New breakthroughs in pathophysiology and treatment for Noise Induced Hearing Loss (NIHL)

It's easy to say that we should avoid loud noises, but in reality, this is not always possible. Front-line soldiers or first responders do not have time to worry about the long-term effects of loud noise when they are giving their all. If, however, a drug could be developed to minimize the negative effects of loud noises, it would benefit one and all.

Noise-induced hearing loss, with accompanying tinnitus and sound hypersensitivity is a common condition which leads to communication problems and social isolation.

In a research report published in the September 2013 issue of The FASEB Journal, scientists describe exactly what type of damage noise does to the inner ear, and provide insights into a compound that may prevent noise-related damage.

To make this discovery, Shi and colleagues used three groups of 6 - 8 week old mice, which consisted of a control group, a group exposed to broadband noise at 120 decibels for three hours a day for two days, and a third group given single-dose injections of pigment epithelium-derived factor (PEDF) prior to noise exposure. PEDF is a protein found in vertebrates that is currently being researched for the treatment of diseases like heart disease and cancer. The cells that secrete PEDF in control animals showed a characteristic branched morphology, with the cells arranging in a self-avoidance pattern which provided good coverage of the capillary wall. The morphology of the same cells in the animals exposed to wide-band noise, however, showed clear differences -- noise exposure caused changes in melanocytes located in the inner ear.

At the present time, the only treatment strategies for hearing loss are hearing aids and cochlear implants. Drug therapies for noise-induced hearing loss have only recently been proposed and, to date, there are virtually no treatments that can repair the damage to the inner ear and reduce the impact of hearing loss.

Researchers from the University of Auckland, New Zealand, have discovered that a potent new drug restores hearing after noise-induced hearing loss in rats. The landmark discovery found that injection of an agent called 'ADAC', activates adenosine receptors in cochlear tissues, resulting in recovery of hearing function.

Vlajkovic and his team's study investigates the potential of adenosine amine congener (ADAC) -- a selective A1 adenosine receptor agonist -- in the treatment of noise-induced hearing loss. Wistar rats were exposed to narrow-band noise for 2 -- 24 hours in an acoustic chamber to induce cochlear damage and permanent hearing loss. ADAC or placebo control was then administered by injection(s) in the abdomen, either as a single injection at six hours or multiple daily injections. The researchers measured the hearing in the rats before and after the treatments using a technique known as auditory brainstem response (ABR). They also used histological techniques to determine the number of missing cochlear sensory hair cells after noise exposure and the noise-induced production of free radicals.

Their results show that cochlear injury and hearing loss in rats exposed to narrow-band noise can be substantially restored by ADAC administration after noise exposure. Early treatment starting six hours after noise exposure was the most effective and provided greater recovery than late treatment starting 24 hours after noise exposure. The most sustainable treatment strategy was the one involving multiple injections of ADAC for five days after noise exposure. This therapy significantly attenuated noise-induced hearing loss and improved sensory hair cell survival.

Resveratrol, a substance found in red grapes and red wine, may have the potential to protect against hearing and cognitive decline, according to a published laboratory study from Henry Ford Hospital in Detroit.

The study shows that healthy rats are less likely to suffer the long-term effects of noise-induced hearing loss when given resveratrol before being exposed to loud noise for a long period of time. Resveratrol is a very powerful chemical that seems to protect against the body's inflammatory process as it relates to aging, cognition and hearing loss. The latest study focuses on the inflammatory process as it relates to aging, cognition and hearing loss.

It was designed to identify the potential protective mechanism of resveratrol following noise exposure by measuring its effect on cyclooxygenase-2 (or COX-2, key to the inflammatory process) protein expression and formation of reactive oxygen species, which plays an important role in cell signaling and homeostasis.

The study reveals that acoustic over-stimulation causes a time-dependent, up-regulation of COX-2 protein expression, and, resveratrol, significantly reduces reactive oxygen species formation, inhibits COX-2 expression and reduces noise-induced hearing loss following noise exposure in rats. Ultimately, these findings suggest that resveratrol may exert a protective effect from noise-induced hearing loss by the inhibition of COX-2 expression and reactive oxygen species formation, although other mechanism may also be involved.

An epilepsy drug shows promise in an animal model at preventing tinnitus from developing after exposure to loud noise, according to a new study by researchers at the University of Pittsburgh School of Medicine.

The team focused on an area of the brain that is home to an important auditory center called the dorsal cochlear nucleus (DCN). From previous research in a mouse model, they knew that tinnitus is associated with hyperactivity of DCN cells -- they fire impulses even when there is no actual sound to perceive. For the new experiments, they took a close look at the biophysical properties of tiny channels, called KCNQ channels, through which potassium ions travel in and out of the cell.

They found that mice with tinnitus have hyperactive DCN cells because of a reduction in KCNQ potassium channel activity. These KCNQ channels act as effective "brakes" that reduce excitability or activity of neuronal cells.

