Takefumi Mikuriya

Geranylgeranylacetone, a heat shock protein inducer, prevents acoustic injury in the guinea pig

Geranylgeranylacetone (GGA) used widely as anti-ulcer agent is accepted as an inducer of the heat shock proteins (Hsps) at gastric mucosa, liver, heart, and brain. However, there have been no reports that GGA could induce Hsps in the cochlea leading up to the oto-protection. The purpose of the present study was to investigate whether single oral dose of GGA could induce Hsps at cochlea and oral administration had protective effect to the cochlea against noise trauma. We used Hartley guinea pigs and investigated the expression of Hsp70, 40, and 27 in cochlea by Western blot analysis. To evaluate cochlear function, we assessed thresholds of the auditory brain stem response (ABR). For histological assessment, we observed the sensory epithelium using surface preparation technique. GGA (600 mg/kg) or vehicle was given orally to animals. Western blot analysis showed that the expressions of Hsp 70, 40, and 27 were increased 24-48 h after administration of single dose of GGA, whereas there was less expression in the animals given vehicle. In the animals given GGA once a day for a week before sound exposure (130 dB SPL octave band noise with a center frequency of 4 kHz) for 3 h, their ABR threshold elevations were lowered significantly. In addition, significantly fewer defects were observed on outer hair cells of organ of Corti in the animals treated by GGA than those of the animals without GGA. This result shows that pretreatment by GGA have a potential to prevent cochlea damage against the intense noise.

Attenuation of progressive hearing loss in a model of age-related hearing loss by a heat shock protein inducer, geranylgeranylacetone.

Mechanisms of age-related hearing loss (ARHL) have not been elucidated as aging processes are extremely complex. Although oxidative stress and apoptotic cell death are involved in progression of ARHL, number of trial to treat ARHL is limited. Heat shock response is characterized by induction of heat shock proteins (HSPs) in response to stresses such as heat shock, which diminishes during aging. HSPs act as molecular chaperones, and some HSPs also inhibit apoptotic pathways. Here, we examined age-related expression of HSPs in the cochlea of ARHL model DBA/2J mice and control CBA/N mice. Western blot assay revealed that CBA/N mice showed constant expression of Hsp70 and Hsp110 with age, but not in DBA/2J mice. The result suggests that pharmacological upregulation of HSPs might attenuate ARHL. We administered DBA/2J mice with food containing geranylgeranylacetone (GGA) that induces HSPs in the cochlea, and found that its administration suppresses ARHL examined by ABR test and histological examination though protection is specific for the apical part of the cochlea. These results demonstrate that dietary supplementation of GGA could be an effective therapeutic strategy for treatment of ARHL.

Geranylgeranylacetone suppresses noise-induced expression of proinflammatory cytokines in the cochlea

OBJECTIVE Heat shock transcription factor 1 (HSF1) is a master regulator of heat shock response, and also inhibits expression of inflammatory cytokines directly or indirectly. Here, we examined effects of HSF1 activation on the expression of proinflammatory cytokines in mouse cochlea after exposure to noise. METHODS Male CBA/N mice with normal Preyers reflex were exposed to intense noise for 3h. Three hours after noise exposure, bilateral cochleae were removed and expression of major inflammatory cytokines was examined. RESULTS We found that interleukin-6 (IL-6) and interleukin-1β (IL-1β) expression increased significantly after noise exposure, and the expression was suppressed significantly in mice administered with geranylgeranylacetone (GGA), which activates HSF1. Seven days after noise exposure, thresholds for auditory brainstem response were elevated, and GGA administration significantly suppressed this elevation. CONCLUSION These results suggest that HSF1-mediated suppression of proinflammatory cytokines in the cochlea by GGA administration could be an important means of inner ear protection.

The systemic application of diazepam facilitates the reacquisition of a well-balanced vestibular function in a unilateral vestibular re-input model with intracochlear tetrodotoxin infusion using an osmotic pump

Diazepam is a popular medicine used in the treatment of acute vertigo. In the past, many studies investigating the effect of diazepam in peripheral vestibular destruction have been reported. However, no previous study has yet investigated the effect of diazepam on a model with a transient and reversible vestibular function similar to recurrent vertigo as seen in Menieres disease. We thus made a peripheral vestibular re-input model by the unilateral intracochlear administration of tetrodotoxin (TTX) using an osmotic pump and then examined the influence of diazepam on the vestibular system in this model. Hartley white guinea pigs were intracochlearly administered with TTX on the right side for 3 days by an osmotic pump. Animals were divided into three groups, TTX alone (control group (n = 7)), TTX and an intraperitoneal diazepam injection once a day for 3 days (diazepam group (n = 6)) and vehicle injection (vehicle group (n = 6)). A caloric response and vestibuloocular reflex (VOR) were observed at 7 and 14 days after completing 3 days of TTX administration. Seven days after vestibular re-input, a directional preponderance of the nystagmus (DP) to the TTX-treated side was observed in the control and vehicle groups on VOR examination. DP was not observed in the diazepam group on any examined day. The R/L time ratio of caloric response showed no statistical difference between three groups on any examined day. These results suggest that diazepam may thus be useful for patients in an acute stage of peripheral vestibular vertigo by decreasing their vertiginous symptoms.

