New research has identified a particular cellular mechanism associated with the induction of tinnitus in an animal model, representing an important step forward in the effort to better understand and treat this common auditory disorder.
“What had been known from others and our work is that once mice are exposed to loud sounds, some of them develop tinnitus, and the ones that develop tinnitus have hyperactive auditory systems,” said Thanos Tzounopoulos, PhD, senior author of the study, which was published in Proceedings of the National Academy of Sciences.
“We wanted to figure out the cellular mechanism that leads to this hyperactivity,” said Dr. Tzounopoulos, who is associate professor of otolaryngology and neurobiology at the University of Pittsburgh.
In the study, 51.4 percent of 35 mice exposed to noise showed behavioral evidence of tinnitus. Using brain slices that contained the dorsal cochlear nucleus—an auditory brainstem nucleus previously implicated in tinnitus induction—Dr. Tzounopoulos and colleagues showed a reduction in KCNQ potassium channel activity in mice with tinnitus compared with control mice and mice who did not develop tinnitus after noise exposure. This decreased activity was restricted to the same regions that showed tinnitus-specific hyperactivity—those sensitive to high-frequency sounds.
Retigabine, which is approved as an antiseizure drug, enhances the activation of the KCNQ channel. When noise-exposed mice were injected with this agent 30 minutes after noise exposure and then twice a day for five days, the percentage that developed tinnitus went down to 18.8 percent.
IN VIVO TESTING
“I think it's a very good paper,” said Susan Shore, PhD, when asked to comment on the study. Dr. Shore is professor in the departments of otolaryngology, molecular and integrative physiology, and biomedical engineering at the University of Michigan.
“It's very systematic, and it's exploring the possible underlying mechanism that may contribute to tinnitus in these mice,” she added.
Dr. Shore noted the limitation inherent in drawing conclusions from experiments done in slices.
“This is a particular technique where just a little slice of the brain is taken away from the rest of the brain and put in a medium where they can block other neurotransmitters and modulators, for example, that you don't do when you're recording in a live preparation, so I think that it's essential for these results to be replicated in an in vivo preparation where normal neuroplasticity and synaptic inputs from many other places are interacting with these cells,” she said.
WINDOW OF OPPORTUNITY
The finding that retigabine suppressed tinnitus-like behaviors in this animal model is very provocative, said Richard Salvi, PhD, when asked to comment on the research.
“It's a pretty important study because it identifies an ion channel that regulates neuronal excitability, and this channel can be modulated by drugs that might be able to suppress tinnitus,” said Dr. Salvi, who is SUNY distinguished professor in the department of communicative disorders and sciences, as well as director of the Center for Hearing and Deafness, at the University at Buffalo, the State University of New York.
The research suggests areas for future investigation, Dr. Salvi added, such as whether the approach works in other animal models.
“Can you suppress tinnitus induced by ototoxic drugs that induce hearing loss, for example? Are there other behavioral models that really confirm these results? Does this drug retigabine or analogs of this drug suppress tinnitus in humans?
“One of the issues that comes up in the tinnitus literature is whether tinnitus is one unitary phenomenon or whether there are many different types of tinnitus. We used to think at one time there was just one type of cancer, but now we know there are many different types of cancer, and drugs that might be effective in treating one type of cancer might not be effective in treating another type.
“Is this mechanism that they identified common to all forms of tinnitus, or just noise-induced tinnitus?”
There's also a matter of timing.
“Something you would wonder about is, if somebody's had tinnitus for a year or two, or if an animal's had tinnitus for one or two years, can the drug still suppress tinnitus, or is it no longer effective?” Dr. Salvi said. “That would be a future study.”
Dr. Tzounopoulos and colleagues plan to address another question related to timing.
“There's a tiny window in which you can manipulate the channel and prevent the development of tinnitus,” Dr. Tzounopoulos said. “We want to determine this window; we want to see how much time we have to interfere before tinnitus becomes permanent.”
The researchers also plan to collaborate with chemists on developing more specific compounds that affect only the subunits of the KCNQ channel implicated in tinnitus, he said.
“About 50 percent of the mice who are exposed to a loud sound develop tinnitus and this downregulation in the channel. The question is, what determines which ones get it and which ones don't? We want to figure out if there is any protection to the ones that don't get it, or if there's some compensation that occurs there. These are the immediate things we're looking at right now.”
HJ Return to thehearingjournal.com