Human genetic differences in ototoxic sensitivity are well-known, particularly mitochondrial mutations that convey increased susceptibility to aminoglycoside-induced hearing loss (Fischel-Ghodsian, 1998)

Human genetic differences in ototoxic sensitivity are well-known, particularly mitochondrial mutations that convey increased susceptibility to aminoglycoside-induced hearing loss (Fischel-Ghodsian, 1998). confer protection. Surprisingly, aminoglycoside-induced hair cell death was highly attenuated in wild type Tupfel long-fin (TL fish; the background strain for the mutant line) compared to wild type ?AB zebrafish. Pharmacologic manipulation of p53 suggested that the strain difference might result from decreased p53 in TL hair cells, allowing for increased hair cell survival. Overall, our studies identified additional steps in the Rabbit Polyclonal to DSG2 cell death cascade triggered by aminoglycoside damage, suggesting possible drug targets to combat hearing loss resulting from aminoglycoside exposure. and studies in chickens and rodents suggest that classical apoptosis plays a dominant role in aminoglycoside damage, primarily activating the mitochondrial cell death pathway driven by caspase-9 and caspase-3 (e.g., Forge and Li, 2000; Cunningham et al., 2002; Matsui et al., 2002, 2004; Cheng et al., 2003). However, other research in mammals and zebrafish demonstrates caspase-independent cell death vs. differences and differences in drug treatment paradigms. Reactive oxygen species formation is a hallmark feature in many aminoglycoside ototoxicity studies, and antioxidants confer some level of protection (Hirose et al., 1999; McFadden et al., 2003; Choung et al., 2009; Poirrier et al., 2010; Esterberg et al., 2016). Other studies suggest involvement of numerous cell death and survival cascades, including c-Jun N-terminal kinase (JNK) and p53 signaling (Wang et al., 2003; Sugahara et al., 2006; Coffin et al., 2013a; Anttonen et al., 2016). Despite these studies, we still have an incomplete picture of the signaling events that occur in aminoglycoside-damaged hair cells. A better understanding of cell death and survival signaling due to aminoglycoside exposure will provide more targets for therapeutic intervention. The present study uses the larval zebrafish lateral line to better understand cell death processes after aminoglycoside exposure. The lateral line is used by zebrafish to detect near field vibrations in the water caused by abiotic or biotic sources such as prey, predators, or water current (Montgomery et al., 1997; Coombs et al., 2014). The lateral line system contains clusters of neuromastssensory hair and supporting cells encapsulated in a jelly-like cupulathat are arranged along the head and trunk of the fish. Lateral line hair cells are structurally and functionally similar to the Trigonelline Hydrochloride hair cells of the mammalian inner ear and show similar responses to aminoglycosides and other Trigonelline Hydrochloride hair cell toxins (Harris et al., 2003; Ou et al., 2007; Coffin et al., 2010). In the lateral line, neomycin and gentamicin activate distinct, yet somewhat overlapping, responses Trigonelline Hydrochloride in damaged hair cells, suggesting that not all cell death responses are common across aminoglycosides and that a greater understanding of these differences is necessary to develop appropriate therapeutics (Coffin et al., 2009, 2013a,b; Owens et al., 2009; Hailey et al., 2017). Neomycin induces changes in calcium mobilization, mitochondrial membrane potential, and reactive oxygen species generation, and damage is dependent on the mitochondrial protein Bax (Owens et al., 2007; Coffin et al., 2013a; Esterberg et al., 2013, 2014, 2016). Although gentamicin toxicity in the lateral line is less well-studied, prior research shows that gentamicin-induced damage is independent of Bax and substantially dependent on p53 signaling (Coffin et al., 2013a). In a previous study, we screened a cell death inhibitor library to identify novel regulators of aminoglycoside-induced hair cell death in the lateral line (Coffin et al., 2013b). This study identified several compounds that modulate aminoglycoside-induced hair cell death in the lateral line, including a Bax channel blocker, the p53 inhibitor pifithrin- (PFT), the Omi/HtrA2 inhibitor Ucf-101, and the autophagy inhibitor 3-MA (Coffin et al., 2013a,b). Here, we used this cell death inhibitor dataset as the input for pathway analysis using Cytoscape GeneMANIA to identify additional protein targets that may modulate aminoglycoside.