Impact of Sazetidine-A and Similar Nicotinic Drugs on Tinnitus

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Researchers at the Southern Illinois University School of Medicine have successfully tested a drug (sazetidine-A) related to the smoking cessation drug Chantix, in a sound-exposure animal model of tinnitus. Human clinical trials could begin as early as 2022…

This information is unclassified and from an Annual Progress Report prepared for the U.S. Army Medical Research and Development Command. From the report:

Tinnitus is the perception of sound in the absence of an environmental stimulus. This phantom sound in the head, is most commonly caused by noise exposure, resulting in damage to the inner ear. Within the veteran population seeking VA care, 16-27% suffer from serious hearing loss and tinnitus. Unfortunately, those most affected are bound to the sounds in their heads have difficulty concentrating, suffer from depression and may even contemplate suicide. We posit that breaking the bond between attention and tinnitus will ameliorate the impact of tinnitus. Drugs acting at receptors that bind the brain chemical acetylcholine (nAChRs), a substance involved in brain circuits that control attention could ameliorate tinnitus. We have successfully tested the drug (sazetidine-A), in an established sound-exposure animal model of tinnitus.

SOURCE: https://apps.dtic.mil/sti/pdfs/AD1114579.pdf

Preliminary studies are now starting to support their hypothesis: drugs that act at specific receptors that bind the brain chemical acetylcholine (nAChRs), a substance released by brain circuits that control attention, could alleviate tinnitus.

And these drugs, which include sazetidine-A (related to smoking cessation drug Chantix) and varenicline, could allow tinnitus sufferers with “habituation-proof” tinnitus to finally find relief thanks to a pill that — hypothetically — works to “disconnect” the looped circuit that may be preventing habituation (or extinguishment) from taking its normal course.

The result? Hopefully a way for people with severe disabling tinnitus to “get used to it” and have their tinnitus diminish, on its own, like most people… thanks to a drug involving the chemical substance involved in brain circuits that control attention. By addressing that chemically-based “habituation-proof” circuit, it could unlock the normalizing process.

Whether these drugs can do that remains to be proven. But the evidence from preliminary studies suggests it might be possible. That’s what this project is exploring.

From the progress report (which is dated August 2020 but only released publicly more recently):

4. Impact The results form SA1, delineated above, are the first of their kind to show significant tinnitus-related attentional abnormalities in principal AI output neurons. First they show significant abnormalities in the number and size of the presynaptic excitatory messages arriving at these neurons. Secondly they show significant tinnitus-related differences in nAChR sensitivity at different doses of acetylcholine. Since we will be pharmacologically targeting these receptors in attempts to normalize their tinnitus pathology, understanding these tinnitus-related differences is critical. The ability of sazetidine-A to effect disproportional changes in resting membrane potential and action potential threshold in animals with behavioral evidence of tinnitus suggests a unique receptor target. Finally, preliminary data suggests that sazetidine-A was able to normalize a tinnitus-related increased sensitivity to acetylcholine. Collectively, we feel these are exciting and highly publishable findings when matured. They also support the proposed SA2&3 studies.

The SA1, SA2, SA3 refer to “Specific Aims”, which are like goals/stages of the project. Right now, the researchers are in the final “stage” of this project. Human clinical trials would be a separate project that follows the completion of this one. I’m speculating, and I don’t know the future. But that’s where this is headed, as of now.

These findings and the theory behind these exciting hypotheses will continue to be studied and tested as part of this ongoing research project, “Nicotinic Receptor Pathology in Tinnitus: Auditory Cortex and Selective Desensitizing Nicotinic Agents” — which is supported by a grant of nearly $1.8 million, courtesy of the Department of Defense and the Congressionally Directed Medical Research Program.

Importantly, the research is aimed at treating the most severe cases of tinnitus: tinnitus that cannot be ignored or simply tuned out. Their goal is to develop new drugs capable of ameliorating tinnitus in “those most affected”, the people who are “bound to the sounds in their heads” and who “cannot do regular work”, “have great difficulty concentrating”, and “may even contemplate suicide”.

