MDL 28170 Attenuates Gentamicin Ototoxicity

Aminoglycosides are highly effective antibiotics; however, their clinical utility is severely limited by their nephrotoxic and ototoxic side-effects. The selective destruction of hair cells in the inner ear by aminoglycoside antibiotics is thought to arise from a carefully orchestrated programme of cell death involving caspases and calcium activated proteases or calpains. To more fully evaluate the role of calpains in aminoglycoside ototoxicity, we applied the cell permeant, selective calpain inhibitor MDL 28170, to gentamicin (GM) treated cochlear organotypic cultures and evaluated the degree of hair cell damage at various drug concentrations. Mean hair cell losses in cochlear cultures treated for 24hours with 250, 500 and 1000 μM of GM were 17, 64 and 81%, respectively. Cochlear cultures treated with 200 μM of MDL 28170 alone for 24hours had no adverse effects on hair cell survival. However, the two highest doses of MDL 28170 (500 and 1000 μM) resulted in disorganization of hair cell rows, stereocilia damage and 30–35% hair cell loss. Addition of MDL 28170 to cochlear cultures treated with 500 and 1000 μM GM enhanced hair cell survival in a dose-dependent manner. Two hundred μM of MDL 28170, which by itself had no adverse effects on hair cells survival, significantly enhanced hair cell survival (30–35%), but failed to provide complete protection against GM ototoxicity. Since MDL 28170 can cross the blood-brain barrier and prevent neurodegeneration, it could conceivably be used in vivo to attenuate aminoglycoside ototoxicity.

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