scholarly journals HIF-1α as a Target Molecule in the Use of Triazino-Indole Derivative on the Acoustic Trauma Model

2021 ◽  
Vol 11 (3) ◽  
pp. 365-372
Author(s):  
Vladimir L. Pastushenkov ◽  
Leonid G. Buynov ◽  
Maksim S. Kuznetsov ◽  
Vladimir V. Dvorianchikov ◽  
Lev A. Glaznikov ◽  
...  
Keyword(s):  
Hair Cells ◽  
Indole Derivative ◽  
Hypoxia Inducible Factor ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Acoustic Trauma ◽  
Drug Dose ◽  
F1 Hybrids ◽  
Target Molecule ◽  
Trauma Model

The effect of triazino-indole derivative (Trisan) on hypoxia-inducible factor (HIF) expression level in the organ of Corti, when administering it for therapeutic and preventive purposes, was investigated using an acoustic trauma model in experimental animals (female F1 hybrids of CBA and C57BL/6 lines). Cytoflavin was used as a comparator product. Study product Trisan (1% solution) was injected intravenously, intramuscularly and intraperitoneally, in the dose of 5, 7 and 10 mg/kg 2 h after the acoustic trauma for therapeutic purposes and in the dose of 5, 7 and 10 mg/kg for 3 days before the acoustic trauma for preventive purposes. IHC methods were used to investigate the organ of Corti. Trisan was observed to increase HIF expression in hair cells and neurons of the spiral ganglion in case of acoustic trauma. Depending on the dose, the increased HIF-1 expression in hair cells and spiral ganglion occurred both after therapeutic and preventive use of Trisan. Maximum HIF expression in hair cells and ganglion was noted at the therapeutic and preventive drug dose of 10 mg/kg. Following experimental results, we conclude that the otoprotective effect of triazino-indole derivative is realized via its effect on HIF metabolism, which makes it a target molecule for the drug.

scholarly journals Induction of Redox-Active Gene Expression by CoCl2 Ameliorates Oxidative Stress-Mediated Injury of Murine Auditory Cells

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 399 ◽  
Author(s):  
Jhang Ho Pak ◽  
Junyeong Yi ◽  
Sujin Ryu ◽  
In Ki Kim ◽  
Jung-Woong Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ganglion Cells ◽  
Stria Vascularis ◽  
Hypoxia Inducible Factor ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Luciferase Reporter ◽  
Related Factor ◽  
Redox Active

Free radicals formed in the inner ear in response to high-intensity noise, are regarded as detrimental factors for noise-induced hearing loss (NIHL). We reported previously that intraperitoneal injection of cobalt chloride attenuated the loss of sensory hair cells and NIHL in mice. The present study was designed to understand the preconditioning effect of CoCl2 on oxidative stress-mediated cytotoxicity. Treatment of auditory cells with CoCl2 promoted cell proliferation, with increases in the expressions of two redox-active transcription factors (hypoxia-inducible factor 1α, HIF-1α, nuclear factor erythroid 2-related factor 2; Nrf-2) and an antioxidant enzyme (peroxiredoxin 6, Prdx6). Hydrogen peroxide treatment resulted in the induction of cell death and reduction of these protein expressions, reversed by pretreatment with CoCl2. Knockdown of HIF-1α or Nrf-2 attenuated the preconditioning effect of CoCl2. Luciferase reporter analysis with a Prdx6 promoter revealed transactivation of Prdx6 expression by HIF-1α and Nrf-2. The intense immunoreactivities of HIF-1α, Nrf-2, and Prdx6 in the organ of Corti (OC), spiral ganglion cells (SGC), and stria vascularis (SV) of the cochlea in CoCl2-injected mice suggested CoCl2-induced activation of HIF-1α, Nrf-2, and Prdx6 in vivo. Therefore, we revealed that the protective effect of CoCl2 is achieved through distinctive signaling mechanisms involving HIF-1α, Nrf-2, and Prdx6.

scholarly journals Caffeine Induces Autophagy and Apoptosis in Auditory Hair Cells via the SGK1/HIF-1α Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaomin Tang ◽  
Yuxuan Sun ◽  
Chenyu Xu ◽  
Xiaotao Guo ◽  
Jiaqiang Sun ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Stria Vascularis ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Spiral Ganglion Neurons ◽  
Auditory Hair Cells ◽  
Qrt Pcr ◽  
Ganglion Neurons

