Biomedical subjects

Thomas R Van De Water

Publications and source records attributed to Thomas R Van De Water.

15 recordsLinked to original sources

PubMed2006

Blocking c-Jun-N-terminal kinase signaling can prevent hearing loss induced by both electrode insertion trauma and neomycin ototoxicity.

Neomycin ototoxicity and electrode insertion trauma both involve activation of the mitogen activated protein kinase (MAPK)/c-Jun-N-terminal kinase (JNK) cell death signal cascade. This article discusses mechanisms of cell death on a cell biology level (e.g. necrosis and apoptosis) and proposes the blocking of JNK signaling as a therapeutic approach for preventing the development of a permanent hearing loss that can be initiated by either neomycin ototoxicity or electrode insertion trauma. Blocking of JNK molecules incorporates the use of a peptide inhibitor (i.e. D-JNKI-1), which is specific for all three isoforms of JNK and has been demonstrated to prevent loss of hearing following either electrode insertion trauma or loss of both hearing and hair cells following exposure to an ototoxic level of neomycin. We present previously unpublished results that control for the effect of perfusate washout of aminoglycoside antibiotic by perfusion of the scala tympani with an inactive form of D-JNKI-1 peptide, i.e. JNKI-1(mut) peptide, which was not presented in the original J. Neurosci. article that tested locally delivered D-JNKI-1 peptide against both noise- and neomycin-induced hearing loss (i.e. Wang, J., Van De Water, T.R., Bonny, C., de Ribaupierre, F., Puel, J.L., Zine, A. 2003a. A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss. J. Neurosci. 23, 8596-8607). D-JNKI-1 is a cell permeable peptide that blocks JNK signaling at the level of the three JNK molecular isoforms, which when blocked prevents the increases in hearing thresholds and the loss of auditory hair cells. This unique therapeutic approach may have clinical application for preventing: (1) hearing loss caused by neomycin ototoxicity; and (2) the progressive component of electrode insertion trauma-induced hearing loss.

Animals↗

PubMed2006

Vector-mediated delivery of bcl-2 prevents degeneration of auditory hair cells and neurons after injury.

OBJECTIVE: To test the hypothesis that bcl-2 prevents oxidative stress-induced apoptosis of auditory sensory cells in explants of the organ of Corti and dissociated cell cultures of the spiral ganglion. METHODS: Organ of Corti explants and dissociated spiral ganglion cell cultures obtained from 3-day-old (P3) rats or adult spiral ganglion cell cultures from 28-day-old (P28) rats were transduced with vectors containing a human bcl-2 gene. Cultures were then exposed to neomycin, cisplatin or subjected to withdrawal of neurotrophin supplementation. Outcome measures included hair cell and neuron counts, mitochondrial membrane potential and a histological measure of apoptosis. RESULTS: Expression of bcl-2 in the organ of Corti explants and neuronal cell cultures provided a significant level of protection against cell death. Bcl-2 expression in the organ of Corti explants also protected mitochondria from loss of membrane potential and blocked an early step in the commitment of hair cells to apoptosis. CONCLUSION: Expression of bcl-2 in cochlear tissues protects sensory cells from a variety of insults that have been demonstrated to damage the inner ear.

Adenoviridae↗

PubMed2006

Glutathione ester protects against hydroxynonenal-induced loss of auditory hair cells.

OBJECTIVE: Test the ability of glutathione monoethyl ester (GSH(e)) to protect auditory hair cells against the ototoxic effects of 4-hydroxy-2,3-nonenal (HNE). STUDY DESIGN AND SETTING: Organ of Corti explants were either untreated or treated with one of a series of four concentrations of GSH(e) for one day, then exposed to HNE. Counts of FITC-phalloidin-labeled hair cells determined both HNE ototoxicity and GSH(e) otoprotection. RESULTS: HNE was toxic to hair cells at physiologically relevant levels, eg, 400 muM, and GSH(e) provided a significant level of protection against HNE ototoxicity (P < 0.05) at all levels tested, ie, 1.16 to 9.3 mM. CONCLUSION: GSH(e) protects auditory hair cells from damage and loss initiated by a naturally occurring ototoxic molecule, ie, HNE (a by-product of oxidative stress). SIGNIFICANCE: Treatment with GSH(e) may be an effective therapy to protect the cochlea against the adverse effects of traumas (eg, electrode insertion) that generate oxidative stress.

