Caspase inhibitors block zinc-chelator induced death of retinal ganglion cells.

Abstract

Zinc-chelating agents, including ethambutol and its metabolite 2,2'(ethylenediamino)-dibutyric acid (EDBA) are toxic to retinal ganglion cells through a glutamate dependent mechanism. We explored whether such cell death was mediated through the caspase family of cysteine proteases. Retinal cultures were treated with EDBA alone, or EDBA plus a variety of known caspase inhibitors, and ganglion cell viability was assayed. EDBA killed 20-30% of ganglion cells. A general caspase inhibitor, BAF, prevented EDBA induced ganglion cell death. Specific inhibitors of caspase-3 and caspase-6 showed a similar ability to BAF in preventing EDBA mediated ganglion cell loss, whereas inhibitors of caspase-8 and caspase-9 were not able to rescue EDBA treated ganglion cells. A caspase-1,4 inhibitor was less effective than BAF. These studies show that a caspase mediated mechanism of apoptosis accents for a portion of EDBA mediated retinal ganglion cell death. This toxicity was mediated by downstream effector caspases, 3 and 6. Caspase inhibitors may prevent ganglion cell death secondary to ethambutol treatment.

• Authors: K S Shindler, D Zurakowski, E B Dreyer
• Journal: Neuroreport (Neuroreport) Vol. 11 Issue 10 Pg. 2299-302 (Jul 14 2000) ISSN: 0959-4965 [Print] England
• PMID: 10923689 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Caspase Inhibitors
• Chelating Agents
• Cysteine Proteinase Inhibitors
• Enzyme Inhibitors
• Ethylenediamines
• Neuroprotective Agents
• EDBA
• Ethambutol
• Casp3 protein, rat
• Casp6 protein, rat
• Caspase 3
• Caspase 6
• Zinc

Topics

• Animals
• Caspase 3
• Caspase 6
• Caspase Inhibitors
• Cells, Cultured
• Chelating Agents (toxicity)
• Cysteine Proteinase Inhibitors (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Ethambutol (toxicity)
• Ethylenediamines (toxicity)
• Neuroprotective Agents (pharmacology)
• Rats
• Rats, Long-Evans
• Retinal Ganglion Cells (cytology, drug effects)
• Zinc (physiology)