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

Zinc-chelating agents, including ethambutol and its metabolite 2,2'(ethylen ediamino)-dibutyric acid (EDBA) are toxic to retinal ganglion cells through a glutamate dependent mechanism. We explored whether such cell death was m ediated through the caspase family of cysteine proteases. Retinal cultures were treated with EDBA alone, or EDBA plus a variety of known caspase inhib itors, and ganglion cell viability was assayed. EDBA killed 20-30% of gangl ion cells. A general caspase inhibitor, BAF, prevented EDBA induced ganglio n cell death. Specific inhibitors of caspase-3 and caspase-6 showed a simil ar ability to BAF in preventing EDBA mediated ganglion cell loss, whereas i nhibitors of caspase-8 and caspase-9 were not able to rescue EDBA treated g anglion cells. A caspase-1,4 inhibitor was less effective than BAF. These s tudies show that a caspase mediated mechanism of apoptosis accents for a po rtion of EDBA mediated retinal ganglion cell death. This toxicity was media ted by downstream effector caspases, 3 and 6. Caspase inhibitors may preven t ganglion cell death secondary to ethambutol treatment. NeuroReport 11:229 9-2302 (C) 2000 Lippincott Williams & Wilkins.