Biomedical subjects

A Zine

Publications and source records attributed to A Zine.

12 recordsLinked to original sources

PubMed2004

The MAPK/JNK signalling pathway offers potential therapeutic targets for the prevention of acquired deafness.

The c-Jun N-terminal kinases (JNKs) are also called stress activated protein kinases (SAPKs) and are members of the family of mitogen activated protein kinases (MAPKs). While the functions of the JNKs under physiological conditions are diverse and not completely understood, there is increasing evidence that JNKs are potent effectors of apoptosis of oxidative stress-damaged cells in both the brain and the mammalian inner ear following a trauma. The activation of the inducible transcription factor c-Jun by N-terminal phosphorylation is a central event in JNK-mediated apoptosis of oxidative stress-damaged auditory hair cells following exposure to either acoustic trauma or a toxic level of an aminoglycoside antibiotic and also the apoptosis of auditory neurons as a consequence of a loss of the trophic support provided by the auditory hair cells. In this review, we summarise what is known about the expression and activation of G-proteins, JNKs, c-Jun and c-Fos under oxidative stress conditions within the mammalian cochlea. A particular focus is put on a new peptide conjugate that is a promising protective agent(s) and pharmacological strategies for preventing cochlear damage induced by both acoustic trauma and aminoglycoside ototoxic damage.

Aminoglycosides↗

PubMed2003

A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss.

Hearing loss can be caused by a variety of insults, including acoustic trauma and exposure to ototoxins, that principally effect the viability of sensory hair cells via the MAP kinase (MAPK) cell death signaling pathway that incorporates c-Jun N-terminal kinase (JNK). We evaluated the otoprotective efficacy of D-JNKI-1, a cell permeable peptide that blocks the MAPK-JNK signal pathway. The experimental studies included organ cultures of neonatal mouse cochlea exposed to an ototoxic drug and cochleae of adult guinea pigs that were exposed to either an ototoxic drug or acoustic trauma. Results obtained from the organ of Corti explants demonstrated that the MAPK-JNK signal pathway is associated with injury and that blocking of this signal pathway prevented apoptosis in areas of aminoglycoside damage. Treatment of the neomycin-exposed organ of Corti explants with D-JNKI-1 completely prevented hair cell death initiated by this ototoxin. Results from in vivo studies showed that direct application of D-JNKI-1 into the scala tympani of the guinea pig cochlea prevented nearly all hair cell death and permanent hearing loss induced by neomycin ototoxicity. Local delivery of D-JNKI-1 also prevented acoustic trauma-induced permanent hearing loss in a dose-dependent manner. These results indicate that the MAPK-JNK signal pathway is involved in both ototoxicity and acoustic trauma-induced hair cell loss and permanent hearing loss. Blocking this signal pathway with D-JNKI-1 is of potential therapeutic value for long-term protection of both the morphological integrity and physiological function of the organ of Corti during times of oxidative stress.

Acoustic Stimulation↗

PubMed2001

Hes1 and Hes5 activities are required for the normal development of the hair cells in the mammalian inner ear.

The mammalian inner ear contains two sensory organs, the cochlea and vestibule. Their sensory neuroepithelia are characterized by a mosaic of hair cells and supporting cells. Cochlear hair cells differentiate in four rows: a single row of inner hair cells (IHCs) and three rows of outer hair cells (OHCs). Recent studies have shown that Math1, a mammalian homolog of Drosophila atonal is a positive regulator of hair cell differentiation. The basic helix-loop-helix (bHLH) genes Hes1 and Hes5 (mammalian hairy and Enhancer-of-split homologs) can influence cell fate determination by acting as negative regulators to inhibit the action of bHLH-positive regulators. We show by using reverse transcription-PCR analysis that Hes1, Hes5, and Math1 are expressed in the developing mouse cochleae. In situ hybridization revealed a widespread expression of Hes1 in the greater epithelial ridge (GER) and in lesser epithelial ridge (LER) regions. Hes5 is predominantly expressed in the LER, in supporting cells, and in a narrow band of cells within the GER. Examination of cochleae from Hes1(-/-) mice showed a significant increase in the number of IHCs, whereas cochleae from Hes5(-/-) mice showed a significant increase in the number of OHCs. In the vestibular system, targeted deletion of Hes1 and to a lesser extent Hes5 lead to formation of supernumerary hair cells in the saccule and utricle. The supernumerary hair cells in the mutant mice showed an upregulation of Math1. These data indicate that Hes1 and Hes5 participate together for the control of inner ear hair cell production, likely through the negative regulation of Math1.

Animals↗

PubMed2000

Spatial expression patterns of epidermal growth factor receptor gene transcripts in the postnatal mammalian cochlea.

