The therapeutic effect and mechanism of Chinese medicine Xuan-Yun-Ding on posterior circulation ischemia with vertigo in a rabbit model.

The aim of research is to unveil the mechanisms of the beneficial effects of XYD on PCIV in a rabbit model. 40 New Zealand white rabbits were randomly divided into 5 groups,including normal control group (NC), model control group (MC), low-dose of XYD group (LXYD), high-dose of XYD group (HXYD) and Yang-Xue-Qin-Nao group (YXQN). PCIV rabbit model was established by feeding high-fat diet companied with paravertebral sclerotherapy and rotation exercise. The general observation, step-down test, rheoencephalogram, blood tests, histopathological detection and the plasma concentration of the effective component of XYD were investigated. After pharmacological intervening, the step-down time, REG, PL, IPL, blood viscosity, the levels of blood lipids, CRGP were significantly improved. Moreover, the vertebral artery showed the reduced stenosis of arterial lumen and less proliferation of fibrous tissue in the arterial wall in the LXYD, HXYD and YXQN group. Based on the LC-MS detection, the blood concentrations of puerarin in the LXYD and HXYD group were significantly increased after pharmacological intervening. XYD could ameliorate the symptoms of vertigo, Qi-deficiency and blood stasis in PCIV rabbits via effectively regulating the levels of blood lipids and vasoactive substances, decreasing blood viscosity, increasing CBF and protecting vestibular function.

Effect of Phlorofucofuroeckol A and Dieckol Extracted from Ecklonia cava on Noise-induced Hearing Loss in a Mouse Model.

One of the well-known causes of hearing loss is noise. Approximately 31.1% of Americans between the ages of 20 and 69 years (61.1 million people) have high-frequency hearing loss associated with noise exposure. In addition, recurrent noise exposure can accelerate age-related hearing loss. Phlorofucofuroeckol A (PFF-A) and dieckol, polyphenols extracted from the brown alga Ecklonia cava, are potent antioxidant agents. In this study, we investigated the effect of PFF-A and dieckol on the consequences of noise exposure in mice. In 1,1-diphenyl-2-picrylhydrazyl assay, dieckol and PFF-A both showed significant radical-scavenging activity. The mice were exposed to 115 dB SPL of noise one single time for 2 h. Auditory brainstem response(ABR) threshold shifts 4 h after 4 kHz noise exposure in mice that received dieckol were significantly lower than those in the saline with noise group. The high-PFF-A group showed a lower threshold shift at click and 16 kHz 1 day after noise exposure than the control group. The high-PFF-A group also showed higher hair cell survival than in the control at 3 days after exposure in the apical turn. These results suggest that noise-induced hair cell damage in cochlear and the ABR threshold shift can be alleviated by dieckol and PFF-A in the mouse. Derivatives of these compounds may be applied to individuals who are inevitably exposed to noise, contributing to the prevention of noise-induced hearing loss with a low probability of adverse effects.

ROS-Responsive Nanoparticle as a Berberine Carrier for OHC-Targeted Therapy of Noise-Induced Hearing Loss.

Overproduction of reactive oxygen species (ROS) and inflammation are two key pathogeneses of noise-induced hearing loss (NIHL), which leads to outer hair cell (OHC) damage and hearing loss. In this work, we successfully developed ROS-responsive nanoparticles as berberine (BBR) carriers (PL-PPS/BBR) for OHC-targeted therapy of NIHL: Prestin-targeting peptide 2 (PrTP2)-modified nanoparticles (PL-PPS/BBR), which effectively accumulated in OHC areas, and poly(propylene sulfide)120 (PPS120), which scavenged ROS and converted to poly(propylene sulfoxide)120 in a ROS environment to disintegrate and provoke the rapid release of BBR with anti-inflammatory and antioxidant effects. In this study, satisfactory anti-inflammatory and antioxidant effects of PL-PPS/BBR were confirmed. Immunofluorescence and scanning electron microscopy (SEM) images showed that PL-PPS/BBR effectively accumulated in OHCs and protected the morphological integrity of OHCs. The auditory brainstem response (ABR) results demonstrated that PL-PPS/BBR significantly improved hearing in NIHL guinea pigs after noise exposure. This work suggested that PL-PPS/BBR may be a new potential treatment for noise-associated injury with clinical application.

