Does Vestibular End-Organ Function Recover after Gentamicin-Induced Trauma in Guinea Pigs?

Abstract

Until 1993 it was commonly accepted that regeneration of vestibular hair cells was not possible in mammals. Two histological studies then showed structural evidence for spontaneous regeneration of vestibular hair cells after gentamicin treatment. There is less evidence for functional recovery going along with this regenerative process; in other words, do regenerated hair cells function adequately? This study aims to address this question, and in general evaluates whether spontaneous functional recovery may occur, in the short or long term, in mammals after ototoxic insult. Guinea pigs were treated with gentamicin for 10 consecutive days at a daily dose of 125 mg/kg body weight. Survival times varied from 1 day to 16 weeks. Vestibular short-latency evoked potentials (VsEPs) to linear acceleration pulses were recorded longitudinally to assess otolith function. After the final functional measurements we performed immunofluorescence histology for hair cell counts. Auditory brainstem responses (ABRs) to click stimuli were recorded to assess cochlear function. As intended, gentamicin treatment resulted in significant loss of utricular hair cells and accompanying declines in VsEPs. Hair cell counts 8 or 16 weeks after treatment did not significantly differ from counts after shorter survival periods. Maximal functional loss was achieved 1-4 weeks after treatment. After this period, only 2 animals showed recovery of VsEP amplitude - all other animals did not reveal signs of regeneration or recovery. In contrast, after initial ABR threshold shifts there was a small but significant recovery. We conclude that spontaneous recovery of otolith function, in contrast to cochlear function, is very limited in guinea pigs. These results support the concept of intratympanic gentamicin treatment where gentamicin is used for chemoablation of the vestibular sensory epithelia.

Electrophysiological Measurements of Peripheral Vestibular Function—A Review of Electrovestibulography

“…Here, responses typically start with a small (~0.5–1 μV) P1 peak (Figure 3A; which corresponds to the initial peak in facial nerve recordings; (Aran et al, 1980; Jones, 1992; Nazareth and Jones, 1998), and a series of slightly larger positive and negative peaks thereafter (Elidan et al, 1987a; Jones and Pedersen, 1989; Jones and Jones, 1999; Plotnik et al, 1999b; Bremer et al, 2014). This VsEP primarily reflects the response of various vestibular brainstem nuclei and nerves (Nazareth and Jones, 1998), much the same way the ABR reflects central auditory neuron responses (Figure 3B).…”

“…The VsEP has been further demonstrated in pigeon (Wit et al, 1981), chicken (Jones and Pedersen, 1989; Jones and Jones, 1996, 2000; Nazareth and Jones, 1998), canary (Jones S. M. et al, 1998), quail (Jones et al, 1997), mouse (Jones and Jones, 1999; Jones et al, 2006), rat (Lange, 1988; Plotnik et al, 1999a,b), chinchilla (Böhmer, 1995; Böhmer et al, 1995; Plotnik et al, 2005), guinea pig (Cazals et al, 1987; Jones and Jones, 1999; Oei et al, 2001; Kingma and Wit, 2010; Brown et al, 2013; Chihara et al, 2013; Bremer et al, 2014), rhesus monkey (Böhmer et al, 1983) cat (Elidan et al, 1987a,b; Böhmer, 1995), and human (Elidan et al, 1991a,b; Knox et al, 1993; Pyykkö et al, 1995; Rodionov et al, 1996; Loose et al, 2002). The VsEP has predominantly been evoked by a brief (2 ms) “linear” BCV pulse stimulus, with the response evoked by skull jerk rather than acceleration (Jones T. A. et al, 2011).…”

“…Moreover, the location of the recording electrodes significantly determines the VsEP waveform. The non-inverting VsEP recording electrode has been placed at various locations including the vertex (Elidan et al, 1982; Jones, 1992; Bremer et al, 2014), at different sub-cranial locations (Jones et al, 2002), within the vestibular nucleus (Cazals et al, 1987), within the facial nerve canal (Böhmer, 1995; Kingma and Wit, 2009; Bremer et al, 2012; Chihara et al, 2013), or on the round window (Aran et al, 1980). The inverting electrode is typically placed subcutaneously at a relatively non-responsive area such as the pinna or mastoid, and the ground (or common) electrode is placed at a distal location on the body, such as the neck.…”

“…The VsEP has been studied in animal models of otoconia deficiencies (Jones et al, 1999, 2004; Zhao et al, 2008), aging (Mock et al, 2011; Vijayakumar et al, 2015), hyper-gravity (Jones et al, 2000), gentamicin treatment (Perez et al, 2000; Bremer et al, 2014; King et al, 2017), endolymphatic hydrops (Kingma and Wit, 2009, 2010; Chihara et al, 2013), diuretic effects (Bremer et al, 2012), anesthetics (Gaines and Jones, 2013), pharmacological agents (Irons-Brown and Jones, 2004), inner ear genetic disorders (Jones S. M. et al, 2011; Lee et al, 2013; Robertson et al, 2008; Mathur et al, 2015), and noise trauma (Sohmer et al, 1999; Biron et al, 2002). More recently, studies have demonstrated abnormal VsEP responses in knockout mice lacking nicotinic acetylcholine receptors (Morley et al, 2017), which are expressed at the peripheral vestibular efferent synapse (Holt et al, 2015), on vestibular HCs (Simmons and Morley, 2011), and within peripheral and central vestibular neurons (Happe and Morley, 1998).…”

Treatment of peripheral vestibular dysfunction using photobiomodulation

“…Aminoglycosides are pharmacologic agents that are known to result in peripheral vestibulopathy. 2,3 Gentamicin, a type of aminoglycoside, can result in vestibular damage, but it is still widely used due to its effectiveness and low cost. The impact of gentamicin on the peripheral vestibular system can vary from minimal damage to complete loss of function.…”