Recent in vitro studies demonstrated that members of the epidermal growth factor (EGF) family are involved in hair cell replacement in the postnatal mammalian organ of Corti (OC) after ototoxic damage. This suggests a role for the EGF receptor (EGFR) in this process. We examined the expression of EGFR mRNA within the normal postnatal day 3 (P3) and adult rat cochlear epithelium by RT-PCR and examined its cellular localization with non-radioactive in situ hybridization in P3 and adult cochleae. RT-PCR demonstrated that EGFR mRNA is expressed in P3 and adult cochlear epithelium. In situ hybridization localized high levels of EGFR transcripts in the OC, spiral ganglion, Kölliker's organ and detectable levels in the supporting cells and the stria vascularis of P3 cochlea. In the adult cochlea, EGFR transcripts were detected only in the spiral ganglion. Our results support that the EGFR is implicated in the differentiation of several cochlear cell types and in the response of OC to ototoxic damage of the P3 rat. In the adult, it may participate in the maintenance of the mature neurons and its absence in the OC may contribute to the lack of regenerative responses in the adult cochlea.

Animals↗

PubMed2000

[Hereditary neuropathy with tendency to pressure palsies (HNPP) in a child: clinical and biological diagnosis. A case report].

UNLABELLED: HNPP occurs rarely but not exceptionally during childhood. CASE REPORT: José M., seven years old, presented an isolated radial nerve palsy of progressive onset with no other clinical feature. There was no family history of neurological disorder. The electromyogram (EMG) showed a 'mosaic-like' pattern of extended sensitive and motor alterations, with diminished conduction velocities and amplitudes and increased distal latencies. HNPP was considered through the association of an isolated radial nerve palsy with an asymptomatic polyneuropathy, and was confirmed by molecular biology. CONCLUSION: HNPP is generally considered on clinical features, heredity and EMG findings. Molecular biology confirms the diagnosis in most of the cases, even in apparently sporadic patients, and is of great interest in atypical cases.

Child↗

PubMed2000

Notch signaling regulates the pattern of auditory hair cell differentiation in mammals.

The development of the mammalian cochlea is an example of patterning in the peripheral nervous system. Sensory hair cells and supporting cells in the cochlea differentiate via regional and cell fate specification. The Notch signaling components shows both distinct and overlapping expression patterns of Notch1 receptor and its ligands Jagged1 (Jag1) and Jagged2 (Jag2) in the developing auditory epithelium of the rat. On embryonic day 16 (E16), many precursor cells within the Kölliker's organ immunostained for the presence of both Notch1 and Jag1, while the area of hair cell precursors did not express either Notch1 and Jag1. During initial events of hair cell differentiation between E18 and birth, Notch1 and Jag1 expression predominated in supporting cells and Jag2 in nascent hair cells. Early after birth, Jag2 expression decreased in hair cells while the pattern of Notch1 expression now included both supporting cells and hair cells. We show that the normal pattern of hair cell differentiation is disrupted by alteration of Notch signaling. A decrease of either Notch1 or Jag1 expression by antisense oligonucleotides in cultures of the developing sensory epithelium resulted in an increase in the number of hair cells. Our data suggest that the Notch1 signaling pathway is involved in a complex interplay between the consequences of different ligand-Notch1 combinations during cochlear morphogenesis and the phases of hair cell differentiation.

Animals↗

PubMed1999

Tissue-specific levels and cellular distribution of epidermal growth factor receptors within control and neomycin-damaged neonatal rat Organ of Corti.

Epidermal growth factor receptor (EGFR) levels were assayed by an enzyme-linked immunosorbent assay (ELISA) in microdissected organ of Corti (OC) from neonatal rats directly after isolation and after 3 days in culture with and without neomycin treatment. In addition, the cellular distribution of the EGFR in the OC was determined by immunohistochemistry. The in vitro level of EGFR determined by ELISA assays doubled after neomycin damage to OC, suggesting that EGFR is subject to up-regulation following this treatment. Immunohistochemistry of both in vivo and in vitro controls indicates that EGFR is predominantly localized in the stereociliary bundles of the hair cells; supporting cells and the apical junctions between the remaining Kolliker organ cells were also immunolabeled. In neomycin-treated cultures, sensory cells were degenerated, so no labeling could be seen. However, supporting and Kolliker organ cells continued to show labeling. In addition, nerve fibers in the region of the future osseous spiral lamina and projecting out toward the damaged sensory epithelium were immunostained. The up-regulation of the EGFR and its redistribution within the OC following neomycin damage support the earlier observation that growth factors that act through EGFR, such as EGF and transforming growth factor-alpha can induce neonatal mammalian auditory hair cell replacement under culture conditions, after aminoglycoside treatment.

Animals↗

PubMed1998

Replacement of mammalian auditory hair cells.

We investigated the potential for hair cell regeneration in neonatal rat organs of Corti grown in culture following destruction of hair cells by neomycin toxicity. Replacement hair cells were observed by light and scanning electron microscopy in lesion sites in the cultures treated with transforming growth factor-alpha, epidermal growth factor or a combination of both factors for 5-7 days post-injury. These new cells had morphological characteristics of immature hair cells. Autoradiographic localization of [3H]thymidine-labelled cells on semi-thin sections indicated that these replacement hair cells did not arise through renewed mitotic division, although an important mitotic proliferation was observed outside the area of supporting and sensory cells.

Animals↗

PubMed1997

Localization of proteins associated with the outer hair cell plasma membrane in the gerbil cochlea.