Effects of Kainic Acid-Induced Auditory Nerve Damage on Envelope-Following Responses in the Budgerigar (Melopsittacus undulatus).

Sensorineural hearing loss is a prevalent problem that adversely impacts quality of life by compromising interpersonal communication. While hair cell damage is readily detectable with the clinical audiogram, this traditional diagnostic tool appears inadequate to detect lost afferent connections between inner hair cells and auditory nerve (AN) fibers, known as cochlear synaptopathy. The envelope-following response (EFR) is a scalp-recorded response to amplitude modulation, a critical acoustic feature of speech. Because EFRs can have greater amplitude than wave I of the auditory brainstem response (ABR; i.e., the AN-generated component) in humans, the EFR may provide a more sensitive way to detect cochlear synaptopathy. We explored the effects of kainate- (kainic acid) induced excitotoxic AN injury on EFRs and ABRs in the budgerigar (Melopsittacus undulatus), a parakeet species used in studies of complex sound discrimination. Kainate reduced ABR wave I by 65-75 % across animals while leaving otoacoustic emissions unaffected or mildly enhanced, consistent with substantial and selective AN synaptic loss. Compared to wave I loss, EFRs showed similar or greater percent reduction following kainate for amplitude-modulation frequencies from 380 to 940 Hz and slightly less reduction from 80 to 120 Hz. In contrast, forebrain-generated middle latency responses showed no consistent change post-kainate, potentially due to elevated "central gain" in the time period following AN damage. EFR reduction in all modulation frequency ranges was highly correlated with wave I reduction, though within-animal effect sizes were greater for higher modulation frequencies. These results suggest that even low-frequency EFRs generated primarily by central auditory nuclei might provide a useful noninvasive tool for detecting synaptic injury clinically.

Alpha2-adrenergic dysregulation in congenic DxH recombinant inbred mice selectively bred for a high fear-sensitized (H-FSS) startle response.

Patients with anxiety disorders and posttraumatic stress disorder (PTSD) exhibit exaggerated fear responses and noradrenergic dysregulation. Fear-related responses to α2-adrenergic challenge were therefore studied in DxH C3H/HeJ-like recombinant inbred (C3HLRI) mice, which are a DBA/2J-congenic strain selectively bred for a high fear-sensitized startle (H-FSS). C3HLRI mice showed an enhanced acoustic startle response and immobility in the forced swim test compared to DBA/2J controls. The α2-adrenoceptor antagonist yohimbine (Yoh; 5.0 mg/kg) induced an anxiogenic and the α2-adrenoceptor agonist clonidine (Clon; 0.1 mg/kg) an anxiolytic effect in the open field (OF) in C3HLRI but not DBA/2J mice. In auditory fear-conditioning, Yoh (5.0 mg/kg)-treated C3HLRI mice showed higher freezing during fear recall and extinction learning than DBA/2J mice, and a higher ceiling for the Yoh-induced deficit in fear extinction. No strain differences were observed in exploration-related anxiety/spatial learning or the Clon-induced (0.1 mg/kg) corticosterone surge. A global analysis of the behavioral profile of the two mouse strains based on observed and expected numbers of significant behavioral outcomes indicated that C3HLRI mice showed significantly more often fear- and stress-related PTSD-like behaviors than DBA/2J controls. The analysis of the robustness of significant outcomes based on false discovery rate (FDR) thresholds confirmed significant differences for the strain-Yoh-interactions in the OF center and periphery, the Yoh-induced general extinction deficit, strain differences in conditioned fear levels, and at the dose of 5.0 mg/kg for the Yoh-induced ceiling in freezing levels among others. The current findings are consistent with previous observations showing alterations in the central noradrenergic system of C3HLRI mice (Browne et al., 2014, Stress 17:471-83). Based on their behavioral profile and response to α2-adrenergic stimulation, C3HLRI mice are a valuable genetic model for studying adrenergic mechanisms of anxiety disorders and potentially also of PTSD.

