Kohei Yamahara

Insulin-like growth factor 1: A novel treatment for the protection or regeneration of cochlear hair cells

Sensorineural hearing loss (SNHL) is mainly caused by cochlear hair cell damage. Because cochlear hair cells and supporting cells lose their ability to proliferate in postnatal mammals, SNHL was thought to be an intractable disease. The maintenance of hair cell and supporting cell numbers after cochlear injury is therefore important for the treatment of sensorineural hearing loss. To achieve such treatment, protection and/or regeneration of hair cells is necessary. Progress in cochlear injury research, developmental biology, and regenerative medicine has led to the discovery of cochlear hair cells being protected or regenerated not only by direct reaction of hair cells themselves but also by that of supporting cells. Insulin-like growth factor 1 (IGF1) is considered a novel and potent treatment for SNHL based on the findings of various in vivo and in vitro experiments and clinical trials. The application of IGF1 maintains hair cell number of postnatal mammalian cochleae after various kinds of ototoxicity including aminoglycoside treatment, noise exposure, and ischemia. The positive effects of IGF1 on hair cell damage have been confirmed with in vivo animal experiments; hearing recovery in patients with sudden sensorineural hearing loss refractory to systemic glucocorticoid treatment has also been shown to occur following IGF1 treatment. The mechanisms of IGF1-induced maintenance of hair cell number have been investigated using a cochlear explant culture system, which demonstrated that IGF1 acts on supporting cells, leading to the inhibition of hair cell apoptosis and the proliferation of supporting cells. Netrin1 has furthermore been identified as one of the effectors whose expression is increased by IGF1 treatment.

Netrin 1 mediates protective effects exerted by insulin-like growth factor 1 on cochlear hair cells

ABSTRACT Sensorineural hearing loss (SNHL) is mainly caused by the damage of cochlear hair cells (HCs). As HCs and supporting cells (SCs) do not proliferate in postnatal mammals, the loss of HCs and SCs is irreversible, emphasizing the importance of preserving their numbers to prevent SNHL. It is known that insulin‐like growth factor 1 (IGF1) is instrumental in the treatment of SNHL. Our previous study indicates that IGF1 protects HCs against aminoglycoside by activating IGF1 receptor and its two major downstream pathways, PI3K/AKT and MEK/ERK, in SCs, which results in the upregulation of the expression of the Netrin1‐encoding gene (Ntn1). However, the mechanisms underlying IGF1‐induced protection of HCs via SC activation as well as the role of NTN1 in this process have not been elucidated. Here, we demonstrated that NTN1, similar to IGF1, promoted HC survival. NTN1 blocking antibody attenuated IGF1‐induced HC protection from aminoglycoside, indicating that NTN1 is the effector molecule of IGF1 signaling during HC protection. In situ hybridization demonstrated that IGF1 potently induced Ntn1 expression in SCs. NTN1 receptors were abundantly expressed in the cochlea; among them, UNC5B mediated IGF1 protective effects on HCs, as NTN1 binding to UNC5B inhibited HC apoptosis. These results provide new insights into the mechanisms underlying IGF1 protection of cochlear HCs, suggesting a possibility of using NTN1 as a new treatment for SNHL. HIGHLIGHTSNetrin1 protects cochlear hair cells from aminoglycoside via the Unc5b receptor.Netrin1 and Unc5b mediate the protective effect of IGF1 towards cochlear hair cells.Netrin1 inhibits apoptosis of hair cells caused by aminoglycoside.

Expression of the Olig gene family in the developing mouse inner ear

Transcription factors are believed to play key roles in determining cell fate in inner ear development. Olig genes, which are basic helix-loop-helix transcription factors, have been reported to play important roles in the development of the central nervous system. However, members of this family have not previously been implicated in inner ear development, despite the similarity between otocyst and neural tube development. Olig1 begins to be expressed at the ventral domain of the otocyst at embryonic day (E) 9.5, and Olig1 expression in the epithelium of the developing inner ear persists to E15.5. Olig2 expression is localized to the cochleovestibular ganglia from E12.5 through E14.5. Olig3 has a diffuse expression pattern in the developing inner ear from E12.5 through the postnatal stage. Furthermore, at early stages of inner ear development, the Olig1 expression domain overlaps a region that is positive for Sox2 and Jagged1. This observation indicates that Olig1 may play an important role in the specification of the prosensory domain in the developing inner ear. As Olig genes are expressed in the mouse developing inner ear in a temporospatially distinct fashion, they may play substantial roles in the regulation of mammalian inner ear development.

