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Targets to prevent hearing loss caused by certain antibiotics

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Some life-saving antibiotics cause hearing loss, and now, for the first time, some researchers think they know why and are one step closer to preventing it.

Aminoglycosides (AGs), such as gentamicin, are potent, broad-spectrum antibiotics used to treat a wide variety of life-threatening infections.

However, they do have a downside: they are ototoxic, which means a person taking them may develop hearing or balance problems because they cause irreversible damage to cochlear hair cells.

Until now, scientists knew very little about the molecular pathways critical to hair cell survival that are affected by exposure to these antibiotics.

But in a new study from the journal Development cellAmerican researchers have discovered that the dysfunction of a process within the cell, called autophagy, is linked.

By reducing the expression of a protein involved in autophagy in cochlear hair cells, they were able to prevent hair cell death and subsequent hearing loss caused by systemic exposure to AGs.

“This work identifies several potential therapeutic targets for preventing aminoglycoside-induced hearing loss,” says lead author Bo Zhao, assistant professor of otolaryngology at Indiana University School of Medicine, USA. United States.


Read more: Loss of hair cells may explain hearing loss.


What is autophagy?

Autophagy is the process by which cells “eat” pieces of themselves – hence the name. It comes from the Greek “autos” meaning self and “phageîn” meaning to eat.

Thanks to autophagy, unwanted or damaged molecules are eliminated and recycled from the cell. First, they are marked for disposal, enveloped by a membrane (becoming an autophagosome) which then fuses with a lysosome (an acidic organelle filled with enzymes) which breaks them down into nutrients that the cell can then reuse.

But when autophagy is abnormal or triggered inappropriately, it can cause cell damage and death.

In a cell line from the inner ear of mice, researchers found that FAs bind and trigger the translocation of a protein called RIPOR2.

Usually, this enzyme is found at the base of tiny hair-like structures called stereocilia in the cochlear hair cell. But all the AGs tested, and none of the other types of antibiotics examined, cause it to translocate to another region – the pericuticular collar – inside the cell.

There, RIPOR2 interacts with GABARAP, a component of the autophagy pathway that plays a major role in the elimination and recycling of dysfunctional cellular components.

“As aminoglycosides specifically trigger a rapid localization change of RIPOR2 in hair cells, we hypothesize that RIPOR2 is essential for aminoglycoside-induced hair cell death,” Zhao explains.

“We then discovered that RIPOR2 regulates the autophagy pathway in hair cells. Knowing this, we developed other laboratory models without the expression of several key autophagy proteins that did not show hair cell death or hearing loss when treated with the antibiotic.” Dr. Jinan Li, postdoctoral fellow in Zhao’s lab and first author of the paper. .

Reducing RIPOR2 expression prevents hearing loss in mice

The team then injected AG into mice that had been genetically modified to produce significantly lower levels of the RIPOR2 protein and, surprisingly, no significant loss of hair cells occurred.

These results suggest that reduced RIPOR2 expression protects hair cells from AG-induced death.

Next, auditory brainstem response tests to “click stimuli” were measured in normal and genetically modified mice to determine whether reducing RIPOR2 expression could prevent GA-induced hearing loss.

And while the normal mice were found to be profoundly deaf after treatment with AG, remarkably, there was no significant change in the hearing thresholds of the mice that produced less RIPOR2.

The authors state that the proteins identified in this study could potentially be used as drug targets to prevent aminoglycoside-induced hearing loss in future studies.