Residual inhibition: From the putative mechanisms to potential tinnitus treatment.

Neurons in various sensory systems show some level of spontaneous firing in the absence of sensory stimuli. In the auditory system spontaneous firing has been shown at all levels of the auditory pathway from spiral ganglion neurons in the cochlea to neurons of the auditory cortex. This internal "noise" is normal for the system and it does not interfere with our ability to perceive silence or analyze sound. However, this internal noise can be elevated under pathological conditions, leading to the perception of a phantom sound known as tinnitus. The efforts of many research groups, including our own, led to the development of a mechanistic understanding of this process: After cochlear insult the input to the central auditory system becomes markedly reduced. As a result, the neural activity in the central auditory system is enhanced to compensate for this reduced input. Such hyperactivity is hypothesized to be interpreted by the brain as a presence of sound. This implies that suppression of hyperactivity should reduce/eliminate tinnitus. This review explores research from our laboratory devoted to identifying the mechanism underlying residual inhibition of tinnitus, a brief suppression of tinnitus following a sound stimulus. The key mechanisms that govern neural suppression of spontaneous activity in animals closely resemble clinical psychoacoustic findings of residual inhibition (RI) observed in tinnitus patients. This suppression is mediated by metabotropic glutamate receptors (mGluRs). Lastly, drugs targeting mGluRs suppress spontaneous activity in auditory neurons and reduce/eliminate behavioral signs of tinnitus in mice. Thus, these drugs are therapeutically relevant for tinnitus suppression in humans.

Oral administration of an herbal medicine to prevent progressive hearing loss in a mouse model of diabetes.

OBJECTIVE: Tsumura Suzuki Obese Diabetes (TSOD) mice exhibit early age-associated hearing loss. Histopathological analysis of these mice shows narrowing of capillaries in the stria vascularis and chronic reduction of blood flow in the cochlea. In this study, we investigated the effect of oral administration of a herbal medicine or calorie restriction on hearing in TSOD mice. METHODS: TSOD mice were divided into 4 groups: CR (calorie restriction), BF and DS (treated with the herbal medicines, Bofutsushosan and Daisaikoto, respectively), and the control group. Body weight, blood glucose levels, and auditory brainstem responses (ABRs) were measured. The cochleae were excised and evaluated histopathologically. RESULTS: Blood glucose levels were suppressed in the CR, BF, and DS groups. In addition, the elevation of ABR thresholds was inhibited in the CR, BF, and DS groups. Cochlear blood vessels remained wide in the three treatment groups compared with the control group. These results suggested that the administration of these herbal medicines improved glucose tolerance and yielded results similar to those on calorie restriction. CONCLUSION: Oral administration of 2 herbal medicines can prevent hearing function disorder in a model mouse of diabetes. The results may clarify the possibility of clinical application.

Attenuation of adverse effects of noise induced hearing loss on adult neurogenesis and memory in rats by intervention with Adenosine A2A receptor agonist.

