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TrkB agonist

BDNF Outperforms TrkB Agonist 7,8,3′-THF in Preserving the Auditory Nerve in Deafened Guinea Pigs

October 28, 2020

CATEGORY:
Research

TITLE:
BDNF Outperforms TrkB Agonist 7,8,3′-THF in Preserving the Auditory Nerve in Deafened Guinea Pigs

DESCRIPTION:
In deaf subjects using a cochlear implant (CI) for hearing restoration, the auditory nerve is subject to degeneration, which may negatively impact CI effectiveness. This nerve degeneration can be reduced by neurotrophic treatment. Here, we compare the preservative effects of the naturally occurring tyrosine receptor kinase B (TrkB) agonist brain-derived neurotrophic factor (BDNF) and the small-molecule TrkB agonist 7,8,3′-trihydroxyflavone (THF) on the auditory nerve in deafened guinea pigs. THF…

CONTENT:
Brain Sci. 2020 Oct 28;10(11):E787. doi: 10.3390/brainsci10110787.

ABSTRACT

In deaf subjects using a cochlear implant (CI) for hearing restoration, the auditory nerve is subject to degeneration, which may negatively impact CI effectiveness. This nerve degeneration can be reduced by neurotrophic treatment. Here, we compare the preservative effects of the naturally occurring tyrosine receptor kinase B (TrkB) agonist brain-derived neurotrophic factor (BDNF) and the small-molecule TrkB agonist 7,8,3′-trihydroxyflavone (THF) on the auditory nerve in deafened guinea pigs. THF may be more effective than BDNF throughout the cochlea because of better pharmacokinetic properties. The neurotrophic compounds were delivered by placement of a gelatin sponge on the perforated round window membrane. To complement the histology of spiral ganglion cells (SGCs), electrically evoked compound action potential (eCAP) recordings were performed four weeks after treatment initiation. We analyzed the eCAP inter-phase gap (IPG) effect and measures derived from pulse-train evoked eCAPs, both indicative of SGC healthiness. BDNF but not THF yielded a significantly higher survival of SGCs in the basal cochlear turn than untreated controls. Regarding IPG effect and pulse-train responses, the BDNF-treated animals exhibited more normal responses than both untreated and THF-treated animals. We have thus confirmed the protective effect of BDNF, but we have not confirmed previously reported protective effects of THF with our clinically applicable delivery method.

PMID:33126525 | DOI:10.3390/brainsci10110787

SOURCE:
Brain sciences

DATE – PUBLISHED:
28 Oct 2020

DATE – ADDED:
Sat, 31 Oct 2020 06:00:00 -0400

DATE – FOUND:
10/31/20 12:11PM

PUBMED ID:
pubmed:33126525

DOI:
10.3390/brainsci10110787

PUBMED LINK:
https://pubmed.ncbi.nlm.nih.gov/33126525/

DOI LINK:
https://doi.org/10.3390/brainsci10110787

PUBLISHER LINK:
https://www.mdpi.com/2076-3425/10/11/787

Trk Agonist Drugs Rescue Noise-Induced Hidden Hearing Loss [Preprint]

July 1, 2020

https://www.biorxiv.org/content/10.1101/2020.07.01.182931v1.full

https://www.biorxiv.org/content/10.1101/2020.07.01.182931v1

Trk Agonist Drugs Rescue Noise-Induced Hidden Hearing Loss
Katharine A. Fernandez, Takahisa Watabe, Mingjie Tong, Xiankai Meng, Kohsuke Tani, Sharon G. Kujawa, View ORCID ProfileAlbert S. B. Edge
doi: https://doi.org/10.1101/2020.07.01.182931
This article is a preprint and has not been certified by peer review [what does this mean?].
AbstractFull TextInfo/HistoryMetrics Preview PDF
Abstract
TrkB agonist drugs are shown here to have a significant effect on the regeneration of afferent cochlear synapses after noise-induced synaptopathy. The effects were consistent with regeneration of cochlear synapses that we observed in vitro after synaptic loss due to kainic acid-induced glutamate toxicity and were elicited by administration of TrkB agonists, amitriptyline and 7,8-dihydroxyflavone, directly into the cochlea via the posterior semicircular canal 48 h after exposure to noise. Synaptic counts at the inner hair cell and wave 1 amplitudes in the ABR were partially restored 2 weeks after drug treatment. Effects of amitriptyline on wave 1 amplitude and afferent auditory synapse numbers in noise-exposed ears after systemic (as opposed to local) delivery were profound and long-lasting; synapses in the treated animals remained intact one year after the treatment. However, the effect of systemically delivered amitriptyline on synaptic rescue was dependent on dose and the time window of administration: it was only effective when given before noise exposure at the highest injected dose. The long-lasting effect and the efficacy of post-exposure treatment indicate a potential broad application for the treatment of synaptopathy, which often goes undetected until well after the original damaging exposure(s).

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