Activation of Kv7.4 in the cochlea as a therapeutic approach in a mouse model of age-reated hearing loss

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dc.contributor.advisor Nieder, Andreas (Prof. Dr.) Peixoto Pinheiro, Eva Barbara 2023-02-20T15:22:23Z 2023-02-20T15:22:23Z 2023-02-20
dc.identifier.uri de_DE
dc.description.abstract Age-related hearing loss (ARHL) is the largest contributor to the substantial hearing loss prevalence and is recognized as a significant factor in psychological and medical morbidity. There is thus a tremendous need for a safe and effective pharmacological treatment. The loss of auditory hair cells, consisting of outer hair cells (OHCs) and inner hair cells (IHCs), has been described as the major cochlear pathology of ARHL. The OHC physiology depends largely on functional potassium ion (K+) recycling in the cochlea. One major component of the K+ recycling circuit is the voltage-gated potassium channel of subfamily q, member 1 (Kv7.1), which is localized in the stria vascularis (SV). Loss of KV7.1 has been associated with congenital deafness caused by impaired K+ secretion. Furthermore, OHC survival is linked to the voltage-gated potassium channel of subfamily q, member 4 (Kv7.4), which dominantly determines their membrane potential. Impaired surface expression of Kv7.4 leads to functional impairment and has also been associated with ARHL. Although multiple chemical Kv7 channel openers have been developed as a therapeutic approach, their applicability has not yet been demonstrated in an in vivo model. The aim of the present study was to investigate the effect of pharmacological Kv7.4 channel activation in the senescence-accelerated mouse prone strain 8 (SAMP8) model as a novel therapeutic approach against ARHL. Surprisingly, we observed a significant threshold variability in the auditory decline of SAMP8 mice over age. In search of an underlying cause, age- related OHC loss could not be linked to this threshold variability. However, an altered Kv7.4 expression in OHCs was linked to the SAMP8 auditory threshold variability over age, preceding OHC loss. Pharmacological Kv7.4 channel activation by novel, small- molecule Kv7.4 agonists was then investigated in SAMP8 mice using different routes of administration: ACOU085 was locally via transtympanic application and ACOU082 was systemically administered via topical application. We demonstrated that the locally administered ACOU085 readily diffused into the cochlea and was able to significantly reduce age-related auditory threshold shifts as well as OHC loss in SAMP8 mice. Our findings in an in-vivo mouse model suggest that pharmacological activation of Kv7.4 is a promising approach to prevent and decelerate age-related decline of auditory function and morphological OHC loss linked to ARHL. en
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podok de_DE
dc.rights.uri de_DE
dc.rights.uri en
dc.subject.ddc 500 de_DE
dc.subject.other Kv7.4 en
dc.subject.other ARHL en
dc.subject.other SAMP8 en
dc.subject.other potassium channels en
dc.subject.other cochlea en
dc.title Activation of Kv7.4 in the cochlea as a therapeutic approach in a mouse model of age-reated hearing loss en
dc.type PhDThesis de_DE
dcterms.dateAccepted 2023-01-19
utue.publikation.fachbereich Biologie de_DE
utue.publikation.fakultaet 7 Mathematisch-Naturwissenschaftliche Fakultät de_DE
utue.publikation.noppn yes de_DE


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