Coenzyme Q10 Protects Hair Cells against Aminoglycoside

It is well known that the production of free radicals is associated with sensory cell death induced by an aminoglycoside. Many researchers have reported that antioxidant reagents protect sensory cells in the inner ear, and coenzyme Q10 (CoQ10) is an antioxidant that is consumed as a health food in many countries. The purpose of this study was to investigate the role of CoQ10 in mammalian vestibular hair cell death induced by aminoglycoside. Cultured utricles of CBA/CaN mice were divided into three groups (control group, neomycin group, and neomycin + CoQ10 group). In the neomycin group, utricles were cultured with neomycin (1 mM) to induce hair cell death. In the neomycin + CoQ10 group, utricles were cultured with neomycin and water-soluble CoQ10 (30–0.3 µM). Twenty-four hours after exposure to neomycin, the cultured tissues were fixed, and vestibular hair cells were labeled using an anti-calmodulin antibody. Significantly more hair cells survived in the neomycin + CoQ10 group than in the neomycin group. These data indicate that CoQ10 protects sensory hair cells against neomycin-induced death in the mammalian vestibular epithelium; therefore, CoQ10 may be useful as a protective drug in the inner ear.

Effectiveness of the leukotriene receptor antagonist pranlukast hydrate for the treatment of sleep disorder in patients with perennial allergic rhinitis

Abstract Conclusion: We found that addition of pranlukast to the conventional treatment for perennial allergic rhinitis may contribute to improvements in sleep disorder symptoms through a decrease in nasal congestion. Objective: We aimed to determine whether the leukotriene receptor antagonist pranlukast hydrate is effective in treating sleep disorder in patients with perennial allergic rhinitis. Methods: We conducted a questionnaire survey to determine the symptoms of rhinitis and sleep disturbances in 48 adult patients with perennial allergic rhinitis who visited the outpatient otolaryngology departments in hospitals in Yamaguchi Prefecture, Japan. The subjects presented with nasal symptoms and symptoms of sleep disorder during the last 2 weeks of treatment for allergic rhinitis that lasted for at least 1 month. A questionnaire based on the Pittsburgh Sleep Quality Index and Athens Insomnia Scale with some modifications was administered before and 4 weeks after the addition of pranlukast to the conventional treatment. Results: Addition of pranlukast improved the symptoms of perennial allergic rhinitis, with responses to all items of the questionnaire administered 4 weeks after pranlukast addition indicating significant improvements. Furthermore, the improvement in sleep disorder symptoms significantly correlated with improvement in nasal congestion, but not with improvements in sneezing and nasal discharge.

Effects of substance P during the recovery of hearing function after noise-induced hearing loss

Substance P (SP) is a widely distributed neurotransmitter in living tissues and is involved in various repair processes. We investigated the possibility that SP may ameliorate cochlear hair cell damage produced by noise exposure. The present study examined the effect of SP in protecting the cochlea from noise damage in guinea pigs exposed to noise after an infusion of SP into the inner ear. Changes in the hearing threshold (auditory brain response, ABR), number of synaptic ribbons, and the appearance of the outer hair cells after noise exposure were analyzed at 2 severity levels of noise-induced hearing loss. The moderate noise-induced hearing loss (110dB, 3h) group showed recovery in the ABR threshold over time, finally reaching a level slightly above pre-exposure levels, with only slight injury to the synaptic ribbons and minimal changes in the appearance of the outer hair cells. Our results indicated that in moderate hearing loss, SP exhibited a protective effect on the inner ear, both functionally and structurally. While the final magnitude of ABR threshold elevation was greater in severe noise-induced hearing loss, the synaptic ribbons and outer hair cells showed signs of severe damage.

The Effectiveness of Epinastine Hydrochloride for Pediatric Sleep- Disordered Breathing Related Symptoms Caused By Hyperesthetic Non- Infectious Rhinitis

Objectives: The aims of this study were to prospectively evaluate the effectiveness of oral epinastine hydrochloride in pediatric outpatients with Sleep-Disordered Breathing- (SDB) related symptoms caused by hyperesthetic non-infectious rhinitis, and to assess their Quality of Life (QOL) prior to and following treatment. Study design: Prospective Methods: Pediatric outpatients (9 boys and 10 girls; average age, 5.6 years [SD=1.4]), with SDB related symptoms influenced by hyperesthetic non-infectious rhinitis were recruited. The children were all treated with oral epinastine hydrochloride dry syrup for 4 weeks. Before and after the 4-week treatment period, the following data were collected from each participant: otolaryngological findings, obstructive sleep apnea-18 (OSA-18) scores, and evaluation of QOL. Results: Epinastine hydrochloride significantly improved the swelling of the inferior nasal turbinate mucosa and decreased the quantity of nasal discharge. The initial total mean OSA-18 score was 58.5, whereas the total score reduced to 22.8 after oral epinastine hydrochloride treatment. Significant (p < 0.01) differences were found between pre- and post-treatment total OSA-18 scores as well as pre- and post-treatment measurements of domains of sleep disturbance, physical symptoms, and caregiver concerns. Conclusions: Epinastine hydrochloride therapy may improve nasal findings and QOL in pediatric outpatients with SDB related symptoms caused by hyperesthetic non-infectious rhinitis.