Aldehydes↗

PubMed2006

D-JNKI-1 treatment prevents the progression of hearing loss in a model of cochlear implantation trauma.

HYPOTHESES: 1) Hearing loss caused by electrode insertion trauma has both acute and delayed components; and 2) the delayed component of trauma-initiated hearing loss can be prevented by a direct delivery of a peptide inhibitor of the c-Jun N-terminal kinase cell death signal cascade, that is, D-JNKI-1, immediately after the electrode insertion within the cochlea. BACKGROUND: Acute trauma to the macroscopic elements of the cochlea from electrode insertion is well known. The impact of trauma-induced oxidative stress within injured cochlear tissues and the efficacy of drugs (e.g., D-JNKI-1) to prevent apoptosis of damaged hair cells is not well defined. METHODS: Hearing function was tested by pure-tone evoked auditory brainstem responses (ABRs) and distortion products of otoacoustic emissions (DPOAEs). D-JNKI-1 in artificial perilymph (AP) or AP alone was delivered into the scala tympani immediately after electrode trauma and for 7 days. Controls were nontreated contralateral and D-JNKI-1-treated ears without electrode insertion trauma. RESULTS: There was no increase in the hearing thresholds of either the contralateral control ears or in the D-JNKI-1 without trauma animals. There was a progressive increase in ABR thresholds and decrease in DPOAE amplitudes after electrode insertion trauma in untreated and in AP-treated cochleae. Treatment with D-JNKI-1 prevented the progressive increase in ABR thresholds and decrease in DPOAE amplitudes that occur after electrode insertion trauma. CONCLUSION: Hearing loss caused by cochlear implant electrode insertion trauma in guinea pigs has both acute and delayed components. The delayed component can be prevented by treating the cochlea with D-JNKI-1.

Analysis of Variance↗

PubMed2006

Vibrant soundbridge surgery: evaluation of transcanal surgical approaches.

UNLABELLED: Since its introduction, surgery for the placement of the Vibrant Soundbridge (VSB) device has been performed using a facial recess approach. Because of the size of the VSB device, this approach requires a large facial recess that can lead to complications, i.e., facial palsy and/or taste disturbance. The purpose of this study is to develop and compare transcanal surgical approaches for leading the VSB into the middle ear. SETTING: Cadaver temporal bones in a university temporal bone laboratory. MATERIALS AND METHODS: First, two experienced senior surgeons validated the three possible approaches in human temporal bone: 1) the classical facial recess approach; 2) a small mastoidectomy, elevation of a tympanomeatal flap, small atticotomy, 0.5-mm cutting of the bony external auditory canal (EAC) from the cortical plane on its approximately two-thirds to three-fourths and then a trough to pass the electrode array into the middle ear; and 3) similar to the second approach but with replacing the cutting of the bony EAC with a tunnel from the mastoid cavity to the EAC. Both the second and third approaches were transcanal. Next, five residents and six attending surgeons performed the three operations and evaluate these different approaches by using analog visual scales (VAS) for each procedure. They assess the following: 1) the ease of passing the electrode array and the Floating Mass Transducer (FMT) into the middle ear, 2) the ease for FMT clipping, and 3) their self-confidence using each approach. Time required for the three operations was measured. Measurements of landmarks were obtained on all temporal bones. Two patient cases illustrate the clinical application of this new surgical approach. RESULTS: The two transcanal approaches were assessed to be easier, faster, and safer methods for VSB surgery than the classic facial recess approach. CONCLUSION: VSB surgery has been performed using a facial recess approach with risk for facial nerve and taste disturbance. Transcanal approaches are good alternative for this surgery. Three major limitations are to be assessed in future patient studies: the pathologic findings of the EAC, the design of the FMT regarding the axis of the ossicular chain, the long-term evaluation of the skin of the external ear canal.