Tzounopoulos and his team tested whether an FDA-approved epilepsy drug called retigabine, which specifically enhances KCNQ channel activity, could prevent the development of tinnitus. Thirty minutes into the noise exposure and twice daily for the next five days, half of the exposed group was given injections of retigabine. The researchers found that mice that were treated with retigabine immediately after noise exposure did not develop tinnitus.

Such a medication could be a very helpful preventive strategy for soldiers and other people who work in situations where exposure to very loud noise is likely,

Source:

1. Federation of American Societies for Experimental Biology. "Now hear this: Scientists discover compound to prevent noise-related hearing loss." ScienceDaily, 29 Aug. 2013. Web. 29 Sep. 2013. 
2. Srdjan M. Vlajkovic, Kyu-Hyun Lee, Ann Chi Yan Wong, Cindy X. Guo, Rita Gupta, Gary D. Housley, Peter R. Thorne.Adenosine amine congener mitigates noise-induced cochlear injury. Purinergic Signalling, 2010; DOI:10.1007/s11302-010-9188-5
3. M. D. Seidman, W. Tang, V. U. Bai, N. Ahmad, H. Jiang, J. Media, N. Patel, C. J. Rubin, R. T. Standring. Resveratrol Decreases Noise-Induced Cyclooxygenase-2 Expression in the Rat Cochlea. Otolaryngology -- Head and Neck Surgery, 2013; DOI: 10.1177/0194599813475777
4. J. W. Middleton, T. Kiritani, C. Pedersen, J. G. Turner, G. M. G. Shepherd, T. Tzounopoulos. Mice with behavioral evidence of tinnitus exhibit dorsal cochlear nucleus hyperactivity because of decreased GABAergic inhibition. Proceedings of the National Academy of Sciences, 2011; 108 (18): 7601 DOI:10.1073/pnas.1100223108

The Exciting Science Behind Taste

We know that the human tongue can detect five tastes -- sweet, salt, sour, bitter and umami (a taste for identifying protein rich foods).

Taste cells are found in papillae, the little bumps on our tongues. These cells contain the receptors that interact with chemicals in foods to allow us to sense sweet, salty, sour, bitter, and umami. Taste cells are located in clusters called taste buds, which in turn are found in papillae, the raised bumps visible on the tongue's surface.

Two types of taste cells contain chemical receptors that initiate perception of sweet, bitter, umami, salty, and sour taste qualities. A third type appears to serve as a supporting cell.

A remarkable characteristic of these sensory cells is that they regularly regenerate. All three taste cell types undergo frequent turnover, with an average lifespan of 10-16 days. As such, new taste cells must constantly be regenerated to replace cells that have died.

When sweet, bitter and umami molecules reach the tongue, they activate taste receptors in specialized cells called Type II taste cells. 'how do these taste cells tell the brain that they have detected something?' This question has been a longstanding missing link in our understanding of taste perception. The scientists already knew that activation of taste receptors on Type II cells initiates a complex chain of events inside the taste cells. What they found, as reported in the current issue of Nature, is that the final step involves the opening of a pore formed by CALHM1 (calcium-homeostasis-modulator-1) in the taste cell membrane. The open channel allows molecules of the neurotransmitter ATP to leave the taste cell and relay a signal to adjacent nerve cells connected to the brain.

Monell molecular neurobiologist Ichiro Matsumato, PhD, contributed to the work by showing that the gene for CALHM1 is expressed in Type II taste cells, but not in other types of taste tissue. Their findings demonstrate that the CALHM1 pore is localized specifically in cells that detect sweet, bitter and umami taste.

The necessity of CALHM1 for the ability to taste sweet, bitter, and umami was demonstrated in behavioral tests performed by Tordoff. Reasoning that mice lacking the CALMH1 channel would not be able to release ATP to send information about sweet, bitter and umami taste detection to the brain, Tordoff tested the taste preferences of Calhm1 'knockout' mice. Engineered by co-author Philippe Marambaud, PhD, of the Feinstein Institute for Medical Research, the knockout mice lack the gene that codes for CALHM1.

"Like humans, mice with an intact CALHM1 gene avidly drink sucrose and other sweeteners, and avoid bitter compounds such as quinine. However, mice lacking CALHM1 are very unusual," said Tordoff. "These mice treat sweeteners and bitter compounds as if they were water. They behave as if they can't taste them at all."

Responses to salty and sour tastes were not affected by the missing gene because perception of these taste qualities is mediated via a different set of taste cells.

Of the five taste sensations -- sweet, bitter, sour, salty and umami -- sour is arguably the strongest yet the least understood. Sour is the sensation evoked by substances that are acidic, such as lemons and pickles. The more acidic the substance, the more sour the taste.

