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Toward Clinical Pharmacologic Otoprotection
Published in Stavros Hatzopoulos, Andrea Ciorba, Mark Krumm, Advances in Audiology and Hearing Science, 2020
Colleen G. Le Prell, Kelly Roth, Kathleen C. M. Campbell
Salicylate, the active ingredient in aspirin, has been widely studied for its role in both otoprotection and hearing loss. High dose aspirin has been shown to induce tinnitus and hearing loss that may or may not be permanent (Boettcher and Salvi, 1991; Brien, 1993; Curhan et al., 2010). High dose aspirin appears to cause transient hearing loss (Boettcher and Salvi, 1991; Cazals, 2000), whereas very high doses or prolonged salicylate treatment may cause permanent hearing loss and cochlear damage (Chen et al., 2010; Deng et al., 2013). Salicylate appears to damage spiral ganglion neurons, but spares cochlear OHCs (Gao, 1999; Wei et al., 2010); this damage seems paradoxical because salicylate also has neuroprotective and antiinflammatory properties due to its free radical scavenging properties (Li et al., 2002; Minami et al., 2004; Dinis-Oliveira et al., 2007). Some of the reversible effects of salicylate include blockade of the cochlear mechanoelectric transducer (MET) channels and the motor protein prestin (Alvan et al., 2017).
Cochlear mechanisms and processes
Published in Stanley A. Gelfand, Hearing, 2017
Outer hair cell electromotility, which drives the cochlear amplifier, appears to be generated by the interaction of two mechanisms or “motors” (e.g., Dallos et al. 2006; Fettiplace and Hackney, 2006; Kennedy et al. 2006; Hudspeth, 2008; Peng and Ricci, 2011). The somatic motor relies on prestin, which has been identified as the motor protein of the OHC (Zheng et al., 2000; Oliver et al., 2001; Santos-Sacchi et al., 2001; Dallos and Fakler, 2002; Liberman et al., 2002; Dallos et al., 2006). The prestin motor is believed to operate by shuttling chloride ions back and forth between the inner and outer parts of the cell membrane, as illustrated in Figure 4.34). Shortening is triggered by depolarization, which causes the prestin molecule to transport the chloride ion toward its inner side (Figure 4.34a), and lengthening is triggered by hyperpolarization, which causes the prestin molecule to move the chloride ion toward its outer side (Figure 4.34b). The hair bundle motor relies on the force generated by the changing compliance of the stereocilia bundle that occurs with the opening and closing of the transduction pores (Fettiplace, 2006; Fettiplace and Hackney, 2006; Kennedy et al., 2006).
Anatomy of the Cochlea and Vestibular System: Relating Ultrastructure to Function
Published in John C Watkinson, Raymond W Clarke, Christopher P Aldren, Doris-Eva Bamiou, Raymond W Clarke, Richard M Irving, Haytham Kubba, Shakeel R Saeed, Paediatrics, The Ear, Skull Base, 2018
In experiments in which OHC function is disrupted or OHCs are destroyed, in the continued presence of functioning IHCs, there are hearing threshold shifts of 40–60 dB and a loss of fine-tuning of ANF responses (i.e. the sharpness of tuning, whereby an individual nerve fibre is especially sensitive to a specific or characteristic frequency).108 Thus OHCs are critical for the exquisite frequency discrimination of which the cochlea is normally capable. These and other data have suggested the OHCs are the cellular basis of the ‘cochlear amplifier’.109,110 A particularly unusual feature of OHCs is that they exhibit a unique form of motility. Isolated OHCs maintained in short-term culture undergo fast reversible axial length changes at up to auditory frequencies (at least 20 kHz) when stimulated electrically. It is thought that, in vivo, changes in OHC-membrane potential deriving from the normal MET mechanism drive the length changes.43,109,110 Thus motion of the BM induces these motile responses, which are thought to feedback into the BM motion, thereby removing local damping and enhancing the movements. The end result of this cochlear amplification process is to fine-tune and amplify the signal before it reaches the IHCs, which as described do not sit on the flexible BM. Interestingly, as predicted by Thomas Gold in 1948111,112 and shown by David Kemp in 1978,113 the excess energy released by this active process generates sound waves that are emitted from the ear as an