Hearing loss and cognitive decline are commonly associated with aging and morbidity. Present clinical interest lies in whether peripheral hearing loss promotes cognitive decline and if prophylaxis with selective adenosine receptor agonist CGS21680 effectively mitigates the adverse effects. In the current study, male Sprague Dawley rats weighing 200-250 g m were randomly allocated into three groups: Group 1) rats exposed to 100 dB SPL white noise, 2 h a day for 15 consecutive days, 2) rats supplemented with an adenosine receptor agonist, CGS21680 at 100 µg/kg/day prior to noise exposure and 3) unexposed control rats. Baseline hearing and cognition assessed by auditory brainstem response (ABR) and water maze respectively was undertaken for all the groups. Phalloidin stain and synaptic ribbons count in cochlea, and, Ki67, DCX and NeuN in hippocampus were observed by immunohistochemistry. It was inferred that noise exposed rats showed elevated thresholds of ABR and poorer performances in spatial working memory when compared with controls. On the contrary, CGS21680 administered group exhibited improved ABR and cognitive functions with shorter mean latency and path-length to reach the platform, significant reduction in the noise induced loss of synaptic ribbons count and increased number of Ki67 and doublecortin (DCX) positive cells compared to their noise exposed counterparts. Pharmacologic intervention with selective A2A receptor agonist CGS21680 provided adequate protection from noise by effectively maintaining hearing threshold levels, cell viability in cochlea and hippocampus & functional/intact reference memory.

Long­term treatment with salicylate enables NMDA receptors and impairs AMPA receptors in C57BL/6J mice inner hair cell ribbon synapse.

Salicylate is widely used to produce animal models of tinnitus in mice and/or rats. The side effects on auditory function, including hearing loss and tinnitus, are considered the results of the auditory nerve dysfunction. A recent study indicated that chronic treatment with salicylate for several weeks reduces compressed action potential amplitude, which is contradictory to the studies reporting excessive activation of N­methyl­D­aspartate receptors (NMDAR) in tinnitus­induced animals. The specific aims of the experiment were to detect the effect of salicylate on the inner hair cells (IHCs), ribbon synapse, as well as the association between the hearing threshold and the number of mismatched ribbon synapses. In the present study, mice were injected intraperitoneally with a low dose of salicylate (200 mg/kg) for 14 days. The auditory brainstem response and otoacoustic emission were measured to assess auditory function of the mice. The postsynaptic regions of IHC were identified with two types of immunostaining targets: Postsynaptic density protein 95 and Glu2/3. The number of spheres was counted and the synapses were reconstructed in 3­dimensional images. Increases in distortion product otoacoustic emissions amplitudes of the salicylate group were detected, however, an elevation in the hearing threshold was also observed. A mismatch between pre­and post­ribbon synapses was observed. In addition, the cochlear components, including the numbers of outer hair cells and IHCs, were unlikely to be affected by salicylate. IHC ribbon synapses were more susceptible to salicylate stimuli. Furthermore, mismatch of pre­ and post­ribbon synapses may indicate a competitive inhibition between NMDAR and α-amino­3­hydroxy-5-methyl-4-isoxa-zole-propionate receptors and dysfunction of ribbon synapses.

SENS-401 Effectively Reduces Severe Acoustic Trauma-Induced Hearing Loss in Male Rats With Twice Daily Administration Delayed up to 96 hours.

HYPOTHESIS: SENS-401 (R-azasetron besylate) is effective against severe acoustic trauma-induced hearing loss. BACKGROUND: SENS-401 has calcineurin inhibiting properties and attenuates cisplatin-induced hearing loss in a rat model. Cisplatin-induced and acoustic trauma-induced hearing loss share common apoptotic pathways. METHODS: The dose-response relationship of SENS-401 (6.6 mg/kg BID, 13.2 mg/kg BID, 26.4 mg/kg QD) and treatment time-window (13.2 mg/kg BID starting 24, 72, and 96 h posttrauma) versus placebo for 28 days were evaluated in a male rat model of severe acoustic trauma-induced hearing loss (120 dB SPL, 2 h) using auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) measures followed by cochlear outer hair cell (OHC) counting with myosin-VIIa immunolabeling. RESULTS: All SENS-401 doses improved ABR threshold shift and recovery, reaching statistical significance (p < 0.05) for ABR threshold recoveries after 28-days treatment. DPOAE amplitude loss and recovery improved markedly for 13.2 mg/kg BID SENS-401, reaching significance after 14 days (p < 0.05). Significant improvements in ABR threshold shifts/recovery and DPOAE amplitude loss occurred with up to 96-hours delay in initiating SENS-401 (p < 0.05), and in DPOAE amplitude recovery with up to 72-hours delay (p < 0.05). Significantly more surviving OHCs were present after SENS-401 treatment compared with placebo after 24 to 96-hours delay posttrauma, with up to 5.3-fold more cells in the basal cochlea turn. CONCLUSIONS: In vivo data support the otoprotective potential of twice daily oral SENS-401. Improvements in hearing loss recovery make SENS-401 a promising clinical candidate for acoustic trauma-induced hearing loss, including when treatment is not initiated immediately.