Aged↗

PubMed2005

Cochlear temperature correlates with both temporalis muscle and rectal temperatures. Application for testing the otoprotective effect of hypothermia.

CONCLUSIONS: During systemic hypothermia, the internal temperature of the rat cochlea correlates best with the temporalis muscle and rectal temperatures. These positive correlations will be used in future studies to assess the efficacy of mild and moderate hypothermia to protect hearing against the progressive loss caused by electrode insertion in a clinically relevant model of cochlear implantation trauma. OBJECTIVE: To monitor the internal temperature of the cochlea during induced systemic hypothermia using a reference tissue instead of an internal cochlear temperature probe. MATERIAL AND METHODS: The temperatures of the cochlea, brain, temporalis muscle and rectum were determined during periods of normothermia (37 degrees C), mild (33 degrees C) and moderate (30 degrees C) hypothermia and slow rewarming in anesthetized adult Fisher rats. These values were compared using statistical analysis to establish the best correlations between the temperature of the cochlea and the temperature at the three other temperature measurement sites. RESULTS: The strongest correlations with the internal temperature of the cochlea during the induction of mild-to-moderate hypothermia were obtained for the temperatures of the ipsilateral temporalis muscle and rectum.

Animals↗

PubMed2005

Pattern of hearing loss in a rat model of cochlear implantation trauma.

HYPOTHESIS: Trauma caused by cochlear implant electrode insertion is attributable to the combination of direct physical trauma and the delayed cell death of oxidative stress-injured auditory sensory cells. BACKGROUND: Histologic evaluation of cochlear implant electrode trauma has demonstrated that the extent of sensory cell losses is proportional to the degree of injury. However, the impact of delayed oxidative stress within injured cochlear tissues and the progressive loss of injured hair cells by way of apoptosis are at present unknown. METHODS: Laboratory rats were evaluated for hearing acuity before and after electrode insertion, before and after round window membrane incision only. Hearing was measured before trauma or incision and over the next 7 days. Objective measurements of hearing function were distortion products of otoacoustic emissions (DPOAEs) in the frequency range of 2 to 32 kHz and tone-burst (i.e., 4-32 kHz) evoked auditory brain stem responses (ABRs). RESULTS: For the experimental cochleae, there were progressive increases in ABR thresholds and decreases in ABR amplitudes. The amplitude of the DPOAEs in the experimental cochleae also showed progressive decreases. For the contralateral control and round window membrane surgical control ears, there were no significant changes in either DPOAE or ABR thresholds. CONCLUSION: These results document a progressive loss of hearing acuity postimplantation and strongly suggest that electrode insertion trauma generated oxidative stress within injured cochlear tissues.

Animals↗

PubMed2005

Mild hypothermia protects auditory function during cochlear implant surgery.

OBJECTIVE/HYPOTHESIS: Loss of auditory function after cochlear implant (CI) electrode insertion occurs in two stages in the laboratory rat. An immediate loss is followed by a progressive loss over 7 days. Similar stages of acute and progressive neuronal loss occur after trauma in the central nervous system where hypothermia has been shown to have a protective effect. We hypothesize that hypothermia has a similar protective effect against loss of auditory function caused by CI electrode insertion trauma. METHODS: Thirty rats underwent surgery in one cochlea; the contralateral ear was an unoperated control. In the normothermia group, CI electrode insertion trauma was generated with rectal temperature maintained at 37 degrees C throughout the experiment. In the mild hypothermia group, electrode trauma was generated with rectal temperature lowered to 34 degrees C. In the surgical control group, mock surgery was performed at 37 degrees C. Multiple frequency auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) testing of all ears was performed before surgery, immediately afterward, and on postoperative days 3, 5, and 7. RESULTS: Both ABR and DPOAE testing demonstrated partial loss of auditory function after electrode insertion trauma. However, the hypothermia group had significantly less functional loss in the immediate stage and no significant loss in the progressive stage. CONCLUSION: Mild hypothermia protects auditory function during CI electrode insertion.

Animals↗

PubMed2004

Caspase inhibitors, but not c-Jun NH2-terminal kinase inhibitor treatment, prevent cisplatin-induced hearing loss.

