Neurosensory responses of hearing and balance are mediated by receptors in specialized neuroepith... more Neurosensory responses of hearing and balance are mediated by receptors in specialized neuroepithelial sensory cells. Any disruption of the biochemical and molecular pathways that facilitate these responses can result in severe deficits, including hearing loss and vestibular dysfunction. Hearing is affected by both environmental and genetic factors, with impairment of auditory function being the most common neurosensory disorder affecting 1 in 500 newborns, as well as having an impact on the majority of elderly population. Damage to auditory sensory cells is not reversible, and if sufficient damage and cell death have taken place, the resultant deficit may lead to permanent deafness. Cochlear implants are considered to be one of the most successful and consistent treatments for deaf patients, but only offer limited recovery at the expense of loss of residual hearing. Recently there has been an increased interest in the auditory research community to explore the regeneration of mamma...
Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology, Feb 1, 2017
Stereotactic radiosurgery for lateral skull base tumors can cause hearing loss when the cochleae ... more Stereotactic radiosurgery for lateral skull base tumors can cause hearing loss when the cochleae are exposed to high doses of single-fraction radiation. Currently, there are no known nondosimetric preventative treatments for radiation-induced ototoxicity. Intratympanic (IT) dexamethasone (DXM), a synthetic steroid, protects against radiation-induced auditory hair cell (HC) and hearing losses in rats in vivo. Seven rats received radiation (12 Gy) to both cochleae. In irradiated rats and six nonirradiated rats, IT DXM was randomized to one ear, while tympanic puncture without DXM was performed on the contralateral ear. Baseline and 4-week postradiation auditory-evoked potential tests were performed. The cochleae were processed for HC viability. Cochleae exposed to radiation demonstrated more outer HC (OHC) loss in all turns than nonirradiated ears (p <0.05). OHCs were more susceptible to radiation injury than inner HCs in the middle and basal turns (p <0.05). In irradiated cochl...
The 16th day mouse embryo inner ear was explanted and cultured &amp;amp;amp;amp;quot;in vitro... more The 16th day mouse embryo inner ear was explanted and cultured &amp;amp;amp;amp;quot;in vitro&amp;amp;amp;amp;quot; for 6 days, which corresponds to 1 day post-partum development &amp;amp;amp;amp;quot;in vivo&amp;amp;amp;amp;quot;. A normal development occurred both when the inner ear anlage was divided into a vestibular and a cochlear portion and when it was cultured as a whole. The present model system may provide a helpful tool in the study of both normal development and inner ear pathology.
One of the causes of sensorineural hearing loss is the loss of auditory hair cells following expo... more One of the causes of sensorineural hearing loss is the loss of auditory hair cells following exposure to environmental stresses. Auditory hair cell death in response to cochlear trauma occurs via both necrosis and apoptosis. Apoptosis of hair cells involves the caspase and MAPK/JNK pathways which are activated by oxidative stress and secretion of inflammatory cytokines in response to trauma. Identification of the pathways that lead to apoptosis provides therapeutic targets for the conservation of hearing. Antioxidants reduce the level of reactive oxygen species and reactive nitrogen species generated by oxidative stress in response to acoustic trauma, aminoglycoside and platinum-based drugs. Caspase inhibitors affect both the extrinsic and intrinsic apoptotic pathways thereby reducing cisplatin, aminoglycoside, hydraulic trauma and ischemia-induced hearing losses. Corticosteroid therapy reduces inflammation and inhibits apoptosis while activating pro-survival pathways in the organ of Corti following exposure to noise, vibration, cisplatin, aminoglycoside, ischemia/reperfusion injury, bacterial meningitis and electrode insertion trauma. Inhibitors of JNK signaling pathway prevent apoptosis of auditory hair cells following electrode insertion trauma, acute labyrinthitis, acoustic trauma and aminoglycoside ototoxicity. This review provides an overview of the different pathways involved in auditory hair cell death following an environmental stress and both traditional and newly developed drugs that are currently being studied or used for the treatment of acute hearing loss. Recent patents related to otoprotective strategies to conserve hearing and auditory hair cells are also discussed in this review.
