title: Gentamicin administration on the stapes footplate causes greater hearing loss and vestibulotoxicity than round window administration in guinea pigs.
abstract: Clinically, gentamicin has been used extensively to treat the debilitating symptoms of Mèniére's disease and is well known for its vestibulotoxic properties. Until recently, it was widely accepted that the round window membrane (RWM) was the primary entry route into the inner ear following intratympanic drug administration. In the current study, gentamicin was delivered to either the RWM or the stapes footplate of guinea pigs (GPs) to assess the associated hearing loss and histopathology associated with each procedure. Vestibulotoxicity of the utricular macula, saccular macula, and crista ampullaris in the posterior semicircular canal were assessed quantitatively with density counts of hair cells, supporting cells, and stereocilia in histological sections. Cochleotoxicity was assessed quantitatively by changes in threshold of auditory brainstem responses (ABR), along with hair cell and spiral ganglion cell counts in the basal and second turns of the cochlea. Animals receiving gentamicin applied to the stapes footplate exhibited markedly higher levels of hearing loss between 8 and 32 kHz, a greater reduction of outer hair cells in the basal turn of the cochlea and fewer normal type I cells in the utricle in the vestibule than those receiving gentamicin on the RWM or saline controls. This suggests that gentamicin more readily enters the ear when applied to the stapes footplate compared with RWM application. These data provide a potential explanation for why gentamicin preferentially ablates vestibular function while preserving hearing following transtympanic administration in humans.
authors.affiliation: Department of Otolaryngology, University of Melbourne, Melbourne, VIC, Australia; Bionics Institute, Melbourne, VIC, Australia. Electronic address: Eking@bionicsinstitute.org.
authors.forename: E B
authors.initials: EB
authors.lastname: King
authors.forename: A N
authors.initials: AN
authors.lastname: Salt
authors.forename: G E
authors.initials: GE
authors.lastname: Kel
authors.forename: H T
authors.initials: HT
authors.lastname: Eastwood
authors.forename: S J
authors.initials: SJ
authors.lastname: O'Leary
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000633:toxicity; D003051:Cochlea / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005260:Female; D005839:Gentamicins / Q000008:administration & dosage* / Q000633:toxicity*; D006168:Guinea Pigs; D034381:Hearing Loss / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D008575:Meniere Disease / Q000188:drug therapy / Q000503:physiopathology; D012405:Round Window, Ear / Q000187:drug effects* / Q000503:physiopathology; D013199:Stapes / Q000187:drug effects* / Q000503:physiopathology; D014722:Vestibule, Labyrinth / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins
keywords: ABR; GPs; Gd; HCs; IHCs; MRI; Magnetic Resonance Imaging; OHCs; OW; RW; RWM; ST; SV; SVJ; TMPA; auditory brainstem responses; gadolinium; guinea pigs; hair cells; inner hair cells; outer hair cells; oval window (OW); round window; round window membrane; scala tympani; scala vestibuli; stapediovestibular joint; trimethylphenylammonium
references.citation: J Neurophysiol. 2005 Jan;93(1):251-66
references.pmid: 15240767
references.citation: Laryngol Rhinol Otol (Stuttg). 1977 May;56(5):409-14
references.pmid: 141554
references.citation: Eur Arch Otorhinolaryngol. 1998;255(3):127-31
references.pmid: 9561858
references.citation: Otol Neurotol. 2002 Nov;23(6):967-74
references.pmid: 12438864
references.citation: Laryngoscope. 2008 Oct;118(10):1793-800
references.pmid: 18806480
references.citation: Arch Otorhinolaryngol. 1981;233(1):67-73
references.pmid: 6976164
references.citation: Toxicol Lett. 1990 Aug;52(3):227-51
references.pmid: 2202080
references.citation: Hear Res. 1995 Sep;89(1-2):194-202
references.pmid: 8600126
references.citation: Okajimas Folia Anat Jpn. 1993 Mar;69(6):385-99
references.pmid: 8469528
references.citation: Acta Otolaryngol. 1984 May-Jun;97(5-6):593-610
references.pmid: 6464711
references.citation: Microsc Res Tech. 1997 Feb 1;36(3):201-11
references.pmid: 9080410
references.citation: J Assoc Res Otolaryngol. 2009 Jun;10(2):205-19
references.pmid: 19255807
references.citation: J Assoc Res Otolaryngol. 2007 Dec;8(4):497-508
references.pmid: 17899270
references.citation: J Assoc Res Otolaryngol. 2011 Dec;12(6):741-51
references.pmid: 21769689
references.citation: Otol Neurotol. 2011 Jan;32(1):183-5
references.pmid: 21192347
references.citation: Laryngoscope. 1988 Jun;98(6 Pt 2 Suppl 44):1-20
references.pmid: 3287079
references.citation: Otol Neurotol. 2009 Feb;30(2):131-8
references.pmid: 19180674
references.citation: Hear Res. 2003 Aug;182(1-2):24-33
references.pmid: 12948598
references.citation: Hear Res. 2012 Jan;283(1-2):14-23
references.pmid: 22178981
references.citation: Int J Dev Neurosci. 1997 Jul;15(4-5):447-61
references.pmid: 9263025
references.citation: Hear Res. 2001 Apr;154(1-2):88-97
references.pmid: 11423219
references.citation: Arch Otolaryngol. 1984 Jan;110(1):15-21
references.pmid: 6689900
references.citation: J Neurophysiol. 2005 Feb;93(2):643-55
references.pmid: 15456806
references.citation: Hear Res. 2010 Sep 1;268(1-2):250-9
references.pmid: 20561573
references.citation: Hear Res. 2008 Jan;235(1-2):114-24
references.pmid: 18082985
references.citation: Eur Arch Otorhinolaryngol. 1997;254(1):9-14
references.pmid: 9115709
references.citation: Ann N Y Acad Sci. 1999 Nov 28;884:410-24
references.pmid: 10842610
references.citation: Ann Otol Rhinol Laryngol. 2000 Jan;109(1):30-2
references.pmid: 10651408
references.citation: Laryngoscope. 2007 Jul;117(7):1191-8
references.pmid: 17603318
references.citation: Otolaryngol Head Neck Surg. 1999 May;120(5):649-55
references.pmid: 10229588
references.citation: Sci Rep. 2011;1:159
references.pmid: 22355674
references.citation: Laryngoscope. 1999 Oct;109(10):1560-9
references.pmid: 10522922
references.citation: Hear Res. 1991 Nov;56(1-2):37-43
references.pmid: 1769923
references.citation: Audiol Neurootol. 2005 May-Jun;10(3):145-52
references.pmid: 15724085
references.citation: Arch Otorhinolaryngol. 1977 Aug 26;217(3):331-7
references.pmid: 579089
references.citation: Arch Otolaryngol Head Neck Surg. 2004 May;130(5):518-23
references.pmid: 15148170
references.citation: Ann Otol Rhinol Laryngol. 2012 Feb;121(2):119-28
references.pmid: 22397222
references.citation: Acta Otolaryngol. 1969 Feb-Mar;67(2):177-89
references.pmid: 4911527
references.citation: Ann Otol Rhinol Laryngol Suppl. 2000 May;181:20-5
references.pmid: 10821231
references.citation: Hear Res. 2006 Mar;213(1-2):11-6
references.pmid: 16476532