinamide can plunt any negative light influences to cells in culture and/or a defined ischemic insult to the retina as this might suggest its use for the treatment of glaucoma. Light (1000 lux generally, 400·760 nm) caused a generation of reactive oxygen species (ROS) and apoptosis to transformed retinal ganglion cells (RGC-5 cells), fibroblast BJHtert cells and neurones in primary retinal cell cultures. Neurones in primary retinal cultures were particularly susceptible to a light insult followed by the RGC-5 cells and then the BJHtert cells. Moreover, the influence of light was enhanced when cells were stressed caused by reducing serum levels or by the inclusion of sub-lethal amounts of rotenone to the culture medium. Significantly, light exposure did not result in a generation ofROS or cause apoptosis to BJHtert rho cells which lacked functional mitochondria. These studies support the view that light affects mitochondria to cause cell death which is enhanced when the cells are stressed, and that neurones are particularly susceptible because of their reliance on oxidative phosphorylation for general metabolism. Nicotinamide was able to attenuate the detrimental effect ofa light-insult to RGC-5 cells but only if the insult was for a duration of96 and not 48 hours. In contrast, selected substances, thought to act by sustaining mitochondrial function (alipoic acid, trolox, epigallicatechin gallate, metipranolol, coenzyme QIO and melatonin), attenuated the negative influence caused by a light insult of only 48 hours. Detailed studies on RGC-5 cells shows that the degree of apoptosis is dependent on the duration of a light insult and that maximal generation of ROS and reduction of cell ATP occurred at different times. Moreover, apoptosis was caspase-independent, involves the activation and translocation of apoptosis inhibitory factor (AIF) to nuclei as well as an activation of PARP-l, which was particularly significant for a light insult of 96 hours. Evidence is provided to show that nicotinamide blunts the activation of PARP-l at this time point. Exposure of eyes from anesthetised rats which had their pupils maximally dilated to a regem of white (400-760 nm) and red (550-760 nm) of identical intensities revealed that ganglion cell specific proteins and mRNAs were affected by the white but not the red light. The results suggest that light of defined wave-lengths (probably blue-violet range) can affect ganglion cell function in situ. but precisely how this occurs remains unknown. Nicotinamide was also shown to counteract a number of detrimental influences to the retina following ischemialreperfusion that included damage to ganglion cells and other specific retinal cell-types. Evidence is therefore provided to show that nicotinamide can attenuate the negative effects of both ischemia and light, which have been proposed to be a cause for ganglion cell death in glaucoma.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available