Biomedical subjects

Josef M Miller

Publications and source records attributed to Josef M Miller.

25 records · Page 2Linked to original sources

PubMed2002

Effect of noise exposure on blood-labyrinth barrier in guinea pigs.

The influence of noise exposure on the endothelial transport system in the cochlea was investigated using cationic polyethyleneimine (PEI), since systemically administered PEI passes through the capillary endothelial cell and attaches to basal lamina (BL) anionic sites in the cochlea. Under general anesthesia, all guinea pigs were administered an intravenous injection of 0.5% PEI. Thirty minutes later, five animals were exposed to noise (10 kHz, broad band noise, 105 dB SPL) for 30 min, via speakers inserted into the external auditory canal. The remaining five animals (controls) were left without noise exposure for 1 h following PEI injection. All guinea pigs were then immediately sacrificed, and the bony labyrinths were removed. PEI distribution on the BL was assessed in the stria vascularis, spiral ligament, basilar membrane, spiral limbus and Reissner's membrane throughout the cochlea with transmission electron microscopy. Compared to control animals, PEI distribution in the noise-exposed animals was significantly increased in the strial vessels of the basal and second turns and in Reissner's membrane of all turns. In the spiral ligament, basilar membrane and spiral limbus, no significant difference in PEI distribution was observed between the control and noise-exposed animals. These findings indicate that noise exposure increases macromolecular transport in the stria vascularis but not in the spiral ligament, spiral limbus and basilar membrane and that systemically administered macromolecules are more readily transported to Reissner's membrane by noise exposure.

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PubMed2002

Intra-cochlear administration of dexamethasone attenuates aminoglycoside ototoxicity in the guinea pig.

This study demonstrates the attenuation of aminoglycoside ototoxicity by cochlear infusion of dexamethasone (Dex) using a microcannulation-osmotic pump delivery system. The results indicate that treating the cochlea with Dex both before and after kanamycin administration was more effective in preventing ototoxicity than Dex treatment only after kanamycin administration. A concentration of 1 ng/ml Dex showed the greatest protective effect on both kanamycin-induced threshold shift of the auditory brainstem response and outer hair cell survival. These results show that the Dex treatment attenuates both functional and structural damage of the inner ear from aminoglycoside toxicity.

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PubMedDate not supplied

Stress pathways in the rat cochlea and potential for protection from acquired deafness.

Noise overstimulation will induce or influence intracellular molecular pathways in the cochlea. One of these is the 'classical' stress response pathway involving heat shock proteins. Hsp70 is induced in the cochlea by a wide variety of stresses including noise, hyperthermia and ototoxic drugs. When a stress that induces Hsp70 is applied to the cochlea, there is protection from a subsequent noise that would normally cause a permanent hearing loss. An upstream regulator of heat shock protein transcription, heat shock factor 1, is expressed in the cochlea and activated by stress. Mice lacking this heat shock factor have reduced recovery from noise-induced hearing loss. The same noise exposure that induces Hsp70 also increases the level of glial cell line-derived neurotrophic factor in the cochlea. Moreover, when this neurotrophic factor is applied into the perilymph of scala tympani prior to a noise exposure there is a significant reduction in hair cell loss and hearing loss. With the potential for activation of multiple pathways in the response to noise, gene microarrays can be useful to examine global gene expression. Initial studies examined differential gene expression immediately following a mild noise exposure (from which there is complete recovery) versus an intense noise (giving profound permanent deafness). Differential expression of several immediate early genes was found following the intense but not the mild noise exposure.

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PubMedDate not supplied

From gene identification to gene therapy.

Inner ear disease due to hair cell loss is common, and no restorative treatments for the balance and hearing impairment are currently available. To develop clinical means for enhancing protection and regeneration in the inner ear, it is necessary to understand the molecular basis for hereditary and acquired deafness and vestibular disorders. One approach is to identify and characterize genes that regulate protection or repair in other systems. For that purpose, we have used the differential display assay and compared gene expression between normal and acoustically traumatized inner ears of chicks. Several chick cDNAs that were identified are considered as candidates for roles in the reparative process that follows trauma in the basilar papilla. The mammalian vestibular epithelium has a limited regenerative capability. To identify genes that may participate in the regenerative response, we have used gene arrays profiling, comparing normal to drug-traumatized vestibular epithelia. We identified several genes that are differentially expressed in traumatized vestibular epithelium, including several insulin-like growth factor-I binding proteins. To use this molecular knowledge for enhancing protection and repair in the organ of Corti, it is necessary to overexpress the genes of choice in the inner ear. Using viral-mediated gene transfer, we overexpressed transgenic glial cell line-derived neurotrophic factor and demonstrated a robust protective effect against acoustic and ototoxic inner ear trauma. Future identification of the genes that are important for protection and regeneration, along with improved gene transfer technology, will allow the use of gene therapy for treating hereditary and environmental inner ear disease.

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PubMedDate not supplied

Protection and regrowth of the auditory nerve after deafness: neurotrophins, antioxidants and depolarization are effective in vivo.

