Cisplatin-induced metabolome changes in serum: an experimental approach to identify markers for ototoxicity.

BACKGROUND: Ototoxicity from treatment with the anticancer drug cisplatin remains a clinical problem. A wide range of intracellular targets of cisplatin has been found in vivo. AIM: To investigate cisplatin-induced change of the serum metabolite profile and its association with ototoxicity. MATERIAL AND METHODS: Guinea pigs (n = 14) were treated with cisplatin (8 mg/kg b.w., i.v.) 30 min after administration of the otoprotector candidate sodium thiosulfate (group STS; n = 7) or sodium chloride (group NaCl; n = 7). Ototoxicity was evaluated by ABR (3-30 kHz) before and 4 d after drug treatment, and by assessment of hair cell loss. A blood sample was drawn before and 4 d after drug treatment and the polar metabolome in serum was analyzed using LC-MS. RESULTS: Cisplatin-treatment caused significant threshold elevations and outer hair cell (OHC) loss in both groups. The ototoxicity was generally lower in group STS, but a significant difference was reached only at 30 kHz (p = .007). Cisplatin treatment altered the metabolite profile significantly and similarly in both groups. A significant inverse correlation was found between L-acetylcarnitine, N-acetylneuraminic acid, ceramide, and cysteinylserine and high frequency hearing loss in group NaCl. The implication of these correlations should be explored in targeted studies.

BDNF as otoprotectant in toxin-induced hearing loss.

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 µg BDNF; group C (n = 4) received 1 µg/20 µl PaExoA; group D (n = 4) received 2 µg/20 µl PaExoA; group E (n = 5) received 10 µg/20 µl PaExoA injected into the round window niche. Three treatment groups (n = 13) received a single dose of PaExoA and 4 µg of BDNF simultaneously. Group 1 (n = 3) received 1 µg/20 µl PaExoA + 4 µg of BDNF; group 2 (n = 5) received 2 µg/20 µl PaExoA + 4 µg BDNF; group 3 (n = 5) received 10 µg/20 µl PaExoA + 4 µg 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.

Early hearing protection by brain-derived neurotrophic factor.

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 µg/20 µl PaExoA; group 2 (n = 5) received 20 µg/20 µl PaExoA; and group 3 (n = 3) received 25 µg/20 µl PaExoA injected into the round window niche. There were two treatment groups (n = 12): group A (n = 6) received 15 µg/20 µl PaExoA and 4 µg/20 µl BDNF 12 h later; group B (n = 6) received 15 µg/20 µl PaExoA and 4 µg/20 µl 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 µg/20 µl 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.

Protective effect of edaravone against tobramycin-induced ototoxicity.

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.

Innervation of the apical turn of the human cochlea: a light microscopic and transmission electron microscopic investigation.

HYPOTHESIS: A light and transmission electron microscopic investigation of the apical turn of a freshly fixed human cochlea. BACKGROUND: Our knowledge about the human cochlea rests to a large extent on animal species research. An opportunity to obtain tissue from normal-hearing persons occurs during surgery for life-threatening petroclival meningioma. This study presents detail on the morphology and innervation of the apical part of the human cochlea using light microscopic and transmission electron microscopic level sectioning. METHODS: The tissue was histologically processed after removal during petroclival meningioma surgery. The cochlea was serially sectioned perpendicularly to its long axis, and at regular distances semithin sections were reembedded and prepared for transmission electron microscopy. Nerve fibers/fascicles were traced from the area of the spiral ganglion to the level of the inner hair cells, and a cochleotopic "map" of the cochlear nerve supplying the apical portion was constructed. RESULTS: The apical turn was found to be innervated by 3,694 myelinated nerve fibers representing approximately 10% of the total number of fibers innervating the cochlea. The total number of unmyelinated nerve fibers was 513. The majority belonged to the efferent olivocochlear system and the intraganglionic spiral bundle or represented Type II afferent neurons innervating outer hair cells. CONCLUSION: The significance of the anatomic findings in relation to cochlear implantation is discussed.

Morphologic changes in round window membrane after topical hydrocortisone and dexamethasone treatment.

HYPOTHESIS: Are all glucocorticoids supposed to have the same effect on the round window membrane? BACKGROUND: Interest in glucocorticoids for topical treatment of inner ear diseases is increasing. The safety of such treatment should therefore be an important consideration before clinical use. METHODS: In this study the authors investigated the morphology of the round window membrane after topical instillation of dexamethasone or hydrocortisone into the middle ear. Twenty Sprague-Dawley rats were used. Five rats received 5 doses, and five rats 10 doses, of 1 microg (20 microl) dexamethasone in the right ear, and five others were given 5 doses, and five rats 10 doses, of 2% (20 microl) hydrocortisone solution, also in the right ear. Membrane morphology was studied in both light microscopy and transmission electron microscopy. The thickness of exposed membranes was measured and compared with that of control membranes. RESULTS: Thickening and microscopically signs of inflammation were observed in hydrocortisone-exposed membranes but not in dexamethasone-exposed membranes, which did not differ morphologically from those in control ears. CONCLUSION: Although hydrocortisone has anti-inflammatory properties, it seems to provoke inflammation in the round window membrane after topical instillation. Dexamethasone had no such effects, however.