Caffeine is being increasingly used in daily life, such as in drinks, cosmetics, and medicine. Caffeine is known as a mild stimulant of the central nervous system, which is also closely related to neurologic disease. However, it is unknown whether caffeine causes hearing loss, and there is great interest in determining the effect of caffeine in cochlear hair cells. First, we explored the difference in auditory brainstem response (ABR), organ of Corti, stria vascularis, and spiral ganglion neurons between the control and caffeine-treated groups of C57BL/6 mice. RNA sequencing was conducted to profile mRNA expression differences in the cochlea of control and caffeine-treated mice. A CCK-8 assay was used to evaluate the approximate concentration of caffeine. Flow cytometry, TUNEL assay, immunocytochemistry, qRT-PCR, and Western blotting were performed to detect the effects of SGK1 in HEI-OC1 cells and basilar membranes. In vivo research showed that 120 mg/ kg caffeine injection caused hearing loss by damaging the organ of Corti, stria vascularis, and spiral ganglion neurons. RNA-seq results suggested that SGK1 might play a vital role in ototoxicity. To confirm our observations in vitro, we used the HEI-OC1 cell line, a cochlear hair cell-like cell line, to investigate the role of caffeine in hearing loss. The results of flow cytometry, TUNEL assay, immunocytochemistry, qRT-PCR, and Western blotting showed that caffeine caused autophagy and apoptosis via SGK1 pathway. We verified the interaction between SGK1 and HIF-1α by co-IP. To confirm the role of SGK1 and HIF-1α, GSK650394 was used as an inhibitor of SGK1 and CoCl2 was used as an inducer of HIF-1α. Western blot analysis suggested that GSK650394 and CoCl2 relieved the caffeine-induced apoptosis and autophagy. Together, these results indicated that caffeine induces autophagy and apoptosis in auditory hair cells via the SGK1/HIF-1α pathway, suggesting that caffeine may cause hearing loss. Additionally, our findings provided new insights into ototoxic drugs, demonstrating that SGK1 and its downstream pathways may be potential therapeutic targets for hearing research at the molecular level.

scholarly journals Mechanism of antisurdant action of triazin-indole derivative at experimental acoustic trauma

2021 ◽  
Vol 16 (1) ◽  
pp. 13-19
Author(s):  
Vladimir Pastushenkov ◽  
◽  
Maxim Kuznecov ◽  
Vladimir Dvorjanchikov ◽  
Alexander Pastushenkov ◽  
...  
Keyword(s):  
Indole Derivative ◽  
Spiral Ganglion ◽  
Drug Application ◽  
Dosage Level ◽  
Acoustic Trauma ◽  
Drug Dosage ◽  
Immunohistochemical Method ◽  
Control Group ◽  
Reference Drug ◽  
Acoustic Impact

In our research performed using model of acoustic trauma at experimental animals (female of hybrids F1 of CBA and C57BL/6 lines) influence of triazin-indole at expression level of hypoxia induced factor (HIF) in Corti’s organ was studied at its therapy application. As a reference drug cytoflavin was used. Investigated drug in the form of 1 % solution was introduced into animals parenterally in dosage 5, 7, 10 mg/kg with 2 hr intervals after acoustic impact. Injection of cytoflavin as reference drag was performed in 1.7 ml/kg dosage. Level of HIF expression in the drug of Corti’s organ was estimated using immunohistochemical method. It was found out that triazin-indole derivative increases HIF expression in Corti’s cells and in neurons of spiral ganglion at acoustical traumatic impact depending on drug dosage increase. Maximal HIF expression in Corti’s cells and in ganglions were noted at therapeutic dose of the drug 10 mg/kg. In control group and in the group with application citoflavin in dose 1.7 ml/kg minimal HIF expression was observed. According to obtained results of performed investigation the authors concluded that antisurdant property of triazin-indole derivative is realized through the influence on HIF metabolism (probably, by blockage of prolyl hydroxylase) and enables to consider it as a target molecular during the drug application.

scholarly journals NTPDase1 and NTPDase2 Immunolocalization in Mouse Cochlea: Implications for Regulation of P2 Receptor Signaling

