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Time-related Aspects of Otoprotection: Experimental Studies in Rat
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Intratympanic injection of various otoprotectants through the round window membrane (RWM) might become available in the near future as an alternative to the currently available medical and surgical methods used to treat several inner ear diseases. The most common outcome of such diseases is sensorineural hearing loss (SNHL).

Two examples of  these otoprotectants are Edaravone and Brain-Derived Neurotrophic Factor (BDNF), both of which have already proved effective against  noise-induced hair cell loss, barotrauma  and ototoxicity caused by cisplatin. In four different studies we used two electrophysiological methods, auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE), to study the effects of tobramycin and Pseudomonas aeruginosa exotoxin A (PaExoA) on the inner ears of 129 male Sprague-Dawley rats.

In two investigations, not only the otoprotective effects of Edaravone on tobramycin-induced ABR threshold shifts and PaExoA-induced DPOAE  threshold changes, were studied but even different application times, in order to establish in which interval it was still possible to achieve effective otoprotection.We found that Edaravone gave otoprotection from tobramycin when injected simultaneously or within 7 days, but it had only a limited effect on the changes in DPOAE thresholds caused by PaExoA when injected 1, 2, or 4 hours after the exotoxin.

The effect of BDNF on PaExoA-induced ABR threshold shifts was investigated in two studies, where different doses of intratympanically injected PaExoA were used and where BDNF was applied simultaneously, 12 or 72 hours efter exotoxin instillation. We found that BDNF had an otoprotective effect on SNHL induced by different doses PaExoA when injected simultaneously or with no more than 12 hours delay.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 49 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 901
Keyword [en]
sensorineural hearing loss, Edaravone, brain-derived neurotrophic factor, auditory brainstem response, Sprague-Dawley rat, distortion product otoacoustic emission, Pseudomonas aeruginosa exotoxin A.
National Category
Medical and Health Sciences
Research subject
Oto-Rhino-Laryngology
Identifiers
URN: urn:nbn:se:uu:diva-198450ISBN: 978-91-554-8661-7 (print)OAI: oai:DiVA.org:uu-198450DiVA: diva2:616180
Public defence
2013-06-13, Skoogsalen, Akademiska sjukhuset (ingång 78-79), Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2013-05-22 Created: 2013-04-15 Last updated: 2013-08-30
List of papers
1. Protective effect of edaravone against tobramycin-induced ototoxicity
Open this publication in new window or tab >>Protective effect of edaravone against tobramycin-induced ototoxicity
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2009 (English)In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 129, no 1, 8-13 p.Article in journal (Refereed) Published
Abstract [en]

CONCLUSION: It is suggested that simultaneous treatment with the radical scavenger edaravone has an effective protective effect against tobramycin ototoxicity in rat. Even if the edaravone treatment is postponed for 7 days, it can still prevent hearing loss, but a 14 day delay cannot protect from ototoxicity. OBJECTIVES: With the aim of alleviating hearing loss caused by aminoglycoside ototoxicity, we performed a trial to assess the hearing protective efficacy of the radical scavenger edaravone. MATERIALS AND METHODS: In part one of the study, 21 male Sprague-Dawley albino rats were used; 2 rats served as controls for the safety of edaravone. Eight rats each received 10 subcutaneous injections (s.c.) of tobramycin (160 mg/kg b.w.) once daily and saline injection intraperitoneally for 2 weeks. Eleven rats were given 10 s.c. tobramycin injections simultaneously with an intraperitoneal injection of edaravone (3 mg/kg b.w.). In part two, tobramycin was injected in 13 rats (as above). Five of these received two edaravone injections 7 days later and four rats similarly 14 days later. Auditory brainstem response (ABR) was used to assess hearing. RESULTS: All rats treated only with tobramycin showed a deterioration of hearing. None of the rats given simultaneous treatment with tobramycin and edaravone demonstrated hearing loss. A 7 day delay in edaravone injection still prevented hearing loss, but a 14 day delay had only a temporary prophylactic effect.