Otoprotective Effects of Stephania tetrandra S. Moore Herb Isolate against Acoustic Trauma.

Noise is the most common occupational and environmental hazard, and noise-induced hearing loss (NIHL) is the second most common form of sensorineural hearing deficit. Although therapeutics that target the free-radical pathway have shown promise, none of these compounds is currently approved against NIHL by the United States Food and Drug Administration. The present study has demonstrated that tetrandrine (TET), a traditional Chinese medicinal alkaloid and the main chemical isolate of the Stephania tetrandra S. Moore herb, significantly attenuated NIHL in CBA/CaJ mice. TET is known to exert antihypertensive and antiarrhythmic effects through the blocking of calcium channels. Whole-cell patch-clamp recording from adult spiral ganglion neurons showed that TET blocked the transient Ca2+ current in a dose-dependent manner and the half-blocking concentration was 0.6 + 0.1 µM. Consistent with previous findings that modulations of calcium-based signaling pathways have both prophylactic and therapeutic effects against neural trauma, NIHL was significantly diminished by TET administration. Importantly, TET has a long-lasting protective effect after noise exposure (48 weeks) in comparison to 2 weeks after noise exposure. The otoprotective effects of TET were achieved mainly by preventing outer hair cell damage and synapse loss between inner hair cells and spiral ganglion neurons. Thus, our data indicate that TET has great potential in the prevention and treatment of NIHL.

Chronotolerance for cisplatin ototoxicity in the rat.

Cisplatin is a potent chemotherapeutic compound for which ototoxicity is a significant side effect. Cisplatin has shown sensitivity to circadian time, in that cisplatin is most effective as an anti-tumor compound, and least nephrotoxic, when given in the active (dark) period of the light-dark cycle in rodents. The objective of the study was to determine the sensitivity of cisplatin ototoxicity to circadian time. Fifty-seven Fischer 344/NHsd rats were exposed to 12 mg/kg cisplatin by intra-peritoneal injection at one of six time points on a 12 h light-12 h dark cycle: 2, 6, or 10 h after light onset or 2, 6, or 10 h after light offset. Cochlear injury was evaluated using auditory brainstem response threshold shifts and postmortem outer hair cell counts. All animals experienced threshold shift in the highest frequencies tested (30 and 40 kHz). The animals exposed to cisplatin at 6 h after light onset (the inactive period) had significantly higher mid-frequency threshold shifts and outer hair cell losses than the groups exposed during the dark hours. The results indicate that cisplatin is less likely to cause ototoxicity in the Fischer 344/NHsd rat when given during the active period. This finding is consistent with the lower nephrotoxicity that has been detected in cisplatin-exposed animals treated during the dark hours, and the magnitude of differences in threshold shifts between the light and dark exposure indicates that circadian timing has a significant impact on susceptibility to cisplatin ototoxicity.

Influence of Ginkgo Biloba extract (EGb 761) on expression of IL-1 Beta, IL-6, TNF-alfa, HSP-70, HSF-1 and COX-2 after noise exposure in the rat cochlea.