2002 ◽  
Vol 50 (11) ◽  
pp. 1435-1441 ◽  
Author(s):  
Srdjan M. Vlajkovic ◽  
Peter R. Thorne ◽  
Jean Sévigny ◽  
Simon C. Robson ◽  
Gary D. Housley
Keyword(s):  
Hair Cells ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Nerve Fibers ◽  
Outer Hair Cells ◽  
Spiral Ligament ◽  
Receptor Signaling ◽  
P2 Receptor ◽  
Efferent Nerve ◽  
Root Region

Cellular, molecular, and physiological studies have demonstrated an important signaling role for ATP and related nucleotides acting via P2 receptors in the cochlea of the inner ear. Signal modulation is facilitated by ectonucleotidases, a heterologous family of surface-located enzymes involved in extracellular nucleotide hydrolysis. Our previous studies have implicated CD39/NTPDase1 and CD39L1/NTPDase2, members of the ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) family, as major ATP-hydrolyzing enzymes in the tissues lining the cochlear endolymphatic and perilymphatic compartments. NTPDase1 hydrolyzes both nucleoside triphosphates and diphosphates. In contrast, NTPDase2 is a preferential nucleoside triphosphatase. This study characterizes expression of these E-NTPDases in the mouse cochlea by immunohistochemistry. NTPDase1 can be immunolocalized to the cochlear vasculature and neural tissues (primary auditory neurons in the spiral ganglion). In contrast, NTPDase2 immunolabeling was principally localized to synaptic regions of the sensory inner and outer hair cells, stereocilia and cuticular plates of the outer hair cells, supporting cells of the organ of Corti (Deiters’ cells and inner border cells), efferent nerve fibers located in the intraganglionic spiral bundle, and in the outer sulcus and root region of the spiral ligament. This differential expression of NTPDase1 and 2 in the cochlea suggests spatial regulation of P2 receptor signaling, potentially involving different nucleotide species and hydrolysis kinetics.

Ultrastructural Cochlear Changes following Acoustic Hyperstimulation and Ototoxicity

1976 ◽  
Vol 85 (6) ◽  
pp. 740-751 ◽  
Author(s):  
David J. Lim
Keyword(s):  
Hair Cells ◽  
Sensory Cell ◽  
Ganglion Cells ◽  
Organ Of Corti ◽  
Acoustic Trauma ◽  
Nerve Fibers ◽  
Outer Hair Cells ◽  
Type I ◽  
Cell Degeneration ◽  
Inner Hair Cells

Using guinea pigs and chinchillas as experimental animals, modes and patterns of sensory cell damage by acoustic hyperstimulation and kanamycin intoxication were compared. In general, outer hair cells were more vulnerable to both acoustic trauma and ototoxicity (particularly in the basal turn) than inner hair cells. However, in kanamycin ototoxicity, the inner hair cells were more vulnerable in the apical coil. Nerve endings and nerve fibers generally were resistant to both acoustic trauma and kanamycin intoxication, and their degeneration appears to be secondary to the sensory cell degeneration. A large number of unmyelinated nerve fibers were seen in both the organ of Corti and the osseous spiral lamina even three months after the organ of Corti had been completely degenerated by ototoxicity. The total number of unmyelinated and myelinated nerve fibers in the osseous spiral lamina far exceeded the scanty surviving ganglion cells in Rosenthal's canal, indicating the possibility of regeneration of these fibers following kanamycin intoxication. The remaining few ganglion cells were mainly type II or type III cells, and a majority of the type I ganglion cells appeared to be degenerated. Signs of strial damage were observed in both acoustic trauma and ototoxicity, but their pattern did not correlate well with that of sensory cell degeneration.

Blebs in inner and outer hair cells: a pathophysiological hypothesis

2008 ◽  
Vol 122 (11) ◽  
pp. 1151-1155 ◽  
Author(s):  
R Ramírez-Camacho ◽  
J R García-Berrocal ◽  
A Trinidad ◽  
J M Verdaguer ◽  
J Nevado
Keyword(s):  
Hair Cells ◽  
Outer Hair Cell ◽  
Ganglion Cells ◽  
Stria Vascularis ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Outer Hair Cells ◽  
Inner Hair Cells ◽  
Hearing Thresholds