Acids release protons. How protons activate the taste system had not been understood. The USC team expected to find protons from acids binding to the outside of the cell and opening a pore in the membrane that would allow sodium to enter the cell. Sodium's entry would send an electrical response to the brain, announcing the sensation that we perceive as sour.

Instead, the researchers found that the protons were entering the cell and causing the electrical response directly.

"In order to understand how sour works, we need to understand how the cells that are responsive to sour detect the protons," said senior author Emily Liman, associate professor of neurobiology in the USC College of Letters, Arts and Sciences.

"In the past, it's been difficult to address this question because the taste buds on the tongue are heterogeneous. Among the 50 or so cells in each taste bud there are cells responding to each of the five tastes. But if we want to know how sour works, we need to measure activity specifically in the sour sensitive taste cells and determine what is special about them that allows them to respond to protons."

Liman and her team bred genetically modified mice and marked their sour cells with a yellow florescent protein. Then they recorded the electrical responses from just those cells to protons.

The ability to sense protons with a mechanism that does not rely on sodium has important implications for how different tastes interact, Liman speculates.

"This mechanism is very appropriate for the taste system because we can eat something that has a lot of protons and not much sodium or other ions, and the taste system will still be able to detect sour," she said. "It makes sense that nature would have built a taste cell like this, so as not to confuse salty with sour."



References:

1. Akiyuki Taruno, Valérie Vingtdeux, Makoto Ohmoto, Zhongming Ma, Gennady Dvoryanchikov, Ang Li, Leslie Adrien, Haitian Zhao, Sze Leung, Maria Abernethy, Jeremy Koppel, Peter Davies, Mortimer M. Civan, Nirupa Chaudhari, Ichiro Matsumoto, Göran Hellekant, Michael G. Tordoff, Philippe Marambaud, J. Kevin Foskett. CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. Nature, 2013; DOI:10.1038/nature11906
2. Monell Chemical Senses Center. "Scientists help identify a missing link in taste perception."ScienceDaily, 6 Mar. 2013. Web. 8 Mar. 2013.
3. Rui B. Chang, Hang Waters, Emily R. Liman. A proton current drives action potentials in genetically identified sour taste cells. Proceedings of the National Academy of Sciences, 2010; DOI:10.1073/pnas.1013664107
4. University of Southern California (2010, November 25). How people perceive sour flavors: Proton current drives action potentials in taste cells. ScienceDaily. Retrieved March 8, 2013, from http://www.sciencedaily.com­/releases/2010/11/101124114709.htm

Temporary Hearing Deprivation Can Lead to 'Lazy Ear'

Scientists have gained new insight into why a relatively short-term hearing deprivation during childhood may lead to persistent hearing deficits, long after hearing is restored to normal. The research, published by Cell Press in the March 11 issue of the journal Neuron, reveals that, much like the visual cortex, development of the auditory cortex is quite vulnerable if it does not receive appropriate stimulation at just the right time.

It is well established that degraded sensory experience during critical periods of childhood development can have detrimental effects on the brain and behavior. In the classic example, a condition called amblyopia (also known as lazy eye) can arise when balanced visual signals are not transmitted from each eye to the brain during a critical period for visual cortex development.

An analogous problem may exist in the realm of hearing, in that children commonly experience a buildup of viscous fluid in the middle ear cavity, called otitis media with effusion, which can degrade the quality of acoustic signals reaching the brain and has been associated with long-lasting loss of auditory perceptual acuity," explains senior study author, Dr. Daniel Polley from the Massachusetts Eye and Ear Infirmary.

Dr. Polley and his colleague Dr. Maria Popescu from Vanderbilt University implemented a method to reversibly block hearing in one ear in infant, juvenile, and adult rats then looked at how auditory brain areas were impacted by the temporary hearing loss.

They observed that the temporary hearing loss in one ear distorted auditory patterning in the brain, weakened the deprived ear's representation and strengthened the open ear's representation. The scope of reorganization was most striking in the cortex (and not "lower" parts of the auditory pathway) and was more pronounced when hearing deprivation began in infancy than in later life. Therefore, it appears that maladaptive plasticity in the developing auditory cortex might underlie "amblyaudio," in a similar fashion to the contributions of visual cortex plasticity to amblyopia.

"The good news about amblyaudio is that it is unlikely to be a permanent problem for most people," concludes Dr. Polley. "Even if the acoustic signal isn't improved within the critical period, the mature auditory cortex still expresses a remarkable degree of plasticity. We know that properly designed visual training can improve visual acuity in adult amblyopia patients. We are gearing up now to study whether auditory perceptual training may also be a promising approach to accelerate recovery in individuals with unresolved auditory processing deficits stemming from childhood hearing loss."

Journal reference:
Maria V. Popescu, Daniel B. Polley. Monaural Deprivation Disrupts Development of Binaural Selectivity in Auditory Midbrain and Cortex. Neuron, 2010; 65 (5): 718-731 DOI:10.1016/j.neuron.2010.02.019