Leif Nordang

Glutamate is the Afferent Neurotransmitter in the Human Cochlea

Glutamate, the most important afferent neurotransmitter in the auditory system, is thought to be the afferent transmitter between the cochlear inner hair cells and afferent neurons, hitherto visualized only in the cochlea of animal species. It has been identified for the first time in sections from the human inner ear. L-glutamate, NMDAR2B and the enzyme glutamine synthetase were identified by using monoclonal antibodies. The distribution pattern of the transmitter L-glutamate in the human cochlea is similar to that observed in other mammals. L-glutamate was identified adjacent to outer and inner hair cells and in the spiral ganglion. Similar distributions were found for glutamine synthetase and the ionotropic NMDA receptor subunit NMDAR2. The identification of neurotransmitters and their receptors in the human cochlea has implications for the pharmacotherapy of inner ear diseases.

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 &mgr;g (20&mgr;l) dexamethasone in the right ear, and five others were given 5 doses, and five rats 10 doses, of 2% (20&mgr;l) 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.

Hearing Loss in Relation to Round Window Membrane Morphology in Experimental Chronic Otitis media

The present study was performed to test the effect of single and repeated Pseudomonas aeruginosa exotoxin A (PaExoA) instillations in the middle ear of the rat. The hearing level was examined by the ABR technique, round window membrane (RWM) thickness was measured and morphology was studied by light microscopy. The results showed both reversible and permanent hearing loss (HL). In animals that received a single dose of PaExoA, the RWM thickness doubled initially and remained thickened during the observation period. When PaExoA was instilled on several occasions, RWM thickness doubled, before decreasing to near-control levels. This study confirms the toxicity of PaExoA and the partially reversible HL occurring after a single application of the toxin. The diminished effect of repeated toxin instillations – despite the decreasing thickness of the RWM – is discussed.

Nitro-L-arginine methyl ester: a potential protector against gentamicin ototoxicity.

Conclusion The nitric oxide (NO) inhibitor nitro-L-arginine methyl ester (L-NAME) may act as an otoprotectant against high-frequency hearing loss caused by gentamicin, but further studies are needed to confirm this. Objective Aminoglycoside antibiotics are still widely used by virtue of their efficacy and low cost. Their ototoxicity is a serious health problem and, as their ototoxic mechanism involves the production of NO, we need to assess the use of NO inhibitors for the prevention of aminoglycoside-induced sensorineural hearing loss. Material and methods In this experimental study we used 30 Sprague–Dawley rats, 27 of which had gentamicin instilled into the middle ear. The otoprotectant L-NAME was administered topically to 12/27 animals. Its effect was determined in terms of attenuation of hearing loss, measured by shifts in the auditory brainstem response threshold. Results L-NAME reduced gentamicin-induced hearing loss in the high-frequency range, but gave no protection in the middle or low frequencies.

Early hearing protection by brain-derived neurotrophic factor

Abstract 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.

Passage through the round window membrane and inner ear function

The round window membrane (RWM) is an anatomical barrier between the aerated middle ear and the fluid (perilymph) compartments of the cochlea. Permeability of the RWM is regarded as an accident and not as a function of the membrane because of its anatomical characteristics, location and the high prevalence of middle ear disease. This paper provides a review of the effects on cochlear function following experimental exposure of bacterial toxins into the round window niche. Hearing loss is correlated with RWM morphology in experimental chronic otitis media. Following exposure to bacterial toxins there is a time‐dependent response of both the middle ear mucosal changes and the morphological alterations in the epithelium of the endolymphatic duct and sac. Otoprotectants, such as nitric oxide inhibitors, dexamethasone and neurotrophic factors, prevent toxic effects of Pseudomonas aeruginosa exotoxin A. In spite of a limited knowledge on the permeability of the RWM the application of therapeutic substances into the round window niche seems still the most suitable clinical approach to treat inner ear disorders.

Middle Ear Exotoxin and Endolymphatic Sac Response: An Immune Reaction?

Objectives: The endolymphatic sac (ES) is presumed to be involved in immune response in the inner ear. The ES has been shown to respond immunologically to an antigen instilled into the scala tympani. Pseudomonas aeruginosa exotoxin A (PaExoA) is known to pass the round window membrane and to cause cochlear functional impairment. Does the ES in the inner ear respond immunologically to exotoxin exposed in the middle ear? Methods: In the present study, the ES was examined morphologically after application of PaExoA in the middle ear of the rat. The ES changes were correlated with electrophysiological results using ABR measurements. Results: In 18 out of 32 exposed ES we found signs of inflammatory activity with raised numbers of intraluminal macrophages together with signs of epithelial alterations. There were also changes in character and stainability of the intraluminal glycoprotein conjugates. Conclusions: The ES changes may either be due to a direct exposure of toxin to the ES or possibly represent the expression of an augmented general response in the inner ear. These findings are similar to earlier descriptions of changes in the ES after experimental labyrinthitis. This is the first presentation showing altered ES activity following middle ear application of exotoxin.

BDNF as otoprotectant in toxin-induced hearing loss

Abstract 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.