Salicylate Initiates Apoptosis in the Spiral Ganglion Neuron of Guinea Pig Cochlea by Activating Caspase-3

Abstract

Salicylate-induced ototoxicity leading to sensorineural hearing loss (SNHL) and tinnitus is well documented. However, the exact mechanisms are poorly defined. Caspase-3 is a member of the class of effector caspases and has been activated in nearly every model of apoptosis. To examine its role in salicylate-induced injury, we subjected guinea pigs to treatment with a specific inhibitor zDEVD-FMK via the round window niche (RWN) followed by a systemic injection of salicylate at a dose of 200 mg · kg(-1) · d(-1) i.p. for 10 consecutive days. For those animals administered with salicylate, immunohistochemical studies revealed that caspase-3 was activated in the spiral ganglion neurons (SGNs) and method of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) to identify neuronal apoptosis showed that fragmented nuclei were distributed in Rosenthal's canal. Topical administration of the zDEVD-FMK at a concentration of 500 mM blocked caspase-3 activation and had an effect in reducing the number of TUNEL-positive auditory neurons. In contrast, the inhibitor at a concentration of 125 or 250 mM caused no variation in the expression of activated caspase-3, or in the ratio of TUNEL-positive neurons. These results indicate that caspase-3 is a crucial mediator of apoptosis induced by salicylate in the primary auditory neuron in vivo, and suggest that the specific inhibitor at a relatively high concentration may be therapeutically beneficial in salicylate-induced apoptosis.

Salicylate-induced cochlear impairments, cortical hyperactivity and re-tuning, and tinnitus

“…Gene expression analysis and caspase labeling indicated that SGN and nerve fiber degeneration occurred by apoptosis (Wei et al, 2010). More recent in vivo results also indicate that SGN in adult guinea pigs degenerate via caspase-mediated apoptosis after long term treatment with high doses of SS (Feng et al, 2011; Feng et al, 2010). Taken together, these results indicate that SS treatment not only causes damage to SGNs in the developmental stage but also in adult animals.…”

“…Although high dose SS has been reported to cause hair cell damage (Feng et al, 2010), we and others have not observed hair cell degeneration in vitro or in vivo (Chen et al, 2010; Huang et al, 2005; Wei et al, 2010; Yu et al, 2008; Zheng et al, 1996). On the other hand, prolonged, high-dose SS treatment can permanently reduce the neural output of the cochlea (i.e., CAP) by either inducing apoptosis in SGN or impairing neural function (Chen et al, 2010; Feng et al, 2011; Wei et al, 2010). …”

Biphasic Activation of Nuclear Factor-Kappa B in Experimental Models of Subarachnoid HemorrhageIn VivoandIn Vitro

“…As the previous studies described, both the pro- and antiapoptotic genes were involved in neuron survival. Caspase-3 was a crucial mediator of pro-apoptosis for neurons [42]. The overexpression of Bcl-2, which is an antiapoptotic mediator, could promote the neuron survival [43].…”

A Case of Bilateral Sudden Hearing Loss and Tinnitus after Salicylate Intoxication

“…Cochlear outer hair cells are the most widely accepted site of injury 4,5). Spiral ganglion cells represent another site of inflammation 6,7). Hypoxia caused by decreased blood flow to the cochlea has also been proposed as a mechanism of injury 8).…”