The experimental drug did not help with dementia, but cured deafness

Hearing of deaf mice restored with dementia medication

Copper News based on ScienceNOW materials: Drug Enables Deafened Mice to Hear AgainA group of American and Japanese scientists led by stem cell specialist Albert Edge from Massachusetts Eye and Ear Infirmary (Boston) managed to achieve partial regeneration of auditory hair cells affected by prolonged exposure to very intense noise in mice using a drug originally developed for the treatment of Alzheimer's disease.

The results of the work published in the journal Neuron (Mizutari et al., Notch Inhibition Induces Cochlear Hair Cell Regeneration and Recovery of Hearing after Acoustic Trauma) open up prospects for the pharmacological treatment of sensorineural hearing loss in humans.

The hair cells are located in the cochlea, which is located in the inner ear, and provide the process of generating nerve impulses in response to sound waves. When hair cells are damaged, including due to sound exposure, sensorineural deafness occurs, the treatment of which is difficult due to the fact that in mammals, unlike birds and fish, this type of cells does not naturally recover.

During the search for ways to activate the regenerative potential of hair cells, scientists managed to achieve this effect with the help of stem cells. In 2005, stem cell therapy partially restored hearing in adult guinea pigs, then the same effect was achieved in mice, and in 2009 this method was first used to treat sensorineural deafness in an infant who was transfused with a drug of his own cord blood, and gave successful results.

However, the research of Edge and his colleagues was aimed at finding drugs that promote the regeneration of hair cells, since this type of therapy, if successful, will be much more accessible and easy to use.

As such drugs, gamma secretase enzyme inhibitors were selected, originally developed for the treatment of Alzheimer's disease, but during clinical trials proved to be insufficiently effective and causing serious side effects from the intestine and the immune system.

Nevertheless, the Edge-led group discovered during experiments on inner ear stem cells in vitro that this class of drugs promotes the transformation of part of another class of auditory cells, support cells that remain intact in the case of sensorineural deafness, into hair cells. This happens due to the blocking of the Notch cellular signaling pathway by gamma secretase inhibitors as well. Transmembrane proteins of this family regulate cellular differentiation. Blocking Notch allows the support cells to act as precursors of the hair cells and thereby achieve the effect of regeneration of the latter.

To find out if this mechanism would work in vivo, Edge's group selected four drugs belonging to the class of gamma secretase inhibitors, the drug LY411575, which demonstrated the strongest regenerative effect in in vitro experiments. The authors then tested the drug on adult mice that became deaf after two hours of extreme acoustic exposure. As a result of the use of LY411575, hearing in mice was partially restored, and this happened due to the differentiation of support cells into hair cells.

An illustration demonstrating the regeneration of hair cells in mice.
On the left – cells before therapy, on the right – after. Photos of the authors of the study

The authors suggest that in the future, in the case of therapy of sensorineural hearing loss in humans with LY411575, undesirable side effects of the drug, which manifest themselves in the case of its oral use, can be avoided by its direct introduction into the membrane separating the middle and inner ear. Testing on mice showed that this method does not affect the effectiveness of the drug.

Although LY411575 is still far from clinical trials, many additional studies need to be conducted, in particular, to find out whether the effect of the drug persists if it is used not immediately after hearing loss, but delayed in time, the team leader believes that the results are very promising. "It's practically a foot stuck in the door," Edge said.

Portal "Eternal youth" http://vechnayamolodost.ru11.01.2013