There is substantial evidence that the motility of mammalian outer hair cells is generated close to or within the plasma membrane. Several analogies between the outer hair cell cortical lattice and the membrane-related cytoskeleton of erythrocytes have been noted. In erythrocytes a member of the anion exchanger protein family, AE1, also known as Band 3, is involved in membrane-cytoskeleton linkage via Protein 4.1. In the following paper, the presence of these two proteins in gerbilline outer hair cells is confirmed by western blot. Furthermore, co-localization of these two proteins was detected in the lateral wall of outer hair cells by immunofluorescence and postembedding electron immunohistochemistry. Band 3 is restricted to this region, whereas Protein 4.1 has a somewhat more dispersed distribution. Thus, the structure of these sensory receptor cells may result from an adaptation of a strategy used by other motile cells. The proteins investigated likely have a support function and may comprise "pillars" seen between the lateral plasma membrane and the cytoskeleton in micrographs of outer hair cells. The possibility that Band 3 comprises "protein particles" seen in the lateral plasma membrane, or maybe directly involved in the voltage-dependent force generation in outer hair cells, is also discussed.

Animals↗

PubMed1996

Development of intracellular Ca-ATPase in the gerbil outer hair cell lateral wall.

The development of Ca-ATPase immunoreactivity in gerbil outer hair cells (OHCs), assayed by immunofluorescence and postembedding immunocytochemistry, is reported here. In the adult, a linear array of label is seen inside the lateral plasma membrane. The ultrastructural distribution of Ca-ATPase near the OHC lateral plasma membrane was examined using immunogold cytochemistry and showed this calcium pumping enzyme to be present throughout the subsurface cisternal complex (SSC), especially near the innermost layers. During development, Ca-ATPase immunoreactivity appeared in patches near the lateral plasma membrane of some OHCs of the third row by 12 days after birth (DAB). By 15-16 DAB, punctate immunoreactivity was detected in the second and first rows. At 20 DAB, immunostaining near OHC lateral plasma membrane was increased, but was less continuous than OHC staining in the adult cochlea. The appearance of Ca-ATPase in OHCs coincides with the onset of auditory function and isolated OHC motility in the gerbil. The ultrastructural demonstration of abundant sites of calcium pumps in the SSC supports a role for this structure in the intracellular storage of calcium. These findings suggest a possible role of Ca-ATPase and the SSC in the regulation of slow motility of OHCs which has been reported to depend on intracellular calcium concentration.

Animals↗

PubMed1996

Development of the auditory receptors of the rat: a SEM study.

Fetal and postnatal ontogenesis of the rat cochlea, from the 16th gestational day (16DG) until 3 months post partum, were studied using scanning electron microscopy with emphasis on the stereocilia during the earliest stages of development. The epithelium of the cochlear duct in 16DG rat consisted of plygonal cells topped with numerous microvilli and one central kinocilium, which form the so-called Kölliker's organ. Inner hair cells (IHCs) appeared at 18DG in the basal cochlea. They were characterized by tufts of cilia of the same height and with a kinocilium. The first outer hair cells (OHCs) can be seen at 20DG. The earliest stages of ciliary differentiation, at 18DG for IHCs and 20DG for OHCs, were similar on both types of cells and were characterized by the presence of round bundles of cilia arising from the surrounding microvilli. A three-dimensional V-shaped organization for OHCs and the linear arrangement for IHCs appeared by the end of the first postnatal week, accompanied by the disappearance of transient cilia on the modiolar side of the hair cell and the kinocilium on the external side. The apical pole of OHCs reached adult-like morphology before that of IHCs. Various links between stereocilia were detected already at birth. Morphometric analysis showed that auditory cells from the base of the cochlea reached adult size by the end of the first postnatal week while those from the apex increased their size later. A review of the literature including comparative observations across species on the ontogenesis of the stereocilia shows that hair cells of the stato-acoustic system may present the same early ontogenesis.

Animals↗

PubMed1995

Fimbrin expression in the developing rat cochlea.

The expression of fimbrin in the developing rat cochlea was analyzed using an immunohistochemical technique with fimbrin antibody. The cochlea displayed temporal and lateral-longitudinal gradients for fimbrin expression during development. Fimbrin immunoreactivity first appeared in the inner hair cell stereocilia of the basal turn on the first gestational day studied (day 18). At birth, both inner (IHC) and outer hair cell (OHC) stereocilia of the basal turn showed positive labeling with fimbrin antibody. The progression of appearance was always from IHCs to OHCs and fimbrin immunostaining appeared in the apical hair cells by postnatal day 6. Immunostaining was restricted to stereocilia and the cuticular plate, and no immunoreactivity was observed in neighboring structures of the epithelium. Double labeling using both fimbrin antibody and phalloidin binding revealed similar chronological expression from the earliest stage studied. Increasing fimbrin immunoreactivity was observed in hair cells until late postnatal and adult stages. This study suggests that fimbrin is expressed with F-actin during development and fimbrin together with actin may constitute the two basic molecules that participate in stereocilia formation. We speculate that fimbrin may help maintain the parallel growth of actin filaments within the stereocilia. These data additionally support previous findings that hair cell maturation occurs from the base to the apex and from IHCs to OHCs.

Actins↗