Curcuma longa (curcumin) decreases in vivo cisplatin-induced ototoxicity through heme oxygenase-1 induction.

HYPOTHESIS: To investigate whether curcumin may have in vivo protective effects against cisplatin ototoxicity by its direct scavenger activity and/or by curcumin-mediated upregulation of HO-1. BACKGROUND: Cisplatin-induced ototoxicity is a major dose-limiting side effect in anticancer chemotherapy. A protective approach to decrease cisplatin ototoxicity without compromising its therapeutic efficacy remains a critical goal for anticancer therapy. Recent evidences indicate that curcumin exhibits antioxidant, anti-inflammatory, and chemosensitizer activities. METHODS: In male adult Wistar rats, a curcumin dose of 200 mg/kg, selected from a dose-response curve, was injected 1 hour before cisplatin administration and once daily for the following 3 days. A single dose of cisplatin (16 mg/kg) was administered intraperitoneally. Rats were divided as follows: 1) control, 2) curcumin control, 3) vehicle control, 4) cisplatin, 5) cisplatin+ vehicle, and 6) curcumin+cisplatin. ABRs were measured before and at Days 3 and 5 after cisplatin administration. Rhodamine-phalloidin staining, 4-hydroxy-2-nonenal and heme-oxigenase-1 immunostainings, and Western blot analyses were performed to assess and quantify OHC loss, lipid peroxidation, and the endogenous response to cisplatin-induced damage and to curcumin protection. RESULTS: Curcumin treatment attenuated hearing loss induced by cisplatin, increased OHC survival, decreased 4-HNE expression, and increased HO-1 expression. CONCLUSION: This preclinical study demonstrates that systemic curcumin attenuates ototoxicity and provides molecular evidence for a role of HO-1 as an additional mediator in attenuating cisplatin-induced damage.

Noise-induced hearing loss (NIHL) as a target of oxidative stress-mediated damage: cochlear and cortical responses after an increase in antioxidant defense.

This study addresses the relationship between cochlear oxidative damage and auditory cortical injury in a rat model of repeated noise exposure. To test the effect of increased antioxidant defenses, a water-soluble coenzyme Q10 analog (Qter) was used. We analyzed auditory function, cochlear oxidative stress, morphological alterations in auditory cortices and cochlear structures, and levels of coenzymes Q9 and Q10 (CoQ9 and CoQ10, respectively) as indicators of endogenous antioxidant capability. We report three main results. First, hearing loss and damage in hair cells and spiral ganglion was determined by noise-induced oxidative stress. Second, the acoustic trauma altered dendritic morphology and decreased spine number of II-III and V-VI layer pyramidal neurons of auditory cortices. Third, the systemic administration of the water-soluble CoQ10 analog reduced oxidative-induced cochlear damage, hearing loss, and cortical dendritic injury. Furthermore, cochlear levels of CoQ9 and CoQ10 content increased. These findings indicate that antioxidant treatment restores auditory cortical neuronal morphology and hearing function by reducing the noise-induced redox imbalance in the cochlea and the deafferentation effects upstream the acoustic pathway.

Efficacy of different routes of administration for Coenzyme Q10 formulation in noise-induced hearing loss: systemic versus transtympanic modality.

CONCLUSION: The effectiveness of a coenzyme Q10 formulation, Q-ter, given via transtympanic injection is interesting for the future application of this minimally invasive procedure in the treatment of reactive oxygen species (ROS)-induced hearing loss. OBJECTIVE: We focused on antioxidant therapy in noise-induced hearing loss (NIHL). Our study was designed to evaluate the effectiveness of Q-ter for different schedules of drug administration to establish the best modality for treatment. METHODS: Rats were exposed to acoustic trauma (10 kHz at 120 dB for 60 min) and received Q-ter according to two modalities: systemic (Q-ter 100 mg/kg for 4 days 1 h before and 3 days post noise exposure) and transtympanic (Q-ter 20 and 40% concentration 1 h before noise exposure). Auditory brainstem response (ABR), immunohistochemical and morphological studies were performed. RESULTS: Q-ter administration significantly decreased NIHL at day 21 from noise exposure. The improvement of auditory function by Q-ter was paralleled by a significant reduction in oxidative stress. The transtympanic and systemic routes of drug administration showed a similar degree of protection.