Cisplatin is an effective anti-neoplastic agent used in the treatment of squamous cell cancer of ... more Cisplatin is an effective anti-neoplastic agent used in the treatment of squamous cell cancer of the head and neck, but with serious side effects. One serious side effect is damage to both the auditory hair cells and the auditory neurons. The damage to the neurons has been shown to be a direct effect and not due to the loss of the neurotrophic support provided by the hair cells. Several neurotrophins have been shown to lessen the extent of cisplatin induced damage of auditory neurons in vitro, but these neurotrophins have had no effect on the extent of damage to the hair cells. D-methionine (D-met) has been demonstrated to provide protection against cisplatin&amp;amp;amp;amp;#39;s nephrotoxicity in vivo and ototoxicity in vitro. In this study the combination of brain derived neurotrophic factor (BDNF) with D-met has shown that both auditory neurons and auditory hair cells can be protected from cisplatin induced damage in vitro. These results demonstrate that this type of combination therapy (i.e. a neurotrophin combined with a free radical scavenger) can provide more complete protection for the auditory receptor against cisplatin toxicity than either of these agents alone. Because both BDNF and D-met have been shown to have trophic activity in vitro we proposed that the combination of these agents will also provide effective protection against cisplatin induced ototoxicity and neurotoxicity of the auditory receptor in vivo.
Recent experiments have demonstrated the effectiveness of members of the neurotrophin family of g... more Recent experiments have demonstrated the effectiveness of members of the neurotrophin family of growth factors in supporting the survival of primary auditory neurons following ototoxic trauma. In this report, we examined the implications of these results in light of current knowledge about activity dependent central nervous system reorganization. We suggest that the use of trophic factors in conjunction with patterned stimulation of afferent nerve fibers could preserve the majority of the tonotopic arrangement of the central pathway. We propose experiments to test the effects of NT-3 induced neuron survival on the organization of primary auditory cortex.
Conclusions A cocktail combining NAC, Mannitol, and Dexamethasone may be used to prevent loss of ... more Conclusions A cocktail combining NAC, Mannitol, and Dexamethasone may be used to prevent loss of residual hearing post-implantation. There is a window of opportunity to treat the cochlea before the onset of cell death in HCs. Objective Inner ear trauma caused by cochlear implant electrode insertion trauma (EIT) initiates multiple molecular mechanisms in hair cells (HCs) or support cells (SCs), resulting in initiation of programmed cell death within the damaged tissues of the cochlea, which leads to loss of residual hearing. In earlier studies L-N-acetylcysteine (L-NAC), Mannitol, and dexamethasone have been shown independently to protect the HCs loss against different types of inner ear trauma. These three molecules have different otoprotective effects. The goal of this preliminary study is to test the efficacy of a combination of these molecules to enhance the otoprotection of HCs against EIT. Methods OC explants were dissected from P-3 rats and placed in serum-free media. Explants were divided into control and experimental groups. (1) untreated controls; (2) EIT. Experimental group: (1) EIT + L-NAC (5, 2, or 1 mM); (2) EIT + Mannitol (100, 50, or 10 mM); (3) EIT + Dex (20, 10, or 5 μg/mL); (4) EIT + L-NAC + Mannitol + Dex. After EIT was caused in an in-vitro model of CI, explants were cultured in media containing L-NAC alone, Mannitol alone, or Dex alone at decreasing concentrations. Concentrations of L-NAC, Mannitol, and Dex that showed 50% protection of hair cell loss individually were used as a combination in experimental group 4. Results There was an increase of total hair cell (THC) loss in the EIT OC explants when compared with control group HC counts or the tri-therapy cochlea. This study defined the dosage of L-NAC, Mannitol, and Dex for the survival of 50% protection of hair cells in vitro. Their combination provided close to 96% protection, demonstrating an additive effect.
Objective: To compare absorbable gelatin sponge (AGS) with polyurethane foam (PUF) as middle ear ... more Objective: To compare absorbable gelatin sponge (AGS) with polyurethane foam (PUF) as middle ear packing material after mucosal trauma. Method: Controlled animal experiment. Thirty-six guinea pigs underwent middle ear surgery with mucosal trauma performed on both ears. One ear was packed with either PUF or AGS. Contralateral ears were used as nonpacked paired controls. Auditory brainstem response (ABR) thresholds were measured preoperatively and repeated at 1, 2, and 6 weeks postoperatively. Histological analysis was done by a pathologist blinded to the type of packing using hematoxylin and eosin staining to measure inflammatory reaction and trichome staining to measure fibrosis in each group. Results: ABR recordings demonstrates that threshold level changes from baseline were minor in the PUF and the control groups. Threshold levels were higher in the AGS group compared with both control groups and the PUF group for the 1 KHz and 0.5 KHz frequencies. Macoscopic analysis showed no t...
