tretinoin and Hearing-Loss--Noise-Induced

Noise is one of the most common causes of hearing loss in industrial countries. There are many studies about chemical agents to prevent noise-induced hearing loss (NIHL). However, there is no commercially available drug yet. Retinoic acid is an active metabolite of Vitamin A; it has an anti-apoptic role in NIHL. This study aims to verify the differences among selective agonists of retinoic acid receptors (RARs) in NIHL. All-trans retinoic acid (ATRA), AM80 (selective retinoic acid receptor α agonist), AC261066 (Selective retinoic acid receptor β1 agonist), and CD1530 (Selective retinoic acid λ agonist) were injected to 6-7 weeks old CJ5BL/6 mice before noise (110 dB for 3 h) exposure. In the auditory brainstem response test pre-, post 1, 3, and 7 days after noise exposure, not only ATRA but all kinds of selective RAR agonists showed protective effects in hearing threshold and wave I amplitude. Though there was no significant difference in the level of protective effects between agonists, α agonist showed the most prominent effect in preserving hearing function as well as outer hair cells after noise exposure. In conclusion, selective agonists of RAR demonstrate comparable protective effects against NIHL to retinoic acid. Given that these selective RAR agonists have less side effects than retinoic acid, they may be promising potential drugs against NIHL.

Topics: Animals; Benzoates; Hearing Loss, Noise-Induced; Mice, Inbred C57BL; Naphthols; Noise; Receptors, Retinoic Acid; Tetrahydronaphthalenes; Thiazoles; Tretinoin

All-trans retinoic acid (ATRA) is reported to reduce hair cell loss and hearing deterioration caused by noise-induced hearing loss (NIHL). The present study investigates the involvement of peroxiredoxin 6 (Prdx 6) in ATRA-mediated protection of temporary threshold shift of hearing. Mice fed with ATRA before or after exposure to white noise showed a faster recovery than untreated controls within 1 week, with a concomitant increase of cochlear Prdx 6 expression. Treatment of mouse auditory cells with ATRA induced Prdx 6 expression. A putative retinoic acid (RA)-response element (RARE) was identified in a murine Prdx 6 promoter region. Prdx 6 promoter activities were elevated in wild-type reporter plasmid-transfected cells, whereas no significant change in activity was in those with RARE-disrupted mutant reporter. RA receptor α (RARα) functions as a transactivator of Prdx 6 gene expression. These findings suggest that ATRA-induced Prdx 6 expression may be associated with rapid recovery from temporary NIHL.

Topics: Animals; Auditory Fatigue; Binding Sites; Cell Line; Cochlea; Disease Models, Animal; Dose-Response Relationship, Drug; Hearing; Hearing Loss, Noise-Induced; Mice; Mice, Inbred BALB C; Mutation; Peroxiredoxin VI; Promoter Regions, Genetic; Receptors, Retinoic Acid; Recovery of Function; Response Elements; Retinoic Acid Receptor alpha; Signal Transduction; Time Factors; Transcriptional Activation; Transfection; Tretinoin; Up-Regulation

The early post-exposure treatment with All-trans retinoic acid (ATRA) can reduce hair cell loss and hearing deterioration in mice in which permanent threshold shift has been induced.. One of the mechanism by which intense noise induces apoptosis of cochlea hair cells is the C-Jun NH(2)-terminal kinase (JNK) pathway. ATRA is a potent inhibitor of activator protein 1, a transcription factor of the JNK pathway. In this study we evaluated that the effect of post-exposure treatment of ATRA on noise-induced hearing loss and aimed to determine a time window for effective post-exposure treatment of ATRA.. All mice were exposed to white noise for 3 h per day for three consecutive days and induced permanent threshold shift. The treatment groups fed with ATRA from 1 h, one day, two days, and three days after noise exposure for five days were compared with mice fed with same dosage of sesame oil. We measured the threshold shifts of hearing and survival rates of hair cells on the cytocochleogram.. Mice fed with ATRA beginning within two days after noise had less threshold shifts and more hair cell survivals than mice fed with sesame oil.

Topics: Animals; Apoptosis; Disease Models, Animal; Evoked Potentials, Auditory, Brain Stem; Hair Cells, Auditory; Hearing Loss, Noise-Induced; JNK Mitogen-Activated Protein Kinases; Mice; Mice, Inbred BALB C; Transcription Factor AP-1; Tretinoin

Exposure to loud noise can induce temporary or permanent hearing loss, and acoustic trauma is the major cause of hearing impairment in industrial nations. However, the mechanisms underlying the death of hair cells after acoustic trauma remain unclear. In addition to its involvement in cellular stress and apoptosis, the c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase family, is involved in cell survival, transformation, embryonic morphogenesis, and differentiation. JNK is primarily activated by various environmental stresses including noise, and the phenotypic result appears be to cell death. All-trans retinoic acid (ATRA) is an active metabolite of vitamin A that regulates a wide range of biological processes, including cell proliferation, differentiation, and morphogenesis. We evaluated the role of ATRA in preserving hearing in mice exposed to noise that can induce permanent hearing loss. Mice fed with ATRA before and during 3 consecutive days of noise exposure had a more preserved hearing threshold than mice fed sesame oil or saline. Histological and TUNEL staining of the cochlea showed significantly enhanced preservation of the organ of Corti, including outer hair cells and relatively low apoptotic nuclei, in mice-fed ATRA than in mice-fed sesame oil or saline. Phospho-JNK immunohistochemistry showed that ATRA inhibited the activation of JNK. These results suggest that ATRA has an anti-apoptotic effect on cochleae exposed to noise.

Topics: Animals; Apoptosis; Cell Differentiation; Cell Proliferation; Cell Survival; Cochlea; Ear, Inner; Epithelium; Hair Cells, Auditory; Hearing Loss; Hearing Loss, Noise-Induced; Immunohistochemistry; In Situ Nick-End Labeling; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase Kinases; Noise; Organ of Corti; Time Factors; Tretinoin