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Transcriptional or translational inhibition blocks low dose NMDA-mediated cell death
E B Dreyer1, D Zhang, S A Lipton
1Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, MA, USA.
Abstract:
Glutamate toxicity in nerve cells has been well documented and may play a role in a broad spectrum of neurological and ophthalmic diseases. Recent work in several laboratories has suggested that an apoptotic-like mechanism may be implicated in glutamate toxicity under certain circumstances. We therefore studied the effects of transcriptional and translational inhibition on glutamate-mediated cell death in retinal ganglion cells. We now report that either cycloheximide or actinomycin D can, even when added 2 h after the initial excitotoxic insult, save retinal ganglion cells from low dose glutamate toxicity. However, cycloheximide or actinomycin D are unable to prevent glutamate-mediated death at higher concentrations of excitotoxin. This result indicates that at low doses, the neurotoxic effects of glutamate may develop through an apoptotic-like mechanism.
Insights
Glutamate toxicity can harm nerve cells, potentially causing neurological and ophthalmic diseases. Inhibiting protein synthesis protects retinal cells from low-dose glutamate toxicity, suggesting an apoptotic-like cell death pathway.
Area of Science:
- Neuroscience
- Cell Biology
- Ophthalmology
Background:
- Glutamate excitotoxicity is a known mechanism of nerve cell damage.
- Emerging evidence suggests apoptosis-like pathways may contribute to glutamate toxicity.
- Retinal ganglion cells are vulnerable to excitotoxic injury.
Purpose of the Study:
- To investigate the role of protein synthesis in glutamate-mediated cell death.
- To determine if inhibiting transcription or translation can protect retinal ganglion cells from glutamate toxicity.
- To elucidate the mechanism of glutamate neurotoxicity in retinal cells.
Main Methods:
- Exposure of retinal ganglion cells to varying concentrations of glutamate.
- Treatment with cycloheximide (translation inhibitor) or actinomycin D (transcription inhibitor).
- Assessment of cell viability following excitotoxic insult and inhibitor treatment.
Main Results:
- Cycloheximide and actinomycin D protected retinal ganglion cells from low-dose glutamate toxicity.
- Protection was observed even when inhibitors were administered 2 hours post-insult.
- Inhibitors failed to prevent cell death at higher glutamate concentrations.
Conclusions:
- Low-dose glutamate toxicity in retinal ganglion cells may involve an apoptotic-like mechanism requiring new protein synthesis.
- Targeting protein synthesis pathways could offer a therapeutic strategy for glutamate-induced neurodegeneration.
- The mechanism of glutamate toxicity is dose-dependent and may involve distinct pathways at different concentrations.