Keyword
Animal, rat, auditory brainstem response, edaravone, aminogycoside, hearing loss, cochlear ototoxicity, cochlear protection, reactive oxygen species, antioxidant
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-113361 (URN)10.1080/00016480802008199 (DOI)000261847700002 ()18607936 (PubMedID)
Available from: 2010-01-27 Created: 2010-01-27 Last updated: 2017-12-12Bibliographically approved
2. BDNF as otoprotectant in toxin-induced hearing loss
Open this publication in new window or tab >>BDNF as otoprotectant in toxin-induced hearing loss
2013 (English)In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 133, no 1, 4-11 p.Article in journal (Refereed) Published
Abstract [en]

Conclusion: Brain-derived neurotrophic factor (BDNF) can prevent auditory brainstem response (ABR) threshold shift changes caused by Pseudomonas aeruginosa exotoxin A (PaExoA). Objective: Peptides of the neurotrophin family are known to prevent neuronal death during embryonic development by interacting with specific membrane receptors. The purpose of this study was to investigate whether a single dose of BDNF is an effective protectant against toxic effects of PaExoA-induced ABR threshold shifts. Materials and Methods: Eight groups of Sprague-Dawley rats were used. There were five control groups (n = 20) as follows. Group A (n = 4) received NaCl solution; group B (n = 3) received 4 mu g BDNF; group C (n = 4) received 1 mu g/20 mu l PaExoA; group D (n = 4) received 2 mu g/20 mu l PaExoA; groupE (n = 5) received 10 mu g/20 mu l PaExoA injected into the round window niche. Three treatment groups (n = 13) received a single dose of PaExoA and 4 mu g of BDNF simultaneously. Group 1 (n = 3) received 1 mu g/20 mu l PaExoA + 4 mu g of BDNF; group 2 (n = 5) received 2 mu g/20 mu l PaExoA + 4 mg BDNF; group 3 (n = 5) received 10 mu g/20 mu l PaExoA+ 4 mu g BDNF. ABR was used to measure efficacy by analyzing threshold shifts before and after injections. Results: A single dose of BDNF prevented changes in ABR thresholds following exposure to increasing concentrations of PaExoA injected into the middle ear.

Keyword
Auditory brainstem response, Brain-derived neurotrophic factor, Pseudomonas aeruginosa exotoxin A, cochlea, round window membrane, rat
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-192429 (URN)10.3109/00016489.2012.712216 (DOI)000312525800001 ()
Available from: 2013-01-24 Created: 2013-01-21 Last updated: 2017-12-06Bibliographically approved
3. Early hearing protection by brain-derived neurotrophic factor
Open this publication in new window or tab >>Early hearing protection by brain-derived neurotrophic factor
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2013 (English)In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 133, no 1, 12-21 p.Article in journal (Refereed) Published
Abstract [en]

Conclusion: Brain-derived neurotrophic factor (BDNF) protects the inner ear from PaExoA (exotoxin A from Pseudomonas aeruginosa)-induced sensory neural hearing loss when administered 12 h after exotoxin, but not after 72 h. Objective: BDNF is a peptide in the neurotrophin family with protective effects against noise-induced hair cell loss and toxic inner ear damage following exposure to cisplatin. The exotoxin A (PaExoA) from P. aeruginosa, the most common microorganism in chronic suppurative otitis media, induces sensorineural hearing loss in rats. Previous study showed that, when given simultaneously with the exotoxin, BDNF protected the inner ear from damage. The aim of this study was to determine if BDNF has a protective effect when given 12-72 h after PaExoA. Materials and Methods : Five groups of Sprague-Dawley rats were used. The three control groups (n = 16) were as follows. Group 1 (n = 8) received 15 mu g/20 mu l PaExoA; group 2 (n = 5) received 20 mu g/20 mu l PaExoA; and group 3 (n = 3) received 25 mu g/20 mu l PaExoA injected into the round window niche. There were two treatment groups (n = 12): group A (n = 6) received 15 mu g/20 mu l PaExoA and 4 mu g/20 mu l BDNF 12 h later; group B (n = 6) received 15 mu g/20 mu l PaExoA and 4 mu g/20 mu l BDNF 72 h later. Brainstem response audiometry (ABR) was performed on day 0 (control), and repeated on days 7, 14, 21, 28, and 35 to analyze the thresholds shifts. Results: Exposure to 15 mu g/20 mu l PaExoA caused persistent and significant ABR impairment in controls when measured after 35 days. A single dose of BDNF given 12 h after PaExoA reduced hearing loss significantly, but when BDNF was given 72 h after PaExoA no protective effect was evident.

Keyword
Brain-derived neurotrophic faktor, Pseudomonas aeruginosa, ABR, cochlea, hearing loss, rat
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-192430 (URN)10.3109/00016489.2012.712217 (DOI)000312525800002 ()
Available from: 2013-01-24 Created: 2013-01-21 Last updated: 2017-12-06Bibliographically approved
4. Temporary dysfunction of outer hair cells after intratympanic application of pseudomonas aeruginosa exotoxin A.
Open this publication in new window or tab >>Temporary dysfunction of outer hair cells after intratympanic application of pseudomonas aeruginosa exotoxin A.
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-198447 (URN)
Available from: 2013-04-15 Created: 2013-04-15 Last updated: 2013-08-30

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