Abstract 611, Date 1:00 pm, Sunday, February 11, 2007 (24 hours) Session D5: Poster
Mefloquine Induced Apoptosis in Hair Cells and Spiral Ganglion Neurons in Cochlear Organotypic Cultures
*Dalian Ding, Weidong Qi, Haiyan Jiang, Richard Salvi
Mefloquine is a widely used anti-malarial drug. Some clinical reports suggest that it may be ototoxic and neurotoxic; however, there is little scientific evidence from which to draw any firm conclusion. In order to evaluate its ototoxic and neurotoxic potential, we treated cochlear organotypic cultures and spiral ganglion cultures with mefloquine. Mefloquine caused a dose-dependent loss of cochlear hair cells at doses exceeding 0.01mM. With increasing dose, hair cell loss progressed from base to apex and from outer hair cells. Spiral ganglion neurons and auditory nerve fibers were also rapidly destroyed by mefloquine in a dose-dependent manner. Cochlear cultures were stained with propidium iodide (PI), to identify morphological changes in the nucleus, and carboxyfluorescein FAM-labeled caspase inhibitor 8, 9 or 3. Virtually all the PI-labeled nuclei in hair cells, spiral ganglion neurons and supporting cells were shrunken or fragmented, morphological features characteristic of cells undergoing apoptosis. Both initiator caspase 8 (membrane damage) and caspase 9 (mitochondrial damage), along with executioner caspase 3, were heavily expressed in cochlear hair cells and spiral ganglions after mefloquine. Initiator caspases 8 and 9 and executioner caspase 3 were also expressed in support cells; however, labeling was less widespread and less intense. These results indicate that mefloquine damages both the sensory and neural elements in the postnatal rat inner ear by activating cell death signaling pathways on the cell°¯s membrane and in mitochondria. Work is currently underway to determine if mefloquine is ototoxic when administered in vivo. Supported in part by NIH grant R01 DC06630-01