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Effect of lipid peroxidation inhibition on retinal ganglion cell death
L A Levin1, J A Clark, L K Johns
1Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison 53792, USA.
Purpose:
To determine whether the lipid peroxidation inhibitor tirilazad mesylate can block the death of retinal ganglion cells induced by the inhibition of oxidative phosphorylation and glycolysis.
Methods:
Rat retinal ganglion cells were labeled retrogradely with the fluorescent tracer DiI, and mixed cultures were prepared. Cell death was induced with chemical hypoxia, hypoglycemia, or glycolysis inhibition, and the effect on cell survival of tirilazad mesylate was assessed.
Results:
Tirilazad mesylate enhanced relative ganglion cell survival after plating, with detectable effects at 200 nM and a maximal increase above diluent control of 148% +/- 2% at 20 microM. Relative survival at 24 hours in the presence of the complex IV inhibitor sodium cyanide (3 mM) was significantly greater when it was co-incubated with tirilazad mesylate than with diluent control (91.8% +/- 4.6% versus 39.3% +/- 7.1%; P = 0.008). Enhanced relative survival with tirilazad mesylate also was seen in cultures containing reduced glucose media.
Conclusions:
The lipid peroxidation blocker tirilazad mesylate inhibits retinal ganglion cell death in vitro. Because irreversible loss of retinal ganglion cells is the final common pathway in a variety of optic neuropathies, this or similar agents may be useful in animal models of optic neuropathies.
Insights
Tirilazad mesylate, a lipid peroxidation inhibitor, protects retinal ganglion cells from death caused by metabolic stress. This finding suggests potential therapeutic applications for optic neuropathies.
Area of Science:
- Neuroscience
- Ophthalmology
- Cell Biology
Background:
- Retinal ganglion cells (RGCs) are crucial for vision.
- RGC death is a hallmark of optic neuropathies.
- Metabolic dysfunction, including inhibited oxidative phosphorylation and glycolysis, can trigger RGC death.
Purpose of the Study:
- To investigate the neuroprotective potential of tirilazad mesylate against RGC death.
- To determine if tirilazad mesylate can block RGC death induced by metabolic inhibition.
Main Methods:
- Primary rat RGC cultures were established.
- RGC death was induced using chemical hypoxia, hypoglycemia, or glycolysis inhibitors.
- The effect of tirilazad mesylate on RGC survival was evaluated.
Main Results:
- Tirilazad mesylate significantly enhanced RGC survival in vitro.
- Protection was observed at concentrations as low as 200 nM, with maximal effects at 20 microM.
- Co-incubation with tirilazad mesylate improved RGC survival under conditions of complex IV inhibition and reduced glucose availability.
Conclusions:
- Tirilazad mesylate effectively inhibits RGC death induced by metabolic insults.
- These findings support the potential utility of tirilazad mesylate in animal models of optic neuropathies.