Caspase inhibitors block zinc-chelator induced death of retinal ganglion cells.
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.
Department of Ophthalmology, University of Pennsylvania, Veteran's Administration, Scheie Eye Institute, Philadelphia 19104, USA.
K S
KS
Shindler
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Zurakowski
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EB
Dreyer
D000818:Animals; D053148:Caspase 3; D053178:Caspase 6; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D002614:Chelating Agents / Q000633:toxicity*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004977:Ethambutol / Q000633:toxicity*; D005029:Ethylenediamines / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects*; D015032:Zinc / Q000502:physiology*
D061945:Caspase Inhibitors; D002614:Chelating Agents; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D005029:Ethylenediamines; D018696:Neuroprotective Agents; C030779:EDBA; D004977:Ethambutol; C505410:Casp3 protein, rat; C505518:Casp6 protein, rat; D053148:Caspase 3; D053178:Caspase 6; D015032:Zinc