Distribution of Gentamicin in the Guinea Pig Inner Ear after Local or Systemic Application

Abstract

Uptake and retention of gentamicin by cells in the guinea pig inner ear after a single peritoneal injection or local application on the round window were investigated using immunocytochemistry to localize the drug. The cells that accumulated the drug under the two conditions were the same, but staining for the drug was more intense and was often accompanied by widespread cochlear degeneration following local application. Soon after drug administration by either route, there was diffuse staining for the drug throughout all tissue within the labyrinth, including bone. At later times when distinct cell staining became evident, virtually all cell types were found to be positive, with several cell types staining more darkly for the drug than hair cells, indicating that hair cells were not the most avid in accumulating gentamicin. The infracuticular portion of auditory and vestibular hair cells as well as type III fibrocytes of the spiral ligament were positively stained in almost all cases and these sites were found to be positive for as long as six months post administration. In animals with loss of the organ of Corti, there was unusually intense staining for gentamicin in root cells of the spiral ligament, in marginal cells of the stria vascularis, and in cells of the spiral limbus. Dark staining of surviving cells in cases with overt tissue destruction suggests that variability in the extent of damage caused by the drug was determined more by the degree of its local uptake than by differences in animals' capacities to metabolize the drug systemically. The present results show that gentamicin may damage or destroy all cochlear cells following a single round window application. The findings broaden the scope of our knowledge of cochlear gentamicin uptake and damage and have implications for treatment of patients with vestibular disorders by infusion of aminoglycosides into the middle ear, as well as implications for prospects of rehabilitating patients that have been deafened by aminoglycosides.

Uptake of fluorescent gentamicin by vertebrate sensory cells in vivo

“…This distribution is contrary to other reports that used multiple injections of gentamicin, e.g. (Hiel et al, 1992a), that might alter the dynamics of gentamicin uptake following successive doses (Imamura and Adams, 2003a), for example increasing cation channel expression (Kitahara et al, 2005) that could facilitate drug uptake.…”

“…Vertebrate inner ear cells take up and retain GTTR in specific cell types in vivo following a single injection, similar to that revealed by immunocytochemical and autoradiographic methods (Balogh et al, 1970;Imamura and Adams, 2003a;von Ilberg et al, 1971). We also observed uptake, retention and clearance of GTTR at other anatomical locations.…”

“…However, this apparent fluorescent gradient was not discernable after 24 h, corroborating immunoenzymatic studies (Imamura and Adams, 2003a). This distribution is contrary to other reports that used multiple injections of gentamicin, e.g.…”

“…Subsequent studies confirmed the rapid uptake of aminoglycosides into the organ of Corti and endocochlear fluids within 2 h following a single injection (Tran Ba Huy et al, 1986;Tran Ba Huy et al, 1983). More recent studies have used fluorescent probes, immunohistochemistry, autoradiography and electron microscopy to localize aminoglycosides in hair cells up to six months after administration (de Groot et al, 1990;Dulon et al, 1993;Hashino et al, 1997;Imamura and Adams, 2003a;Richardson et al, 1997). Subcellular localization of aminoglycosides in hair cells is greatest below the cuticular plate: in lysosomes, multi-vesicular bodies, small tubules and vesicles, suggestive of endocytotic uptake across the apical membrane of hair cells that is bathed in endolymph (de Groot et al, 1990;Hashino and Shero, 1995a;Hashino et al, 2000;Hayashida et al, 1989;Hiel et al, 1992a;Richardson et al, 1997).…”

Sox2 and Jagged1 Expression in Normal and Drug-Damaged Adult Mouse Inner Ear

“…Conceivably, they could be a consequence of a loss of trophic factors normally supplied to SCs by HCs or nerve fibers innervating the HCs leading to the secondary degeneration of the SCs. Immunohistochemical studies suggest SCs may take up aminoglycosides (De Groot et al 1990;Imamura and Adams 2003), but studies examining uptake of radioactively labeled aminoglycoside in organ of Corti cells demonstrate little uptake in SCs.…”