OBJECTIVE: The objective of this study was to investigate the influence of Ginkgo Biloba in early treatment of noise induced hearing loss on expression of IL-6, IL-1 Beta, TNF-alfa, HSP-70, HSF-1 and COX-2 in the rat cochlea. METHODS: Thirty two female rats were randomly divided into four groups (Acoustic Trauma, Ginkgo Biloba, Acoustic Trauma+Ginkgo Biloba, Non Treatment). Auditory brainstem response (ABR) was applied in all the groups. At the end of the study, IL-1Beta, IL-6, TNF-alpha, HSP-70, HSF-1 and COX-2 were studied in cochlear tissue with ELISA and Western blot analysis. RESULTS: There were significant increases in ABR values measured at days 1 and 7 compared to baseline values in Group 3. IL-1 Beta, IL-6 and TNF-alpha values were significantly higher in Group 1 than in the other groups. Whereas HSP-70 and HSF-1 values were found to be significantly lower in Group 1 compared to those in Group 2 and Group 3. COX-2 of Group 1 was significantly higher than the other groups. CONCLUSION: Ginkgo Biloba is helpful in the treatment of noise induced hearing loss and exerts its effect by inhibiting expression of IL-1 Beta, IL-6, TNF-alpha and COX-2 and increasing HSP-70 and HSF-1 values in rat cochlea.

Brainstem auditory evoked responses in 37 dogs with otitis media before and after topical therapy.

OBJECTIVES: The objective of this study was to determine whether intra-aural administration of aqueous solutions of marbofloxacin, gentamicin, tobramycin and ticarcillin (used off-licence) was associated with changes in hearing as measured by brainstem auditory evoked responses. MATERIALS AND METHODS: Dogs diagnosed with otitis media (n=37) underwent brainstem auditory evoked response testing and then were treated for their ear disease. First, the external ear canal and middle ear were flushed with sterile saline followed by EDTA tris with 0·15% chlorhexidine. Then, a combination of aqueous antibiotic mixed with an aqueous solution of EDTA tris was instilled into the middle ear. Follow-up examinations were undertaken for each dog, and treatment was continued until there were no detected infectious organisms or inflammatory infiltrate. Brainstem auditory evoked response testing was repeated after resolution of the infection and discontinuation of therapy. RESULTS: Brainstem auditory evoked responses in dogs treated with aqueous solutions of marbofloxacin or gentamicin remained unchanged or improved after therapy of otitis media but were impaired in dogs treated with ticarcillin or tobramycin. CLINICAL SIGNIFICANCE: If off-licence use of topical antibiotics is deemed necessary in cases of otitis media, aqueous solutions of marbofloxacin and gentamicin appear to be less ototoxic than aqueous solutions of ticarcillin or tobramycin.

Evaluation of Effect of Garlic Aged Extracts and Vitamin B12 on Noise-Induced Hearing Loss.

OBJECTIVE: This study investigated effects of S-allylmercaptocysteine (SAMC), diallyl disulfide (DADS), and vitamin B12 on inner ear functions and morphology after long-period high-level broadband noise exposure. MATERIALS AND METHODS: Twenty-four healthy rats were randomly divided into four groups. First group was chosen as the control group. Vitamin B12, SAMC, and DADS were applied to other groups for 4 weeks. On the 14th day, each group was exposed to broadband noise. Auditory brainstem response test was performed before and immediately after noise exposure and repeated on the 2nd and 14th day. RESULTS: Permanent threshold shifts were significantly lower in groups treated with vitamin B12, SAMC, and DADS. Histologically, cochleae of SAMC and DADS groups were found to be better preserved than the cochleae of vitamin B12 and control groups. CONCLUSION: Physiologically and histologically, SAMC and DADS reduced the long-term effects of noise. However, physiological recovery was not consistent with the morphological findings in vitamin B12 group.

Gas Anesthesia Impairs Peripheral Auditory Sensitivity in Barn Owls (Tyto alba).

