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

a technology of chloride cotransporter and auditory system, which is applied in the direction of biochemistry apparatus and processes, material testing goods, compound screening, etc., can solve the problems of affecting the ability to sleep, relax, irritation, nervousness, despair, frustration, depression, etc., and the treatment of tinnitus remains a major unmet medical need

Inactive Publication Date: 2016-09-22
OTOLANUM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a new compound called a chloride co-transporter modulator (chloride co-transporter modulator) that can be used to treat tinnitus, a condition where people hear sound without external acoustic stimulation. The invention is based on the discovery that tinnitus is caused by a decrease in inhibition and an increase in excitation in the auditory system. The new compound can modulate the activity of chloride co-transporters, which are important in controlling the excitation-inhibition balance in the auditory system. The invention also includes pharmaceutical compositions containing the new compound, a method for treating tinnitus by administering the new compound, and a screening method for identifying new compounds that can treat tinnitus. The invention helps to better understand the mechanism of tinnitus and provides new, effective compounds for its treatment.

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.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0144]Objective

[0145]The loop diuretic furosemide has been proposed as a (reversible) treatment of tinnitus. It has been hypothesized that it attenuates the firing of the auditory nerve by reducing the endocochlear potential (Risey et al., 1995). Yet, concurrently tinnitus is also known as a side effect of furosemide. The inventors sought to elucidate whether and, if yes, how the expression of chloride co-transporters in the cochlea changed following an insult to the cochlea susceptible of inducing tinnitus in order to identify starting points for the development of a novel pharmacotherapy for tinnitus.

[0146]Materials and Methods

[0147]13 anaesthetized adult female Wistar rats were exposed for 2 hours intra-aurally to a continuous 10 kHz tone at an intensity of 120 dB SPL in a sound attenuation booth. This exposure is susceptible of inducing tinnitus in rats (e.g. Tan et al., 2007). The acoustic stimulus was calibrated at the head level of the animal. Four anaesthetized control anima...

example 2

[0152]Objective

[0153]The aim of the 2nd experiment was to assess whether down-regulation of KCC2 observed in the first experiment was related to the pathophysiology of hearing loss or to that of tinnitus, or to both. This down-regulation could suggest that tinnitus induction by furosemide may be related to its known effect on KCC2, rather than through its attenuation of the endocochlear potential, as commonly suspected (e.g. Risey et al., 1995). For this purpose, a behavioural model as described by Rüttiger et al., 2003 was used to discriminate between animals with and without tinnitus.

[0154]Materials and Methods

[0155]36 adult female Wistar rats were trained in a conditioning chamber to actively access a liquid feeder whenever a constant sound was present. During silence, no reward was given. The conditioning was completed when animals performed more accesses to the reward feeder during periods of sound than during periods of silence.

[0156]On Day 0 conditioned rats were anaesthetize...

example 3

[0161]Objective

[0162]The aim of the third experiment was to assess whether pharmacological modulation of intracellular chloride levels in the cochlea following tinnitus-inducing noise trauma can suppress tinnitus. Since bumetanide has a much higher affinity for NKCC1 than tor KCC2 (Payne et al., 2003), its administration should—in view of the previous findings of the present invention—allow for reducing intracellular Cl− levels as the inhibitory effect on NKCC1 would dominate any—undesired—inhibitory effect an KCC2.

[0163]Materials and Methods

[0164]20 adult female Wistar rats were anaesthetized as described above for the previous experiments. First, auditory brainstem response (ABR) measurements were performed. As in Experiment 2, they were then exposed in a sound attenuation booth for 1.5 hours to a continuous 10 kHz tone at an intensity of 120 dB SPL (Group A; n=10) or sham exposed in the same seeing (Group B; n=10).

[0165]Animals were treated bilaterally right after noise trauma wi...

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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, ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/341G01N33/50A61K31/196A61K45/06A61K9/00
CPCA61K31/341A61K45/06G01N2500/04A61K31/196G01N33/5058A61K9/0046A61K31/18A61K31/382A61K31/402A61K31/41A61K31/433A61K31/44A61K31/542A61K31/549A61K31/713G01N33/6872C12N15/1138C12N2310/11C12N2310/12C12N2310/14A61K38/1709A61P27/16A61P43/00A61K2300/00G01N33/502
Inventor KNIPPER, MARLIESRUETTIGER, LUCKAS
Owner OTOLANUM
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