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BDNF

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

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

Brain-derived nerve growth factor in the cochlea: Intracochlear BDNF can improve hearing in guinea pigs but improvement is currently too small for clinical application

https://journalotohns.biomedcentral.com/articles/10.1186/s40463-020-00432-7

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275362/

https://www.ncbi.nlm.nih.gov/pubmed/32503640?dopt=Abstract

Related Articles

Brain-derived nerve growth factor in the cochlea – a reproducibility study.

J Otolaryngol Head Neck Surg. 2020 Jun 05;49(1):37

Authors: Blakley BW, Seaman M, Alenezi A

Abstract

OBJECTIVE: Brain-derived nerve growth factor (BDNF) plays an important role in cochlear development so it is plausible that it could restore hearing loss if delivered directly into the cochlea. We wished to confirm our previous report that a single intracochlear injection of brain-derived nerve growth factor (BDNF) was beneficial for hearing in guinea pigs. We wished to assess the reproducibility of our results and assess possible improved methods with a view to developing a clinical treatment for sensorineural hearing loss.

METHODS: CDDP was used to create partial hearing loss in 25 guinea pigs. After 30 days the animals underwent ABR testing and unilateral BDNF injection through the round window in one ear and saline injection into the other ear. After allowing possible effects to stabilize, thirty days later, ABR threshold testing was repeated to assess change in threshold.

RESULTS: Final ABR thresholds were 60-70 dB and were about 11 dB better in the ears treated with BDNF.

CONCLUSION: Our original finding that Intracochlear BDNF can improve hearing in guinea pigs was confirmed, but the improvement demonstrated by the methods in this paper is too small for clinical application.

PMID: 32503640 [PubMed – as supplied by publisher]

Neurotrophin gene therapy to promote survival of spiral ganglion neurons after deafness

https://www.sciencedirect.com/science/article/abs/pii/S0378595519304563?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/32331858?dopt=Abstract

Related Articles

Neurotrophin gene therapy to promote survival of spiral ganglion neurons after deafness.

Hear Res. 2020 Apr 05;:107955

Authors: Leake PA, Akil O, Lang H

Abstract

Hearing impairment is a major health and economic concern worldwide. Currently, the cochlear implant (CI) is the standard of care for remediation of severe to profound hearing loss, and in general, contemporary CIs are highly successful. But there is great variability in outcomes among individuals, especially in children, with many CI users deriving much less or even marginal benefit. Much of this variability is related to differences in auditory nerve survival, and there has been substantial interest in recent years in exploring potential therapies to improve survival of the cochlear spiral ganglion neurons (SGN) after deafness. Preclinical studies using osmotic pumps and other approaches in deafened animal models to deliver neurotrophic factors (NTs) directly to the cochlea have shown promising results, especially with Brain-Derived Neurotrophic Factor (BDNF). More recent studies have focused on the use of NT gene therapy to force expression of NTs by target cells within the cochlea. This could provide the means for a one-time treatment to promote long-term NT expression and improve neural survival after deafness. This review summarizes the evidence for the efficacy of exogenous NTs in preventing SGN degeneration after hearing loss and reviews the animal research to date suggesting that NT gene therapy can elicit long-term NT expression in the cochlea, resulting in significantly improved SGN and radial nerve fiber survival after deafness. In addition, we discuss NT gene therapy in other non-auditory applications and consider some of the remaining issues with regard to selecting optimal vectors, timing of treatment, and place/method of delivery, etc. that must be resolved prior to considering clinical application.

PMID: 32331858 [PubMed – as supplied by publisher]

Stem Cell Based Drug Delivery for Protection of Auditory Neurons

https://www.frontiersin.org/articles/10.3389/fncel.2019.00177/full

https://www.ncbi.nlm.nih.gov/pubmed/31139049?dopt=Abstract

Related Articles

Stem Cell Based Drug Delivery for Protection of Auditory Neurons in a Guinea Pig Model of Cochlear Implantation.

Front Cell Neurosci. 2019;13:177

Authors: Scheper V, Hoffmann A, Gepp MM, Schulz A, Hamm A, Pannier C, Hubka P, Lenarz T, Schwieger J

Abstract

Background: The success of a cochlear implant (CI), which is the standard therapy for patients suffering from severe to profound sensorineural hearing loss, depends on the number and excitability of spiral ganglion neurons (SGNs). Brain-derived neurotrophic factor (BDNF) has a protective effect on SGNs but should be applied chronically to guarantee their lifelong survival. Long-term administration of BDNF could be achieved using genetically modified mesenchymal stem cells (MSCs), but these cells should be protected – by ultra-high viscous (UHV-) alginate (‘alginate-MSCs’) – from the recipient immune system and from uncontrolled migration. Methods: Brain-derived neurotrophic factor-producing MSCs were encapsulated in UHV-alginate. Four experimental groups were investigated using guinea pigs as an animal model. Three of them were systemically deafened and (unilaterally) received one of the following: (I) a CI; (II) an alginate-MSC-coated CI; (III) an injection of alginate-embedded MSCs into the scala tympani followed by CI insertion and alginate polymerization. Group IV was normal hearing, with CI insertion in both ears and a unilateral injection of alginate-MSCs. Using acoustically evoked auditory brainstem response measurements, hearing thresholds were determined before implantation and before sacrificing the animals. Electrode impedance was measured weekly. Four weeks after implantation, the animals were sacrificed and the SGN density and degree of fibrosis were evaluated. Results: The MSCs survived being implanted for 4 weeks in vivo. Neither the alginate-MSC injection nor the coating affected electrode impedance or fibrosis. CI insertion with and without previous alginate injection in normal-hearing animals resulted in increased hearing thresholds within the high-frequency range. Low-frequency hearing loss was additionally observed in the alginate-injected and implanted cochleae, but not in those treated only with a CI. In deafened animals, the alginate-MSC coating of the CI significantly prevented SGN from degeneration, but the injection of alginate-MSCs did not. Conclusion: Brain-derived neurotrophic factor-producing MSCs encapsulated in UHV-alginate prevent SGNs from degeneration in the form of coating on the CI surface, but not in the form of an injection. No increase in fibrosis or impedance was detected. Further research and development aimed at verifying long-term mechanical and biological properties of coated electrodes in vitro and in vivo, in combination with chronic electrical stimulation, is needed before the current concept can be tested in clinical trials.

PMID: 31139049 [PubMed]