Cisplatin (CDDP) is a highly effective chemotherapeutic agent but with significant ototoxic side effects. Apoptosis is an important mechanism of cochlear hair cell loss following exposure to an ototoxic level of CDDP. This study examines intracellular pathways involved in hair cell death induced by CDDP exposure in vivo to develop effective therapeutic strategies to protect the auditory receptor from CDDP-initiated hearing loss. Guinea pigs were treated with systemic administration of CDDP. Cochlear hair cells from CDDP-treated animals exhibited classic apoptotic alterations in their morphology. Several important signaling events that regulate the death of CDDP-injured cochlear hair cells were identified. CDDP treatment induced the activation and redistribution of cytosolic Bax and the release of cytochrome c from injured mitochondria. Activation of caspase-9 and caspase-3, but not caspase-8, was detected after treatment with CDDP, and the cleavage of fodrin by activated caspase-3 was observed within damaged hair cells. Intracochlear perfusions with caspase-3 inhibitor (z-DEVD-fmk) and caspase-9 inhibitor (z-LEHD-fmk) prevent hearing loss and loss of sensory cells, but caspase-8 inhibitor (z-IETD-fmk) and cathepsin B inhibitor (z-FA-fmk) do not. Although the stress-activated protein kinase/c-Jun NH(2)-terminal kinase (JNK) signaling pathway is activated in response to CDDP toxicity, intracochlear perfusion of d-JNKI-1, a JNK inhibitor, did not protect against CDDP ototoxicity but instead potentiated the ototoxic effects of CDDP. The results of the present study show that blocking a critical step in apoptosis may be a useful strategy to prevent harmful side effects of CDDP ototoxicity in patients having to undergo chemotherapy.

Animals↗

PubMed2004

Evaluation of hearing and auditory nerve function by combining ABR, DPOAE and eABR tests into a single recording session.

In this article, we describe an efficient method for testing both auditory receptor and auditory nerve function in a single recording session. Auditory receptor function is tested in response to pure tone, tone burst and click acoustic stimuli (i.e. distortion products of otoacoustic emissions, DPOAE; and auditory-evoked brainstem responses, ABR). The function of the auditory neurons and nerve is measured in response to direct electric current stimulation (i.e. electrically evoked auditory brainstem responses, eABR). All measurements were obtained from anesthetized laboratory rats during single recording sessions using hardware and software stimulation and analysis programs developed by Intelligent Hearing Systems, Miami, FL.

Acoustic Stimulation↗

PubMed2004

Hmx2 and Hmx3 homeobox genes direct development of the murine inner ear and hypothalamus and can be functionally replaced by Drosophila Hmx.

The Hmx homeobox gene family appears to play a conserved role in CNS development in all animal species examined, and in higher vertebrates has an additional role in sensory organ development. Here, we show that murine Hmx2 and Hmx3 have both overlapping and distinct functions in the development of the inner ear's vestibular system, whereas their functions in the hypothalamic/pituitary axis of the CNS appear to be interchangeable. As in analogous knockin studies of Otx and En function, Drosophila Hmx can rescue conserved functions in the murine CNS. However, in contrast to Otx and En, Drosophila Hmx also rescues significant vertebrate-specific functions outside the CNS. Our work suggests that the evolution of the vertebrate inner ear may have involved (1) the redeployment of ancient Hmx activities to regulate the cell proliferation of structural components and (2) the acquisition of additional, vertebrate-specific Hmx activities to regulate the sensory epithelia.

Animals↗

PubMed2003

Arrest of apoptosis in auditory neurons: implications for sensorineural preservation in cochlear implantation.

