Response of mechanosensory hair cells of the zebrafish lateral line to aminoglycosides reveals distinct cell death pathways

Abstract

We report a series of experiments investigating the kinetics of hair cell loss in lateral line neuromasts of zebrafish larvae following exposure to aminoglycoside antibiotics. Comparisons of the rate of hair cell loss and the differential effects of acute versus chronic exposure to gentamicin and neomycin revealed markedly different results. Neomycin induced rapid and dramatic concentration-dependent hair cell loss that is essentially complete within 90 minutes, regardless of concentration or exposure time. Gentamicin induced loss of half of the hair cells within 90 minutes and substantial additional loss, which was prolonged and cumulative over exposure times up to at least 24 hr. Small molecules and genetic mutations that inhibit neomycin-induced hair cell loss were ineffective against prolonged gentamicin exposure supporting the hypothesis that these two drugs are revealing at least two cellular pathways. The mechanosensory channel blocker amiloride blocked both neomycin and gentamicin-induced hair cell death acutely and chronically indicating that these aminoglycosides share a common entry route. Further tests with additional aminoglycosides revealed a spectrum of differential responses to acute and chronic exposure. The distinctions between the times of action of these aminoglycosides indicate that these drugs induce multiple cell death pathways.

Quinoline Ring Derivatives Protect Against Aminoglycoside-Induced Hair Cell Death in the Zebrafish Lateral Line

“…Significant protection against long-term gentamicin exposure was also found, albeit to a lesser extent. This may lend further support to previous findings suggesting that short-and long-term gentamicin damage occurs through different pathways (Owens et al 2009). However, overall, these shared features between quinoline derivatives suggest a shared mechanism of action.…”

“…In the zebrafish lateral line, gentamicin is known to cause damage after both short and long damage protocols with seemingly different pathways (Owens et al 2009). Each quinoline drug was tested at its previously determined optimal protective dose for 1 h, followed by treatment with gentamicin for a short (400 μM×1 h) or long period (50 μM×6 h).…”

“…Previously, we have demonstrated that gentamicin causes damage after short-and long-term exposures and that this may occur through different pathways (Owens et al 2009). When tested against short-term gentamicin (400 μM for 1 h), we found that all eight quinoline derivatives provided significant protection (F(8, 88)021.88, pG0.0001, one-way ANOVA; Fig.…”

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

“…Previous reports by our group and others suggest that different aminoglycosides appear to activate distinct sets of cell death pathways (Coffin et al , 2013Owens et al 2009;Mazurek et al 2012;Vlasits et al 2012). In the lateral line of larval zebrafish, neomycin induces rapid hair cell death in a dose-dependent manner, while gentamicin activates both rapid and slower cell death responses Owens et al 2009).…”

“…In the lateral line of larval zebrafish, neomycin induces rapid hair cell death in a dose-dependent manner, while gentamicin activates both rapid and slower cell death responses Owens et al 2009). Studies with cell death inhibitors suggest that the rapid phase of death induced by neomycin or gentamicin represents a set of shared cell signaling pathways, while the slower phase activated only by gentamicin represents a distinct set of pathways (Vlasits et al 2012;Coffin et al 2013).…”