Auditory nerve single-unit recordings were obtained from two groups of young barn owls (age, between posthatching days 11 and 86) in terminal experiments under two different anesthetic regimes: ketamine (6-11 mg/kg) plus xylazine (∼2 mg/kg); or isoflurane (1-1.5%) in oxygen, delivered via artificial respiration. In a second series of minimally invasive experiments, auditory brainstem responses (ABRs) were recorded in the same four adult barn owls (Tyto alba; age, between 5 and 32 months) under three different anesthetic protocols: ketamine (10 mg/kg) plus xylazine (3 mg/kg), isoflurane (1-1.5%), and sevoflurane (2-3%) in carbogen. Finally, the ABR measurements on adult owls were repeated in terminal experiments including more invasive procedures such as artificial respiration and higher isoflurane dosage. The main finding was a significant deterioration of auditory sensitivity in barn owls under gas anesthesia, at the level of the auditory nerve (i.e., a very peripheral level of the auditory system). The effect was drastic in the young animals that experienced threshold elevations in auditory nerve single-unit responses of ≥20 dB. ABR thresholds assessed repeatedly in experiments on adult owls were also significantly higher under isoflurane and sevoflurane, on average by 7 and 15 dB, compared with ketamine/xylazine. This difference already occurred with minimal dosages and was reversibly enlarged with increased isoflurane concentration. Finally, there was evidence for confounding detrimental effects associated with artificial respiration over many hours, which suggested oxygen toxicity.

Evaluation of Mitoquinone for Protecting Against Amikacin-Induced Ototoxicity in Guinea Pigs.

HYPOTHESIS: Mitoquinone (MitoQ) attenuates amikacin ototoxicity in guinea pigs. BACKGROUND: MitoQ, a mitochondria-targeted derivative of the antioxidant ubiquinone, has improved bioavailability and demonstrated safety in humans. Thus, MitoQ is a promising therapeutic approach for protecting against amikacin-induced ototoxicity. METHODS: Both oral and subcutaneous administrations of MitoQ were tested. Amikacin-treated guinea pigs (n = 12-18 per group) received water alone (control) or MitoQ 30 mg/l-supplemented drinking water; or injected subcutaneously with 3 to 5 mg/kg MitoQ or saline (control). Auditory brainstem responses and distortion product otoacoustic emissions were measured before MitoQ or control solution administration and after amikacin injections. Cochlear hair cell damage was assessed using scanning electron microscopy and Western blotting. RESULTS: With oral administration, animals that received 30 mg/l MitoQ had better hearing than controls at only 24 kHz at 3-week (p = 0.017) and 6-week (p = 0.027) post-amikacin. With subcutaneous administration, MitoQ-injected guinea pigs had better hearing than controls at only 24 kHz, 2-week post-amikacin (p = 0.013). Distortion product otoacoustic emission (DPOAE) amplitudes were decreased after amikacin injections, but were not different between treatments (p > 0.05). Electron microscopy showed minor difference in outer hair cell loss between treatments. Western blotting demonstrated limited attenuation of oxidative stress in the cochlea of MitoQ-supplemented guinea pigs. CONCLUSIONS: Oral or subcutaneous MitoQ provided limited protection against amikacin-induced hearing loss and cochlear damage in guinea pigs. Other strategies for attenuating aminoglycoside-induced ototoxicity should be explored.

Effects of the cannabinoid CB1 agonist ACEA on salicylate ototoxicity, hyperacusis and tinnitus in guinea pigs.