Hearing preservation at low frequencies by insulin-like growth factor 1 in a guinea pig model of cochlear implantation

Abstract The hybrid or electric‐acoustic stimulation cochlear implant is indicated in patients with a residual hearing at low frequencies. It provides electric and acoustic stimulation for compensating for high‐ and low‐frequency sounds, respectively. However, the implantation procedure damages the cochlea, resulting in loss of the residual‐hearing and diminished effects of the acoustic‐hearing in several patients. To prevent hearing loss after implantation, corticosteroids have been used clinically although their effects are limited. As an alternative to corticosteroids, insulin‐like growth factor 1 (IGF1) has shown potent effects in various types of cochlear injury. In this study, the effects of IGF1 on hearing preservation were examined after cochlear implantation to a normal‐hearing guinea pig model. The electrode was inserted in an atraumatic way through the round window membrane of guinea pigs with the application of a gelatin‐sponge soaked with IGF1 or saline. The auditory brainstem response (ABR) was recorded pre‐operatively, immediately after cochlear implantation, and 7, 14, 28, and 56 days after electrode insertion. In comparison to the control group, the IGF1‐treated group showed better hearing preservation at low frequencies, 7 days after surgery. IGF1 application was effective at low frequencies (2 and 4 kHz) throughout the period of examination. Histological studies revealed that outer hair cell numbers, in the IGF1‐treated group, were maintained in the cochlear region responsible for low‐frequency hearing (upper midbasal turn) and that there was less fibrous tissue formation around the electrode. Both the outer hair cell counts and the extent of fibrosis significantly correlated with the ABR threshold shifts at low frequencies. These results indicate that IGF1 might attenuate loss of low‐frequency hearing after cochlear implantation, suggesting its possible clinical use in soft surgeries involving cochlear implants with electric‐acoustic stimulation for hearing preservation. HighlightsIGF1 preserved low‐frequency hearing 56 days after cochlear implantation.IGF1 maintained outer hair cell numbers in low frequency regions of the cochlea.IGF1 inhibited fibrosis around the electrode.Fibrosis in the basal turn correlates with low‐frequency hearing.

Evaluation of tinnitus retraining therapy for patients with normal audiograms versus patients with hearing loss

OBJECTIVE A few chronic tinnitus patients show normal hearing thresholds in the pure tone audiometry from 125Hz to 8000Hz (≤20dB). We report the characteristics of the course of those patients underwent tinnitus retraining therapy (TRT) compared with other patients suffering from chronic and severe tinnitus. METHODS We identified 13 patients with normal hearing thresholds among 242 patients suffering over 3 months, Tinnitus Handicap Inventory (THI) ≥16/100, and follow up period is over 6 months. We divided into two groups - tinnitus with normal audiometry and with hearing loss - and contrasted these patients with age, gender, tinnitus duration, instruments for TRT, loudness and pitch of the tinnitus, THI and Visual Analogue Scale (VAS) scores. RESULTS The pitch-match of the tinnitus was higher and tinnitus duration was shorter in normal audiometry. The age is younger and the tinnitus loudness was smaller in normal hearing group significantly. THI of normal audiogram group showed significant improvement on 18 months treatment, though it once got worse on 12 months. THI of hearing loss group showed significant decreases in first 3 months and decreased slightly until 48 months treatment. The VAS scores of annoyance also showed a large decrease in first 3 months and decreased slightly until 24 months. Both THI after 48 months and VAS scores after 24 months treatment showed almost stable until 72 months in hearing loss group. CONCLUSION Chronic tinnitus with normal audiometry and with hearing loss both showed adaptation with TRT. Normal audiometry group with chronic tinnitus may have damage in high frequency though there were not significant differences between two groups as to tinnitus pitch-match. They also need at least 18 months TRT to become adaptation, while 48 months treatment is enough and first 3 months treatment is very important for hearing loss with chronic tinnitus.