The management of hearing loss in adults depends of etiology and its severity. It can be as simpl... more The management of hearing loss in adults depends of etiology and its severity. It can be as simple as treating an external otitis, removing an impacted cerumen or a more complex one such as a surgery for otosclerosis. The hearing loss is managed mainly by new advances in hearing aids technology and implantable hearing devices which include BAHA, middle ear implant and cochlear implants. The research is focused on developing new molecules for intracochlear drug therapy to treat noise induced hearing loss, drug ototoxicity as well as hearing loss related to cochlear implant insertion trauma. Antioxidant molecules, molecules against apoptosis are at this time the most promising molecules than need further investigations.
We describe the methodology and rationale behind the delivery of therapeutic medicines to the inn... more 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 perman...
Neurosensory responses of hearing and balance are mediated by receptors in specialized neuroepith... more Neurosensory responses of hearing and balance are mediated by receptors in specialized neuroepithelial sensory cells. Any disruption of the biochemical and molecular pathways that facilitate these responses can result in severe deficits, including hearing loss and vestibular dysfunction. Hearing is affected by both environmental and genetic factors, with impairment of auditory function being the most common neurosensory disorder affecting 1 in 500 newborns, as well as having an impact on the majority of elderly population. Damage to auditory sensory cells is not reversible, and if sufficient damage and cell death have taken place, the resultant deficit may lead to permanent deafness. Cochlear implants are considered to be one of the most successful and consistent treatments for deaf patients, but only offer limited recovery at the expense of loss of residual hearing. Recently there has been an increased interest in the auditory research community to explore the regeneration of mamma...
Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology, Feb 1, 2017
Stereotactic radiosurgery for lateral skull base tumors can cause hearing loss when the cochleae ... more Stereotactic radiosurgery for lateral skull base tumors can cause hearing loss when the cochleae are exposed to high doses of single-fraction radiation. Currently, there are no known nondosimetric preventative treatments for radiation-induced ototoxicity. Intratympanic (IT) dexamethasone (DXM), a synthetic steroid, protects against radiation-induced auditory hair cell (HC) and hearing losses in rats in vivo. Seven rats received radiation (12 Gy) to both cochleae. In irradiated rats and six nonirradiated rats, IT DXM was randomized to one ear, while tympanic puncture without DXM was performed on the contralateral ear. Baseline and 4-week postradiation auditory-evoked potential tests were performed. The cochleae were processed for HC viability. Cochleae exposed to radiation demonstrated more outer HC (OHC) loss in all turns than nonirradiated ears (p <0.05). OHCs were more susceptible to radiation injury than inner HCs in the middle and basal turns (p <0.05). In irradiated cochl...
The 16th day mouse embryo inner ear was explanted and cultured &amp;amp;amp;amp;quot;in vitro... more The 16th day mouse embryo inner ear was explanted and cultured &amp;amp;amp;amp;quot;in vitro&amp;amp;amp;amp;quot; for 6 days, which corresponds to 1 day post-partum development &amp;amp;amp;amp;quot;in vivo&amp;amp;amp;amp;quot;. A normal development occurred both when the inner ear anlage was divided into a vestibular and a cochlear portion and when it was cultured as a whole. The present model system may provide a helpful tool in the study of both normal development and inner ear pathology.