This is described in the project abstract (see below) along with more details about what is being studied and the hypothesis behind this new area of exploration in the realm of chronic tinnitus treatments.

As for the project itself… it is scheduled to complete in July 14, 2022 and… barring any surprises… it looks like human clinical trials could follow shortly after. Why so soon? Because the “new” drugs in question are closely related to already-approved smoking cessation drugs (such as Chantix)… in fact, Chantix might be a viable candidate, though we will have to wait and see to know for sure. In any case, the clinical trial process would likely be faster and less complex, as the safety profile of the drug is already well established in humans.

So it’s got that goin’ for it, which is nice.

Here are the details, including both abstracts (the second one is heavier on the science):

Nicotinic Receptor Pathology in Tinnitus: Auditory Cortex and Selective Desensitizing Nicotinic Agents

Principal Investigator: CASPARY, DONALD M
Institution Receiving Award: SOUTHERN ILLINOIS UNIVERSITY SCHOOL OF MEDICINE
Program: PRMRP

PUBLIC ABSTRACT

Tinnitus is the perception of sound in the absence of an external environmental stimulus. This phantom sound in the head, sometimes referred to as “ringing in the ears,” is a Fiscal Year 2018 Peer Reviewed Medical Research Program topic area. It is most commonly caused by noise exposure, resulting in damage to the inner ear containing the hair cells and nerve fibers that carry sound to the brain. The military working environment presents many high noise situations with noise levels often so intense that standard hearing protection is not adequate. A recent study found that Soldiers deployed to battle zones were ~52 times more likely to suffer auditory damage than non-deployed Soldiers. The American Tinnitus Association reports that within the Veteran population seeking Department of Veterans Affairs (VA) care, 16%-27% suffer from serious hearing loss and tinnitus. The VA awarded disability compensation for serious hearing loss tinnitus to approximately 972,000 Veterans with an annual aggregate cost of nearly $1.5 billion. The U.S. Centers for Disease Control and Prevention estimates that more than 50 million Americans – nearly 15% of the population – experience some form of tinnitus, with 10%-15% of this total suffering extreme and debilitating tinnitus. Conversely, the majority of chronic tinnitus sufferers are able to ignore their tinnitus, tuning out the din while going about their daily lives. Unfortunately, those most affected are bound to the sounds in their heads; they have great difficulty concentrating, suffer from depression, cannot do regular work and may even contemplate suicide. Studies proposed here are focused on developing a treatment for those individuals most impacted by tinnitus. Our hypothesis postulates that breaking the bond between attention and tinnitus will ameliorate the impact of tinnitus, allowing patients to return to a more normal life. We propose that drugs that act at specific receptors that bind the brain chemical acetylcholine (nAChRs), a substance released by brain circuits that control attention could ameliorate tinnitus. Our preliminary studies have successfully tested a drug (sazetidine-A) related to the smoking cessation drug Chantix, in a sound-exposure animal model of tinnitus. All proposed studies will be carried out in our well-established rat tinnitus model, and our laboratories have significant experience in all proposed methods. Proposed studies will test the ability of Chantix to ameliorate tinnitus. Similar to what is seen in human tinnitus patients, our recent studies in a rat tinnitus model finds tinnitus-related deficits in selective attention. We will test if both these drugs related to nicotine can normalize selective attention in our animal model. Proposed basic science studies will test if these agents can normalize aberrant brain cell response properties recorded in structures located at the highest level of the central auditory system, the auditory cortex. Preliminary receptor binding studies suggest that nicotinic acetylcholine receptors are altered in animals with evidence of tinnitus. Proposed studies will map the markers for the different receptor subtypes that make up these acetylcholine receptors in animals with and without tinnitus. Using brain slices from auditory cortex of animals with and without tinnitus, proposed studies will examine the function and the pharmacology of these receptors and the impact of Chantix and similar nicotinic drugs on the response properties of these brain cells. Collectively, these studies will provide new pharmacologic information on possible novel treatments for tinnitus while improving our understanding of the relationship between attention and tinnitus suffering and the cellular mechanisms that underpin this hypothesis.

