Abstract
Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that plays a prominent role in the nervous system, mediating a range of physiologic and pathologic functions. In the auditory system, elevated levels of TNF-α have been implicated in several types of sensorineural hearing loss, including sensorineural hearing loss induced by vestibular schwannoma, a potentially fatal intracranial tumor that originates from the eighth cranial nerve; however, the mechanisms underlying the tumor's deleterious effects on hearing are not well-understood. Here, we investigated the effect of acute elevations of TNF-α in the inner ear on cochlear function and morphology by perfusing the cochlea with TNF-α in vivo in guinea pigs. TNF-α perfusion did not significantly change thresholds for compound action potential (CAP) responses, which reflect cochlear nerve activity, or distortion product otoacoustic emissions, which reflect outer hair cell integrity. However, intracochlear TNF-α perfusion reduced CAP amplitudes and increased the number of inner hair cell synapses without paired post-synaptic terminals, suggesting a pattern of synaptic degeneration that resembles that observed in primary cochlear neuropathy. Additionally, etanercept, a TNF-α blocker, protected against TNF-α-induced synaptopathy when administered systemically prior to intracochlear TNF-α perfusion. Findings motivate further investigation into the harmful effects of chronically elevated intracochlear levels of TNF-α, and the potential for etanercept to counter these effects.
Highlights
Hearing loss is the most common sensory deficit in the world, affecting 466 million people today, and projected to affect 900 million by 2050 [1]
Our results show that acute elevations in intracochlear levels of tumor necrosis factor-alpha (TNF-α) cause a reduction in the compound action potential (CAP) amplitude at 32 kHz in addition to synaptic degeneration along the cochlear length within 6 h of TNF-α administration, without significantly affecting audiometric thresholds
The hypothesis that TNF-α may play a role in vestibular schwannoma (VS)-induced sensorineural hearing loss (SNHL) comes from several studies showing that (a) VS tumor secretions contain high levels of TNF-α [20], (b) VS tumor size and proximity to the inner ear are poorly correlated with SNHL in VS patients [3], and (c) upregulation of TNF-α in the cochlea in response to a variety of etiologies of inner ear disease causes hearing loss [21,22,23,24,25, 42,43,44,45,46]
Summary
Hearing loss is the most common sensory deficit in the world, affecting 466 million people today, and projected to affect 900 million by 2050 [1]. The most common type of deafness is sensorineural hearing loss (SNHL), which is caused by damage to the delicate mechanosensory cells and auditory nerve fibers that reside within the inner ear’s cochlea. The conventional hypothesis regarding the mechanism underlying VS-induced SNHL is that the tumor compresses the vestibulocochlear nerve, preventing neural signals carrying hearing and balance information from traveling from the inner ear to the brain; evidence from multisite, large cohort studies suggests that associations between tumor size and location and SNHL severity are weak [3,4,5,6,7], and that SNHL may [4, 8, 9] or may not [8, 10,11,12,13] worsen with tumor growth over time in VS patients. [1] increased outer hair cell-generated distortion product otoacoustic emission (DPOAE) thresholds are observed in VS patients with minimal SNHL, indicating that outer hair cell damage may occur as a primary event, rather than secondary to neuronal damage [14], [2] 90% of human temporal bones from patients with ipsilateral VS show hair cell and neuronal damage that do not correlate with tumor size [15], and [3] biochemically-measured and radiologically-inferred intracochlear fluid protein levels are elevated in ears from poor-hearing VS tumor patients independent of tumor size [16,17,18]
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