Cannabinoids have been suggested as a therapeutic target for a variety of brain disorders. Despite the presence of their receptors throughout the auditory system, little is known about how cannabinoids affect auditory function. We sought to determine whether administration of arachidonyl-2'-chloroethylamide (ACEA), a highly-selective CB1 agonist, could attenuate a variety of auditory effects caused by prior administration of salicylate, and potentially treat tinnitus. We recorded cortical resting-state activity, auditory-evoked cortical activity and auditory brainstem responses (ABRs), from chronically-implanted awake guinea pigs, before and after salicylate + ACEA. Salicylate-induced reductions in click-evoked ABR amplitudes were smaller in the presence of ACEA, suggesting that the ototoxic effects of salicylate were less severe. ACEA also abolished salicylate-induced changes in cortical alpha band (6-10 Hz) oscillatory activity. However, salicylate-induced increases in cortical evoked activity (suggestive of the presence of hyperacusis) were still present with salicylate + ACEA. ACEA administered alone did not induce significant changes in either ABR amplitudes or oscillatory activity, but did increase cortical evoked potentials. Furthermore, in two separate groups of non-implanted animals, we found no evidence that ACEA could reverse behavioural identification of salicylate- or noise-induced tinnitus. Together, these data suggest that while ACEA may be potentially otoprotective, selective CB1 agonists are not effective in diminishing the presence of tinnitus or hyperacusis.

Cannula-based drug delivery to the guinea pig round window causes a lasting hearing loss that may be temporarily mitigated by BDNF.

Sustained local delivery of drugs to the inner ear may be required for future regenerative and protective strategies. The round window is surgically accessible and a promising delivery route. To be viable, a delivery system should not cause hearing loss. This study determined the effect on hearing of placing a drug-delivery microcatheter on to the round window, and delivering either artificial perilymph (AP) or brain-derived neurotrophic factor (BDNF) via this catheter with a mini-osmotic pump. Auditory brainstem responses (ABRs) were monitored for 4 months after surgery, while the AP or BDNF was administered for the first month. The presence of the microcatheter - whether dry or when delivering AP or BDNF for 4 weeks - was associated with an increase in ABR thresholds of up to 15 dB, 16 weeks after implantation. This threshold shift was, in part, delayed by the delivery of BDNF. We conclude that the chronic presence of a microcatheter in the round window niche causes hearing loss, and that this is exacerbated by delivery of AP, and ameliorated temporarily by delivery of BDNF.

Trigonelline promotes auditory function through nerve growth factor signaling on diabetic animal models.

BACKGROUND: Protection of cochlear function and reconstruction of neuronal networks in damaged auditory sensory structures is crucial for therapeutic treatment of diabetic hearing loss. Nerve growth factor (NGF) has been used as a novel therapeutic target to protect against the neurodegenerative effects of Diabetes Mellitus (DM). PURPOSE: We aimed to evaluate the potential effect of trigonelline (TRG) on reducing auditory damage produced by DM using NGF as a potential marker. METHOD: Docking simulations were carried out using Autodock Vina software and visualized using Discovery Studio. Morphological analysis of hair cells and neuromasts was performed on alloxan-induced diabetic zebrafish by fluorescence and scanning electron microscopy. Blockage of NGF receptor phosphorylation with K-252a was used to evaluate TRG and NGF action. Further assessment of NGF by ELISA on a primary culture of spiral ganglion cells was performed as a marker of neuronal function on the hearing system. Finally, auditory function was assessed in LepR(db/db) mice using auditory brainstem response (ABR) and transient evoked otoacoustic emission (TEOAE) during 8 weeks. RESULTS: Docking simulations showed that TRG binds to the active site of NGF through molecular interactions with Lysine88 (Lys88) and Tyrosine52 (Tyr52). TRG treatment significantly reduced hair cell loss and neuromast damage in diabetic zebrafish (P < .05). Further evaluation revealed a significant increase in the number of neuromasts after NGF administration (P < .001). TRG and NGF action was suppressed during blockage of NGF receptor phosphorylation. Moreover, spiral ganglion cells revealed significant elevation on NGF values after TRG treatment (P < .05). In vivo evaluation of LepR(db/db) mice revealed a significant reduction in the auditory damage produced under diabetic progression, characterized by reduced ABR hearing threshold shifts and increased signal-to-noise ratio in TEOAE (P < .05). CONCLUSIONS: This study suggests that the enhanced hearing function produced by TRG may be mediated by NGF, providing a potential therapeutic strategy for diabetic hearing loss.