TECHNICAL ABSTRACT

Tinnitus is defined as a phantom sound (ringing in the ears) that can significantly affect the quality of life for those who suffer its effects. Noise exposure, with its consequent acoustic damage, is the most common cause of tinnitus. The military working environment presents many situational high noise levels, frequently so intense that standard hearing protection is inadequate. There is a growing awareness that maladaptive attentional mechanisms are involved in the pathology of tinnitus. Individuals most disturbed by their tinnitus have their attention bound to the percept while showing significantly impaired selective attention. Basal forebrain neurons involved in attentional circuits can increase release of the neuromodulator acetylcholine (ACh), where it acts at nicotinic cholinergic receptors (nAChRs), located on terminals and neurons in the primary auditory cortex (AI). This forebrain cholinergic system is a component of a perceptual network that may enhance attention to tinnitus as well as generating emotional reactions to tinnitus. The proposed basic science and translational studies will use a novel pharmacologic approach to treat individuals whose attention is inextricably bound to phantom sounds in their head. Our preliminary data indicate that the nAChR-Beta2 selective partial agonist and desensitizer sazetidine-A reduced the impact of tinnitus in our animal model. The focus of the present proposal is to examine the therapeutic potential of two nAChR partial agonists, sazetidine-A and the smoking cessation drug varenicline. Preliminary binding and subunit expression studies suggest that nAChR subunits are altered in AI of animals with behavioral evidence of tinnitus. All specific aims (SAs) will use an established sound-exposure rat model of tinnitus. SA1A will use immunoprecipitation and florescent in situ hybridization (FISH) to characterize tinnitus-related changes in heteromeric and homomeric nAChRs in AI neurons from animals with and without behavioral evidence of tinnitus. nAChRs comprising different combinations of subunits are present on presynaptic terminals/inputs that innervate neurons across layers of AI. Our preliminary studies show altered numbers and affinity of nAChRs in AI layers IV and VI. SA1B will characterize functional pharmacology of tinnitus-related changes in acetylcholine (ACh) evoked synaptic currents from AI layers IV and VI neurons in an AI slice preparation. SA1C will examine the pharmacologic responses of bath applied sazetidine-A and varenicline on ACh evoked synaptic currents from AI layer IV and VI neurons as in SA1B. SA2A will catalog and compare tinnitus-related changes in AI single-unit responses from awake animals with and without behavioral evidence of tinnitus, while attempting to normalize tinnitus-related aberrant unit responses with systemic injections of sazetidine-A and varenicline. SA3A will test whether varenicline, similar to sazetidine-A, can ameliorate tinnitus in our animal model. SA3B is based on findings that animals with behavioral evidence of tinnitus, similar to human tinnitus sufferers, show impaired selective auditory attention. Others have shown that sazetidine-A can normalize impaired visual attention. SA3B will examine the ability of sazetidine-A and varenicline to normalize impaired selective attention in animals with behavioral evidence of tinnitus. Collectively, results from these proposed studies will directly test the hypothesis that tinnitus can be ameliorated using attention-altering drugs while examining basic science mechanisms underpinning this hypothesis at the level of the auditory cortex.

That’s all for now.

This article is a DRAFT and you are receiving early access because you are subscribed to email updates (or the link was shared by someone who is subscribed). How to get updates:

Updates

I will be releasing more updates and progress reports on this project, as they become available, leading up to July 14, 2022. Sign up for the TinnitusTreatmentReport.com newsletter to get these articles (it’s free and I send updates that do not appear on the front page of this website). I am not involved in the study and I do not have any information about human trials!

References


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