HYPOTHESIS: The JNK/c-Jun cell death pathway is a major pathway responsible for the loss of oxidative stress-damaged auditory neurons. BACKGROUND: Implantation of patients with residual hearing accentuates the need to preserve functioning sensorineural elements. Although some auditory function may survive electrode insertion, the probability of initiating an ongoing loss of auditory neurons and hair cells is unknown. Cochlear implantation can potentially generate oxidative stress, which can initiate the cell death of both auditory neurons and hair cells. METHODS: Dissociated cell cultures of P4 rat auditory neurons identified the apoptotic pathway initiated by oxidative stress insults (e.g., loss of trophic factor support) and characterized this pathway by arresting translation of pathway-specific mRNA with antisense oligonucleotide treatment and with the use of pathway specific inhibitors. The presence or absence of apoptosis-specific protein and changes in the level of neuronal survival measured the efficacy of these interventional strategies. RESULTS: These in vitro studies identified the JNK/c-Jun cascade as a major initiator of apoptosis of auditory neurons in response to oxidative stress. Neurons pretreated with c-jun antisense oligonucleotide and exposed to high levels of oxidative stress were rescued from apoptosis, whereas neurons in treatment control cultures died. Treatment of oxidative-stressed cultures with either curcumin, a MAPKKK pathway inhibitor, or PD-098059, a MEK1 inhibitor, blocked loss of neurons via the JNK/c-Jun apoptotic pathway. CONCLUSION: Blocking the JNK/c-Jun cell death pathway is a feasible approach to treating oxidative stress-induced apoptosis within the cochlea and may have application as an otoprotective strategy during cochlear implantation.

Animals↗

PubMed2003

Pharmacologic manipulation of the labyrinth with novel and traditional agents delivered to the inner ear.

We describe the methodology and rationale behind the delivery of therapeutic medicines to the inner ear. The inner ear has long been impervious to pharmacologic manipulation. This is most likely the result of a protective mechanism called the blood-labyrinth barrier, whose function closely resembles that of the blood-brain barrier. This protective barrier impedes the clinician's ability to treat inner ear diseases with systemically administered medications. Since 1935, otolaryngologists have attempted to manipulate the inner ear with trans-tympanically injected medicines. Success has varied widely, but medicinal ablation of vestibular function can be achieved in this manner. Unfortunately, the auditory system is also at great risk from any medicine that is delivered to the inner ear via the middle ear. Over the past 10 years, significant improvements in drug delivery have allowed for more "titratable" treatment, which has reduced (but not eliminated) the risk of permanent hearing loss. In this article, we discuss both novel and time-tested methods of delivering medicines to the inner ear. We also review the classes of medications that alter inner ear function and the attendant risks of such treatments.

Aminoglycosides↗

PubMed2002

Proliferative generation of mammalian auditory hair cells in culture.

Hair cell (HC) and supporting cell (SC) productions are completed during early embryonic development of the mammalian cochlea. This study shows that acutely dissociated cells from the newborn rat organ of Corti, developed into so-called otospheres consisting of 98% nestin (+) cells when plated on a non-adherent substratum in the presence of either epidermal growth factor (EGF) or fibroblast growth factor (FGF2). Within cultured otospheres, nestin (+) cells were shown to express EGF receptor (EGFR) and FGFR2 and rapidly give rise to newly formed myosin VIIA (+) HCs and p27(KIP1) (+) SCs. Myosin VIIA (+) HCs had incorporated bromodeoxyuridine (BrdU) demonstrating that they were generated by a mitotic process. Ultrastructural studies confirmed that HCs had differentiated within the otosphere, as defined by the presence of both cuticular plates and stereocilia. This work raises the hypothesis that nestin (+) cells might be a source of newly generated HCs and SCs in the injured postnatal organ of Corti.

Animals↗

PubMedDate not supplied

Mechanisms of cell death in the injured auditory system: otoprotective strategies.

Oxidative stress insults such as neurotrophin withdrawal, sound trauma, hypoxia/ischemia, ototoxic antibiotics, and chemotherapeutic agents have been shown to induce apoptosis of both auditory hair cells and neurons. In this paper, we review some components of the apoptotic pathways leading to the death of hair cells and auditory induced by growth factor withdrawal or cisplatin intoxication: (1) reactive oxygen species and free radicals are formed as by-products of several metabolic pathways and these molecules can themselves cause cell damage by reacting with cellular proteins; (2) activation of caspases, and (3) activation of calpain. These mechanisms have several different points at which inhibitors could be targeted to protect cells from programmed cell death, including the prevention of oxidative stress-induced apoptosis and the activation of caspases and calpains.

Animals↗