otoacoustic emission (OAE).114,115 These OAEs can be recorded from probe microphones fitted in the external ear canal and they form the basis of the now routine audiological screening test for hearing impairment that can be performed in newborns or adults, and that provides an objective measure of the ‘health’ of the OHCs.116–118 The fast motile responses of the OHCs, and the concomitant OAEs, are driven by a motor protein called prestin,119 which is unique to OHCs and which is densely packed all down the lateral plasma membrane of the cell.120,121 Mutation or functional absence of the gene encoding prestin causes hearing impairment due to loss of cochlear amplification.122
The applications of targeted delivery for gene therapies in hearing loss
Published in Journal of Drug Targeting, 2023
Melissa Jones, Bozica Kovacevic, Corina Mihaela Ionescu, Susbin Raj Wagle, Christina Quintas, Elaine Y. M. Wong, Momir Mikov, Armin Mooranian, Hani Al-Salami
Studies have also used peptides for targeting outer hair cells, as certain peptides bind specifically to prestin. Prestin is located in outer hair cells of the mammalian cochlea. Researchers in 2012 used PEG-block-polycaprolactone polymersomes with the peptides A665 and A666 bound to target outer hair cells. A665 and A666 are peptides with an affinity to prestin. Results using explant rat cochleae showed the outer hair cells to abundantly internalise the polymersomes and a sparse uptake by alternative cell types, with non-specific uptake mostly limited to high polymer concentrations; indicating the potential use of such peptides to target outer hair cells [94]. Another example used dexamethasone nanoparticles with A666, conducting in vitro experiments using HEI-OC1 cells. The targeted nanoparticles reduced cisplatin induced apoptosis, when compared to nanoparticles without A666 and free dexamethasone. In vivo, the targeted nanoparticles showed improved numbers of surviving outer hair cells following cisplatin treatment, in comparison to cisplatin-treated controls, indicating the benefits of the targeted nanoparticles, both in vitro and in vivo [95]. Hence, a wide variety of cells and their proteins may be used as effective targets for delivery.
Experimental drugs for the prevention or treatment of sensorineural hearing loss
Published in Expert Opinion on Investigational Drugs, 2023
Judith S Kempfle, David H. Jung
Inner hair cells have the ability to transduce mechanical movements into electrical signals via fiber-like structures at the apical end, the stereocilia [12]. Ribbon synapses at the basal end of hair cells release the neurotransmitter glutamate in response to sound-evoked stereocilia motion. Afferent spiral ganglion neurons are stimulated via their α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors, and the electrical signal is then propagated along the auditory pathway. Outer hair cells act in response to auditory signals and function as modulators and amplifiers of sound [13]. The protein Prestin in the membrane of outer hair cells can undergo conformational changes in response to electrical potential, and this electromotility contributes to frequency selectivity and helps to amplify the auditory signal [13]. The electrical gradient between endolymph and perilymph is maintained by the stria vascularis, which flanks the scala media and organ of Corti, and which harbors various ion pumps to restore the resting potential [14].
Phage-displayed peptides targeting specific tissues and organs
Published in Journal of Drug Targeting, 2019
Josu Andrieu, Francesca Re, Laura Russo, Francesco Nicotra
Few homing peptides have been identified for other targets. In Table 7, it can be observed that many types of tissues have been explored. For instance, Rothenfluh and co-workers selected collagen binding peptides, and functionalised poly(propylene sulphide) (PPS) nanoparticles which were administered via intra-articular injection [127]. Another unusual application was presented by Surovtseva and colleagues, where the prestin protein in the cochlea was targeted, providing new insights on the hearing loss associated to outer hair cells [128]. The main drawback of this uncommon targets is that the wider scientific community shows little interest towards them, and they are forgotten once they are published, clinical translation being unlikely.