One of the causes of sensorineural hearing loss is the loss of auditory hair cells following expo... more One of the causes of sensorineural hearing loss is the loss of auditory hair cells following exposure to environmental stresses. Auditory hair cell death in response to cochlear trauma occurs via both necrosis and apoptosis. Apoptosis of hair cells involves the caspase and MAPK/JNK pathways which are activated by oxidative stress and secretion of inflammatory cytokines in response to trauma. Identification of the pathways that lead to apoptosis provides therapeutic targets for the conservation of hearing. Antioxidants reduce the level of reactive oxygen species and reactive nitrogen species generated by oxidative stress in response to acoustic trauma, aminoglycoside and platinum-based drugs. Caspase inhibitors affect both the extrinsic and intrinsic apoptotic pathways thereby reducing cisplatin, aminoglycoside, hydraulic trauma and ischemia-induced hearing losses. Corticosteroid therapy reduces inflammation and inhibits apoptosis while activating pro-survival pathways in the organ of Corti following exposure to noise, vibration, cisplatin, aminoglycoside, ischemia/reperfusion injury, bacterial meningitis and electrode insertion trauma. Inhibitors of JNK signaling pathway prevent apoptosis of auditory hair cells following electrode insertion trauma, acute labyrinthitis, acoustic trauma and aminoglycoside ototoxicity. This review provides an overview of the different pathways involved in auditory hair cell death following an environmental stress and both traditional and newly developed drugs that are currently being studied or used for the treatment of acute hearing loss. Recent patents related to otoprotective strategies to conserve hearing and auditory hair cells are also discussed in this review.
Cisplatin is an effective anti-neoplastic agent used in the treatment of squamous cell cancer of ... more Cisplatin is an effective anti-neoplastic agent used in the treatment of squamous cell cancer of the head and neck, but with serious side effects. One serious side effect is damage to both the auditory hair cells and the auditory neurons. The damage to the neurons has been shown to be a direct effect and not due to the loss of the neurotrophic support provided by the hair cells. Several neurotrophins have been shown to lessen the extent of cisplatin induced damage of auditory neurons in vitro, but these neurotrophins have had no effect on the extent of damage to the hair cells. D-methionine (D-met) has been demonstrated to provide protection against cisplatin&amp;amp;amp;amp;#39;s nephrotoxicity in vivo and ototoxicity in vitro. In this study the combination of brain derived neurotrophic factor (BDNF) with D-met has shown that both auditory neurons and auditory hair cells can be protected from cisplatin induced damage in vitro. These results demonstrate that this type of combination therapy (i.e. a neurotrophin combined with a free radical scavenger) can provide more complete protection for the auditory receptor against cisplatin toxicity than either of these agents alone. Because both BDNF and D-met have been shown to have trophic activity in vitro we proposed that the combination of these agents will also provide effective protection against cisplatin induced ototoxicity and neurotoxicity of the auditory receptor in vivo.
Recent experiments have demonstrated the effectiveness of members of the neurotrophin family of g... more Recent experiments have demonstrated the effectiveness of members of the neurotrophin family of growth factors in supporting the survival of primary auditory neurons following ototoxic trauma. In this report, we examined the implications of these results in light of current knowledge about activity dependent central nervous system reorganization. We suggest that the use of trophic factors in conjunction with patterned stimulation of afferent nerve fibers could preserve the majority of the tonotopic arrangement of the central pathway. We propose experiments to test the effects of NT-3 induced neuron survival on the organization of primary auditory cortex.
Conclusions A cocktail combining NAC, Mannitol, and Dexamethasone may be used to prevent loss of ... more Conclusions A cocktail combining NAC, Mannitol, and Dexamethasone may be used to prevent loss of residual hearing post-implantation. There is a window of opportunity to treat the cochlea before the onset of cell death in HCs. Objective Inner ear trauma caused by cochlear implant electrode insertion trauma (EIT) initiates multiple molecular mechanisms in hair cells (HCs) or support cells (SCs), resulting in initiation of programmed cell death within the damaged tissues of the cochlea, which leads to loss of residual hearing. In earlier studies L-N-acetylcysteine (L-NAC), Mannitol, and dexamethasone have been shown independently to protect the HCs loss against different types of inner ear trauma. These three molecules have different otoprotective effects. The goal of this preliminary study is to test the efficacy of a combination of these molecules to enhance the otoprotection of HCs against EIT. Methods OC explants were dissected from P-3 rats and placed in serum-free media. Explants were divided into control and experimental groups. (1) untreated controls; (2) EIT. Experimental group: (1) EIT + L-NAC (5, 2, or 1 mM); (2) EIT + Mannitol (100, 50, or 10 mM); (3) EIT + Dex (20, 10, or 5 μg/mL); (4) EIT + L-NAC + Mannitol + Dex. After EIT was caused in an in-vitro model of CI, explants were cultured in media containing L-NAC alone, Mannitol alone, or Dex alone at decreasing concentrations. Concentrations of L-NAC, Mannitol, and Dex that showed 50% protection of hair cell loss individually were used as a combination in experimental group 4. Results There was an increase of total hair cell (THC) loss in the EIT OC explants when compared with control group HC counts or the tri-therapy cochlea. This study defined the dosage of L-NAC, Mannitol, and Dex for the survival of 50% protection of hair cells in vitro. Their combination provided close to 96% protection, demonstrating an additive effect.