AbstractIntroduction:The ototoxic effects of cisplatin include loss of outer hair cells, degeneration of the stria vascularis and a decrease in the number of spiral ganglion cells. Scanning microscopy has shown balloon-like protrusions (blebs) of the plasma membrane of inner hair cells following cisplatin administration. The present study was undertaken to identify the possible role of inner and outer hair cell blebs in the pathogenesis of cisplatin-induced ototoxicity.Materials and methods:Twenty-five guinea pigs were injected with cisplatin and their hearing tested at different time-points, before sacrifice and examination with scanning electron microscopy.Results and analysis:Seven animals showed blebs in the inner hair cells at different stages. Hearing thresholds were lower in animals showing blebs.Discussion:Cisplatin seems to be able to induce changes in inner hair cells as well as in other structures in the organ of Corti. Blebbing observed in animals following cisplatin administration could play a specific role in the regulation of intracellular pressure.

scholarly journals Brimonidine Protects Auditory Hair Cells from in vitro-Induced Toxicity of Gentamicin

2017 ◽  
Vol 22 (3) ◽  
pp. 125-134 ◽  
Author(s):  
Maurizio Cortada ◽  
Soledad Levano ◽  
Daniel Bodmer
Keyword(s):  
Protein Expression ◽  
Protective Effect ◽  
Hair Cells ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Neuroprotective Effects ◽  
Auditory Hair Cells ◽  
Expression Levels ◽  
Ganglion Neurons

Brimonidine, an alpha-2 adrenergic receptor (α2-AR) agonist, has neuroprotective effects in the visual system and in spiral ganglion neurons. Auditory hair cells (HCs) express all 3 α2-AR subtypes, but their roles in HCs remain unknown. This study investigated the effects of brimonidine on auditory HCs that were also exposed to gentamicin, which is toxic to HCs. Organ of Corti explants were exposed to gentamicin in the presence or absence of brimonidine, and the α2-AR protein expression levels and Erk1/2 and Akt phosphorylation levels were determined. Brimonidine had a protective effect on auditory HCs against gentamicin-induced toxicity that was blocked by yohimbine. This suggested that the protective effect of brimonidine on HCs was mediated by the α2-AR. None of the treatments altered α2-AR protein expression levels, and brimonidine did not significantly change the activation levels of the Erk1/2 and Akt proteins. These observations indicated that brimonidine, acting directly via α2-AR, protects HCs from gentamicin-induced toxicity. Therefore, brimonidine shows potential for preventing or treating sensorineural hearing loss.

scholarly journals The molecular basis of making spiral ganglion neurons and connecting them to hair cells of the organ of Corti

2011 ◽  
Vol 278 (1-2) ◽  
pp. 21-33 ◽  
Author(s):  
Tian Yang ◽  
Jennifer Kersigo ◽  
Israt Jahan ◽  
Ning Pan ◽  
Bernd Fritzsch
Keyword(s):  
Hair Cells ◽  
Molecular Basis ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Spiral Ganglion Neurons ◽  
Ganglion Neurons

scholarly journals No Protective Effects of Hair Cells or Supporting Cells in Ototoxically Deafened Guinea Pigs upon Administration of BDNF

2021 ◽  
Vol 12 (1) ◽  
pp. 2
Author(s):  
Annamaria Tisi ◽  
Jochebed Rovers ◽  
Henk A. Vink ◽  
Dyan Ramekers ◽  
Rita Maccarone ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Ganglion Cells ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Cell Number ◽  
Gelatin Sponge ◽  
Protective Effects ◽  
Supporting Cells ◽  
Guinea Pig Model

We investigated whether treatment with brain-derived neurotrophic factor (BDNF), which is known to protect spiral ganglion cells (SGCs), could also protect hair cells (HCs) and supporting cells (SCs) in the organ of Corti of a guinea pig model of sensorineural hearing loss. Hearing loss was induced by administration of kanamycin/furosemide and two BDNF treatments were performed: (1) by gelatin sponge (BDNF-GS) with acute cochlear implantation (CI), and (2) through a mini-osmotic pump (BDNF-OP) with chronic CI. Outer HCs (OHCs), inner HCs (IHCs), Border, Phalangeal, Pillar, Deiters’, and Hensen’s cells were counted. The BDNF-GS cochleas had significantly fewer OHCs compared to the untreated ones, while the IHC and SC numbers did not differ between treated and untreated cochleas. The BDNF-OP group showed similar cell numbers to the untreated group. SGC packing density was not correlated with the total number of SCs for either BDNF group. Our data suggest that: (1) BDNF does not prevent cell death in the organ of Corti, and that the protection of SGCs could result from a direct targeting by BDNF; (2) BDNF might induce a different function/activity of the remaining cells in the organ of Corti (independently from cell number).

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