Treatment of tinnitus through modulation of chloride co-transporter nkcc1 in the auditory system

Abstract

The present invention relates to the treatment of prevention of tinnitus. More precisely, the present invention relates to a compound modulating chloride co-transporter NKCC1 (chloride co-transporter modulator) for use in the treatment of tinnitus. In addition, the present invention concerns pharmaceutical composition comprising such an NKCC1 chloride co-transporter modulator as an active agent a method for the treatment or prevention of tinnitus by administering such a chloride co-transporter modulator, and a screening method for the identification and characterization of compounds capable of modulation chloride co-transporter NKCC1.

Description

[0001]The present invention relates to the treatment of tinnitus. More precisely, the present invention relates to a compound modulating chloride co-transporter NKCC1 (chloride co-transporter modulator) for use in the treatment of tinnitus. In addition, the present invention is directed to pharmaceutical compositions comprising such a chloride co-transporter modulator as an active agent, a method for the treatment of tinnitus by administering such a chloride co-transporter modulator, and a screening method for the identification and characterization of compounds capable of modulating chloride co-transporters.BACKGROUND OF THE INVENTION[0002]One in ten adults perceives tinnitus, i.e. sound without external acoustic stimulation. For at least 1 in 100 adults tinnitus even seriously impacts the ability to sleep, relax, or to concentrate, or leads to tiredness, irritation, nervousness, despair, frustration, or depression. Since there are, so far, no drugs available with proven efficacy, ...

AI Technical Summary

Benefits of technology

[0025]Thus, it would provide a major break-through, if there were a better understanding of the precise mechanism underlying the above-mentioned excitatory-inhibitory imbalance of the auditory system. That would lead to urgently needed novel and effective compounds for the treatment of tinnitus. Therefore, it was an object of the present invention to provide novel compounds suitable to interfere with the excitatory-inhibitory imbalance and, thus, suitable to be used for specific and targeted treatment of tinnitus. Further, it was an object of the present invention to provide novel pharmaceutical compositions and novel methods for the treatment of tinnitus.

Problems solved by technology

For at least 1 in 100 adults tinnitus even seriously impacts the ability to sleep, relax, or to concentrate, or leads to tiredness, irritation, nervousness, despair, frustration, or depression.

Since there are, so far, no drugs available with proven efficacy, the treatment of tinnitus still remains a major unmet medical need.

Although numerous attempts have been made to elucidate the pathophysiology of tinnitus and to identify pharmacological and other therapies, no attempt provided any more promising curative treatment (Langguth et al.

According to this hypothesis, a decrease in inhibition and / or increase in excitation may lead to an excitatory-inhibitory imbalance in the auditory system.

This imbalance is suggested to cause neural hyperexcitability in the auditory pathway leading to the perception of phantom sound.

In this respect, it has been experimentally shown that cochlear dysfunction, e.g. resulting from noise overexposure or ototoxic drugs, leads to diminished afferent output to control auditory structures, reduced inhibition in these structures, and as a result increased spontaneous firing rates (Eggermont and Roberts, 2004).

There has been one study claiming successful tinnitus control by combined administration of clonazepam and gabaperttin, however, neither a randomized nor controlled design has been performed (Shulman et al., 2002).

However, no data documenting success of such an approach have been provided.

From the above, it is obvious that the clinical evidence for effective treatment of tinnitus with GABAergic and / or glycinergic pharmacological agents as well as their suggested mechanism of action is rather confusing and may depend on various factors not yet known.

Thus, the above-mentioned findings for the central nervous system cannot be conferred at all to the auditory system.

Therefore, the above-mentioned findings for the central nervous system cannot be presumed to underlie any excitatory-inhibitory imbalance in the auditory system.

Indeed, any excitatory-inhibitory imbalance in the cochlear may be due to disruption on either excitatory and / or inhibitory sides of the balance.

Yet at the same time, furosemide administered at high doses is known to induce temporary tinnitus and hearing loss, occasionally also irreversibly.

No experimental data are provided to show efficacy of their compounds in the treatment of tinnitus.

In summary, it becomes obvious from the above-mentioned summary of the art that the mechanisms in the auditory system in general and the mechanisms leading to tinnitus in particular, are extremely complex and involve a multitude of unanswered questions and observations, which are not well understood.

Additionally, it was shown that NKCC1 antagonism does interfere with that pathophysiological mechanism.

This results then in excitatory-inhibitory imbalance.

Furthermore, such compounds may be antisense RNA binding to the NKCC1 mRNA and thereby blocking its translation, e.g antisense oligonucleotides.

Such compounds may e.g. interfere with regulatory regions of the NKCC1 gene, e.g. by blocking the promoter activity or by blocking transcription factors required for the NKCC1 gene to be transcribed

As Cl− is one of the major biological ions involved in various physiological and pathophysiological processes, any modulation of chloride levels for the purpose of attenuating tinnitus may potentially interfere with ionic homeostasis in the auditory system and in particular in the cochlea.

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