Objective: To compare absorbable gelatin sponge (AGS) with polyurethane foam (PUF) as middle ear ... more Objective: To compare absorbable gelatin sponge (AGS) with polyurethane foam (PUF) as middle ear packing material after mucosal trauma. Method: Controlled animal experiment. Thirty-six guinea pigs underwent middle ear surgery with mucosal trauma performed on both ears. One ear was packed with either PUF or AGS. Contralateral ears were used as nonpacked paired controls. Auditory brainstem response (ABR) thresholds were measured preoperatively and repeated at 1, 2, and 6 weeks postoperatively. Histological analysis was done by a pathologist blinded to the type of packing using hematoxylin and eosin staining to measure inflammatory reaction and trichome staining to measure fibrosis in each group. Results: ABR recordings demonstrates that threshold level changes from baseline were minor in the PUF and the control groups. Threshold levels were higher in the AGS group compared with both control groups and the PUF group for the 1 KHz and 0.5 KHz frequencies. Macoscopic analysis showed no t...
The management of hearing loss in adults depends of etiology and its severity. It can be as simpl... more The management of hearing loss in adults depends of etiology and its severity. It can be as simple as treating an external otitis, removing an impacted cerumen or a more complex one such as a surgery for otosclerosis. The hearing loss is managed mainly by new advances in hearing aids technology and implantable hearing devices which include BAHA, middle ear implant and cochlear implants. The research is focused on developing new molecules for intracochlear drug therapy to treat noise induced hearing loss, drug ototoxicity as well as hearing loss related to cochlear implant insertion trauma. Antioxidant molecules, molecules against apoptosis are at this time the most promising molecules than need further investigations.
We describe the methodology and rationale behind the delivery of therapeutic medicines to the inn... more 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 perman...
The cochleo-vestibular ganglion (CVG) contains the neurons connecting the sensory epithelia of th... more The cochleo-vestibular ganglion (CVG) contains the neurons connecting the sensory epithelia of the inner ear to the cochlear and vestibular nuclei in the medulla. Expression of trkB protein-like immunoreactivity was studied in the developing CVG, using both Western blot and immunocytochemistry on tissue sections. Specific immunoreactivity was observed in the CVG from the 12th gestation day (gd) to the first postnatal week, reflecting the presence of high-affinity receptors for brain-derived neurotrophic factor (BDNF), a member of the NGF family of neurotrophins. Whole explants and dissociated cell cultures of cochlear (CG) and vestibular ganglion (VG) from mouse embryos and postnatal specimens were grown in neurotrophin-free medium to assay changes in neurite outgrowth and neuronal survival in response to the addition of physiological concentrations (0–5 ng/ml) of BDNF. Exogenous BDNF (2 ng/ml) promoted neurite outgrowth and neuronal survival in explants of both CG and VG, and the effects were stage-dependent. The onset of the response to BDNF occurred at gd 11–12. The response then reached a maximum between 14 and 18 gd and subsequently decreased, although it remained significantly present during the first postnatal week. BDNF-induced response was no longer observed in the mature cochlear and vestibular ganglion (after 30 postnatal days). The effects of BDNF on neuronal differentiation and survival were dose-dependent, starting at 0.5 ng/ml, with saturation at 2 ng/ml and half-maximal effect occurring between 1 and 1.5 ng/ml. On the basis of our results, we propose that BDNF may be physiologically involved in the control of both neuronal differentiation, and central and peripheral target-dependent neuronal death, in the CVG of embryos and early postnatal mice. BDNF may act alone or in cooperation with other neurotrophins to establish the afferent innervation of the inner ear sensory epithelium.
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Papers by Thomas Van De Water