Statins protect mice from high-decibel noise-induced hearing loss.

No medical interventions for noise induced hearing loss (NIHL) are approved by the Food and Drug Administration (USA). Here, we evaluate statins in CBA/CaJ mice as potential drugs for hearing loss. Direct delivery of fluvastatin to the cochlea and oral delivery of lovastatin were evaluated.

Statins and hearing.

Statins are a class of drugs that are widely used for the treatment of hyperlipidemia and the prevention of heart attack and stroke. These drugs inhibit the rate-limiting step in the synthesis of cholesterol, HMG-CoA reductase. In addition, statins have effects unrelated to cholesterol, stemming from the non-cholesterol synthesizing arms of the HMG-CoA reductase pathway and the regulation of gene expression.

Hearing differences in Hartley guinea pig stocks from two breeders.

Across the world, dozens of outbred Hartley guinea pig stocks are used for auditory experiments. The genetic makeup of these different stocks will differ due to differences in breeding protocols, history and genetic drift. In fact, outbred breeding protocols are not intended to produce genetically identical animals, neither across breeders, nor across time.

Sex Genotyping of Archival Fixed and Immunolabeled Guinea Pig Cochleas.

For decades, outbred guinea pigs (GP) have been used as research models. Various past research studies using guinea pigs used measures that, unknown at the time, may be sex-dependent, but from which today, archival tissues may be all that remain. We aimed to provide a protocol for sex-typing archival guinea pig tissue, whereby past experiments could be re-evaluated for sex effects.

Fluvastatin protects cochleae from damage by high-level noise.

Exposure to noise and ototoxic drugs are responsible for much of the debilitating hearing loss experienced by about 350 million people worldwide. Beyond hearing aids and cochlear implants, there have been no other FDA approved drug interventions established in the clinic that would either protect or reverse the effects of hearing loss. Using Auditory Brainstem Responses (ABR) in a guinea pig model, we demonstrate that fluvastatin, an inhibitor of HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, protects against loss of cochlear function initiated by high intensity noise.

Directed Differentiation of Human Embryonic Stem Cells Toward Placode-Derived Spiral Ganglion-Like Sensory Neurons.

The ability to generate spiral ganglion neurons (SGNs) from stem cells is a necessary prerequisite for development of cell-replacement therapies for sensorineural hearing loss. We present a protocol that directs human embryonic stem cells (hESCs) toward a purified population of otic neuronal progenitors (ONPs) and SGN-like cells. Between 82% and 95% of these cells express SGN molecular markers, they preferentially extend neurites to the cochlear nucleus rather than nonauditory nuclei, and they generate action potentials.

Drug discovery for hearing loss: Phenotypic screening of chemical compounds on primary cultures of the spiral ganglion.

In the United States there are, at present, no drugs that are specifically FDA approved to treat hearing loss. Although several clinical trials are ongoing, including one testing D-methionine that is supported by the US Army, none of these trials directly address the effect of noise exposure on cochlear spiral ganglion neurons. We recently published the first report of a systematic chemical compound screen using primary, mammalian spiral ganglion cultures in which we were able to detect a compound and others in its class that increased neurite elongation, a critical step in restoring cochlear synapses after noise induced hearing loss.

Novel High Content Screen Detects Compounds That Promote Neurite Regeneration from Cochlear Spiral Ganglion Neurons.

The bipolar spiral ganglion neurons (SGN) carry sound information from cochlear hair cells to the brain. After noise, antibiotic or toxic insult to the cochlea, damage to SGN and/or hair cells causes hearing impairment. Damage ranges from fiber and synapse degeneration to dysfunction and loss of cells.

Targeting of the hair cell proteins cadherin 23, harmonin, myosin XVa, espin, and prestin in an epithelial cell model.

We have developed an advantageous epithelial cell transfection model for examining the targeting, interactions, and mutations of hair cell proteins. When expressed in LLC-PK1-CL4 epithelial cells (CL4 cells), the outer hair cell protein prestin showed faithful domain-specific targeting to the basolateral plasma membrane. We examined the consequences of mutations affecting prestin activity and assigned a targeting role to the cytoplasmic tail.

Selectivity of neural stimulation in the auditory system: a comparison of optic and electric stimuli.

Pulsed, mid-infrared lasers were recently investigated as a method to stimulate neural activity. There are significant benefits of optically stimulating nerves over electrically stimulating, in particular the application of more spatially confined neural stimulation. We report results from experiments in which the gerbil auditory system was stimulated by optical radiation, acoustic tones, or electric current.

Cochlear development: hair cells don their wigs and get wired.

Purpose Of Review: Hair cells and spiral ganglion neurons form functional pairings in the cochlea that transduce the mechanical energy of sound into signals that are carried to the brainstem. Mutations of genes affecting the development and maintenance of these two cell populations cause deafness in humans and other animals. This review highlights recent findings regarding the development of hair cell stereocilia and spiral ganglion neurons in the cochlea.

Espins are multifunctional actin cytoskeletal regulatory proteins in the microvilli of chemosensory and mechanosensory cells.

Espins are associated with the parallel actin bundles of hair cell stereocilia and are the target of mutations that cause deafness and vestibular dysfunction in mice and humans. Here, we report that espins are also concentrated in the microvilli of a number of other sensory cells: vomeronasal organ sensory neurons, solitary chemoreceptor cells, taste cells, and Merkel cells. Moreover, we show that hair cells and these other sensory cells contain novel espin isoforms that arise from a different transcriptional start site and differ significantly from other espin isoforms in their complement of ligand-binding activities and their effects on actin polymerization.