Increased Sensitivity to Noise-Induced Hearing Loss by Blockade of Endogenous PI3K/Akt Signaling.

The PI3K/Akt signaling pathway is involved in mediating survival of sensory hair cells. Here, we investigated the involvement of PI3K/Akt in noise-induced hearing loss in both temporary and permanent threshold shift noise models. The PI3K regulatory subunit p85α and phosphorylation of Akt on serine 473 (p-Akt S473) are downregulated in sensory hair cells, including both outer and inner hair cells, and supporting cells of the mouse organ of Corti 1 h after exposure to permanent-threshold-shift-inducing noise (PTS noise), but not with temporary-threshold-shift-inducing noise (TTS noise). In contrast, the PI3K catalytic subunit p110α and phosphorylation of Akt on threonine 308 (p-Akt T308) do not change with PTS or TTS noise. Additionally, mice pretreated with p85α small interfering RNA (siRNA) have decreased expression of p-Akt1 (S473) in their sensory hair cells and increased sensitivity to TTS noise-induced hearing loss. Finally, Akt1-knockout mice also have enhanced sensitivity to TTS noise-induced hearing loss. In conclusion, this study suggests that endogenous PI3K/Akt signaling is an intrinsic protective mechanism of the inner ear. Blockade of PI3K/Akt signaling pathways increases sensitivity to TTS noise-induced hearing loss.

Ototoxicity in dogs and cats.

A variety of drugs in veterinary use have side effects that can potentially damage the senses of hearing or balance in animals. A large body of literature exists on the incidence and mechanisms of ototoxicity in experimental animals and in humans, but little is documented in domestic dogs and cats. However, the generality of these adverse actions across species allows one to extrapolate and provide the veterinarian with insight into possible complications of chemotherapy.

Cisplatin and aminoglycoside antibiotics: hearing loss and its prevention.

This review introduces the pathology of aminoglycoside antibiotic and the cisplatin chemotherapy classes of drugs, discusses oxidative stress in the inner ear as a primary trigger for cell damage, and delineates the ensuing cell death pathways. Among potentially ototoxic (damaging the inner ear) therapeutics, the platinum-based anticancer drugs and the aminoglycoside antibiotics are of critical clinical importance. Both drugs cause sensorineural hearing loss in patients, a side effect that can be reproduced in experimental animals. Hearing loss is reflected primarily in damage to outer hair cells, beginning in the basal turn of the cochlea. In addition, aminoglycosides might affect the vestibular system while cisplatin seems to have a much lower likelihood to do so. Finally, based on an understanding the mechanisms of ototoxicity pharmaceutical ways of protection of the cochlea are presented.

New developments in aminoglycoside therapy and ototoxicity.

After almost seven decades in clinical use, aminoglycoside antibiotics still remain indispensible drugs for acute infections and specific indications such as tuberculosis or the containment of pseudomonas bacteria in patients with cystic fibrosis. The review will describe the pathology and pathophysiology of aminoglycoside-induced auditory and vestibular toxicity in humans and experimental animals and explore contemporary views of the mechanisms of cell death. It will also outline the current state of protective therapy and recent advances in the development of aminoglycoside derivatives with low toxicity profiles for antimicrobial treatment and for stop-codon suppression in the attenuation of genetic disorders.

Age-related auditory pathology in the CBA/J mouse.

Commercially obtained aged male CBA/J mice presented a complex pattern of hearing loss and morphological changes. A significant threshold shift in auditory brainstem responses (ABR) occurred at 3 months of age at 4 kHz without apparent loss of hair cells, rising slowly at later ages accompanied by loss of apical hair cells. A delayed high-frequency deficit started at 24 kHz around the age of 12 months. At 20-26 months, threshold shifts at 12 and 24 kHz and the accompanying hair cell loss at the base of the cochlea were highly variable with some animals appearing almost normal and others showing large deficits. Spiral ganglion cells degenerated by 18 months in all regions of the cochlea, with cell density reduced by approximately 25%. There was no degeneration of the stria vascularis and the endocochlear potential remained stable from 3 to 25 months of age regardless of whether the animals had normal or highly elevated ABR thresholds. The slow high-frequency hearing loss combined with a modest reduction of ganglion cell density and an unchanged endocochlear potential suggest sensorineural presbycusis. The superimposed early hearing loss at low frequencies, which is not seen in animals bred in-house, may complicate the use of these animals as a presbycusis model.

Oxidative imbalance in the aging inner ear.

The mammalian inner ear loses its sensory cells with advancing age, accompanied by a functional decrease in balance and hearing. This study investigates oxidant stress in the cochlea of aging male CBA/J mice. Glutathione-conjugated proteins, markers of H2O2-mediated oxidation, began to increase at 12 months of age; 4-hydroxynonenal and 3-nitrotyrosine, products of hydroxyl radical and peroxynitrite action, respectively, were elevated by 18 months. Immunoreactivity to these markers was stronger in the supporting cells (Deiters and pillar cells) than the sensory cells and appeared later (23 months) in spiral ganglion cells and in the stria vascularis and spiral ligament. Conversely, antioxidant proteins (AIF) and enzymes (SOD2) decreased by 18 months in the organ of Corti (including the sensory cells) and spiral ganglion cells but not in the stria vascularis. These results suggest the presence of different reactive oxygen species and differential time courses of oxidative changes in individual tissues of the aging cochlea. An imbalance of redox status may be a component of age-related hearing loss.