Deafness, with loss of sensory (hair) cells, results in progressive pathophysiological changes ending in the degeneration of most auditory nerve neurons. It is now possible to consider these events in the broader context of anti-apoptotic survival factors in the peripheral and central nervous system. One consequence of deafferentation of a neuron is the loss of neurotrophins that can lead to a change in oxidative state (formation of free radicals), changes in intracellular Ca(2+), and an up-regulation of apoptotic genes. Interventions that can modify availability of neurotrophins, [Ca(2+)](I), and/or free radical formation or their destructive effects, may preserve the auditory nerve. Some interventions (neurotrophins) may also lead to a regrowth of neurites. Studies in this area are of basic value and also of immediate clinical interest for the application of the cochlear prosthesis to the severe and profoundly deaf, since the benefits of this prosthesis are directly dependent on auditory nerve survival and the proximity of stimulating electrode to neuron. We, and others, have found that auditory nerve degeneration can be prevented by chronic electrical stimulation. We have demonstrated in vivo that this effect can be blocked by tetrodotoxin, thus indicating that propagated action potentials are a necessary condition, and by verapamil (Ca(2+) channel blocker), supporting in vitro studies by others, indicating that L-type Ca(2+) channels are necessary for stimulation-induced rescue of the deafferented auditory nerve. The intensities of electrical stimulation required for rescue are at levels sufficient to express the intermediate-early gene c-fos which can initiate transcription of anti-apoptotic genes and pathways, and up-regulate expression of neurotrophins that may act in an autocrine manner to protect the nerve from death. We, and others, have found that chronic local delivery (osmotic pump and microcannulation of the inner ear fluid spaces) of individual neurotrophins and cocktails of factors can also enhance survival of the deafferented nerve, and some can also initiate a regrowth of degenerated peripheral processes of the nerve into the region of the destroyed sensory epitheliae. Recently, we have shown that this rescue can occur with delayed intervention, after degeneration of some neurons has begun, more closely mimicking the human clinical situation. Finally, we have shown that interventions with antioxidants may also be effective in preventing pathophysiological changes of the auditory nerve following deafness. These studies in the auditory periphery support the 'neurotrophic factor hypothesis' as proposed as a general mechanism underlying neurodegenerative and age-related pathology of the central nervous system. Additional animal studies can yield a rational scientific basis to justify human trials, with a goal to maintain auditory cell survival and initiate and direct fiber growth to the next generation of prosthesis. Intimate contact between electrode and a dense population of auditory neurons should greatly enhance the benefits of these devices for the profoundly deaf.

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PubMedDate not supplied

8-iso-prostaglandin F(2alpha), a product of noise exposure, reduces inner ear blood flow.

Noise exposure induces the formation in the cochlea of 8-isoprostaglandin F(2alpha) (8-iso-PGF(2alpha)), a marker for reactive oxygen species [Ohinata et al., 2000a] and a potent vasoconstrictor, raising the possibility that 8-iso-PGF(2alpha) may be responsible for noise-induced reductions in cochlear blood flow (CBF). To test this hypothesis, CBF was assessed in the guinea pig in response to 'local' (via the anterior inferior cerebellar artery) and systemic (i.v.) delivery of 8-iso-PGF(2alpha) using laser Doppler flowmetry. Local 8-iso-PGF(2alpha) induced a clear reduction in CBF. With systemic infusion, vascular conductance (VC), the ratio of CBF to systemic blood pressure, decreased in a dose-dependent manner up to 30%, consistent with an 8-iso-PGF(2alpha)-induced constriction of the cochlear vasculature. Infusion of SQ29548, a specific antagonist of 8-iso-PGF(2alpha), appropriately blocked an 8-iso-PGF(2alpha)-induced CBF response. Similarly, noise-induced changes in CBF and VC were prevented by infusion of SQ29548 during noise exposure or by antioxidant treatment (glutathione monoethyl ester) prior to exposure. Prevention of isoprostane-mediated vasoconstriction may have clinical utility in the protection from noise-induced hearing loss.

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PubMedDate not supplied

Comparison of the protective efficacy of neurotrophins and antioxidants for vibration-induced trauma.

BACKGROUND: Patients undergoing temporal bone surgery or subjects working with vibrating tools may develop vibration-induced hearing loss (VHL). The aim of this study was to characterize the effects of pretreatment with N-acetylcysteine (NAC) or the neurotrophic factors, brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF), on VHL in an animal model. METHODS: Trauma to the cochlea was created with a vibrating probe placed on the bone of the external ear canal. BDNF and CNTF(Ax1) were delivered into the cochlea with mini-osmotic pumps. NAC was delivered into the cochlea by round window membrane (RWM) injection, by RWM permeation, or by oral administration. Hearing was evaluated with electrocochleography (ECoG). RESULTS: For control animals, vibration resulted in an average immediate threshold shift of 42 +/- 26 dB. NAC provided no protective benefit in animals subjected to VHL, regardless of the delivery method, with average threshold shifts varying from 38 to 56 dB across groups. NAC injection through the round window membrane was toxic, causing a ECoG threshold shift of >25 dB. In BDNF+CNTF(Ax1)-treated animals, immediate hearing loss was similar to that in control animals. There was a trend of threshold recovery by 1 day after vibration; however, the improvement was not statistically significant, nor was there a significant difference in 1-day thresholds across groups. CONCLUSIONS: Local infusion of BDNF and CNTF(Ax1) may enhance the rate of recovery from VHL, compared to control animals. In contrast, NAC had no effect on VHL, and when delivered by RWM injection, was actually toxic to the inner ear.

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