Post-processing analysis of transient-evoked otoacoustic emissions to detect 4 kHz-notch hearing impairment--a pilot study.

BACKGROUND: To identify a parameter to distinguish normal hearing from hearing impairment in the early stages. The parameter was obtained from transient-evoked otoacoustic emissions (TEOAEs), overcoming the limitations of the usually adopted waveform descriptive parameters which may fail in standard clinical screenings. MATERIAL/METHODS: Audiometric examinations and TEOAE analysis were conducted on 15 normal ears and on 14 hearing-impaired ears that exhibited an audiometric notch around 4 kHz. TEOAE signals were analyzed through a multivariate technique to filter out the individual variability and to highlight the dynamic structure of the signals. The new parameter (named radius 2-dimension--RAD2D) was defined and evaluated for simulated TEOAE signals modeling a different amount of hearing impairment. RESULTS: Audiometric examinations indicated 14 ears as impaired-hearing (IH), while the TEOAE ILO92 whole reproducibility parameter (WWR) indicated as IH 7 signals out of 14 (50%). The proposed new parameter indicated as IH 9 signals out of 14 (64%), reducing the number of false negative cases of WWR. CONCLUSIONS: In this preliminary study there is evidence that the new parameter RAD2D defines the topology and the quantification of the damage in the inner ear. The proposed protocol can be useful in hearing screenings to identify hearing impairments much earlier than conventional pure tone audiometry and TEOAE pass/fail test.

Water-soluble Coenzyme Q10 formulation (Q-ter) promotes outer hair cell survival in a guinea pig model of noise induced hearing loss (NIHL).

The mitochondrial respiratory chain is a powerful source of reactive oxygen species (ROS) also in noise induced hearing loss (NIHL) and anti-oxidants and free-radicals scavengers have been shown to attenuate the damage. Coenzyme Q(10) (CoQ(10)) or ubiquinone has a bioenergetic role as a component of the mithocondrial respiratory chain, it inhibits mitochondrial lipid peroxidation, inducing ATP production and it is involved in ROS removal and prevention of oxidative stress-induced apoptosis. However the therapeutic application of CoQ(10) is limited by the lack of solubility and poor bio- availability, therefore it is a challenge to improve its water solubility in order to ameliorate the efficacy in tissues and fluids. This study was conducted in a model of acoustic trauma in the guinea pig where the effectiveness of CoQ(10) was compared with a soluble formulation of CoQ(10) (multicomposite CoQ(10) Terclatrate, Q-ter) given intraperitoneally 1 h before and once daily for 3 days after pure tone noise exposure (6 kHz for 1 h at 120 dB SPL). Functional and morphological studies were carried out by measuring auditory brainstem responses, scanning electron microscopy for hair cell loss count, active caspase 3 staining and terminal deoxynucleotidyl transferase-mediated dUTP labelling assay in order to identify initial signs of apoptosis. Treatments decreased active caspase 3 expression and the number of apoptotic cells, but animals injected with Q-ter showed a greater degree of activity in preventing apoptosis and thus in improving hearing. These data confirm that solubility of Coenzyme Q(10) improves the ability of CoQ(10) in preventing oxidative injuries that result from mitochondrial dysfunction.

Protective properties of idebenone in noise-induced hearing loss in the guinea pig.

Idebenone is a synthetic analogue of coenzyme Q10 with antioxidant properties. The present study investigated the antioxidant activity of idebenone in the rescue of acoustic trauma. Noise-induced hearing loss was induced by exposing guinea pigs to a continuous pure tone and idebenone was injected intraperitoneally 1 h before noise exposure and once daily for 3 days. Guinea pigs treated with idebenone showed significantly smaller auditory threshold shifts than unprotected control animals. Missing and apoptotic cells were identified with scanning electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling assay. Protected animals presented a lesser extent of both apoptotic activation and hair cell loss in the organ of Corti. Our results suggest an antioxidant function of idebenone in protection from noise-induced hearing loss and provide a rationale for exploring therapeutic strategies in humans.