DE10124953A1 - Active agent used for treating acute or chronic tinnitus comprises stimulant of brain-derived nerve growth factor gene exons III and IV e.g. kainate - Google Patents
Active agent used for treating acute or chronic tinnitus comprises stimulant of brain-derived nerve growth factor gene exons III and IV e.g. kainateInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/02—Halogenated hydrocarbons
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
Abstract
Description
Die Erfindung betrifft eine Substanz als Wirkstoff von Arzneimitteln bzw. pharmazeutischen Zubereitungen für die therapeutische Behandlung von Tinnitus.The invention relates to a substance as an active ingredient of pharmaceuticals or pharmaceutical preparations for the therapeutic treatment of tinnitus.
Zwischen 6% und 8% der Bevölkerung in der USA, England oder Deutschland leidet unter Phantom-Geräusch-Wahrnehmungen, dem sogenannten Tinnitus. Zur Zeit wird Tinnitus mit psychosomatischer Behandlung, Relaxations Therapie, Biofeedback, Hypnotherapie, elektrischer Stimulation, Lidocain Iontophorese oder Maskierung therapiert, ein ausschließlich symptomatisches Therapiekonzept. Eine ursächlich angreifende Therapie fehlt bis heute völlig. Auf der Basis der Erkenntnis, daß Tinnitus im Menschen durch Salicylatgaben induziert werden kann, daß beim Tier Salicylatgaben eine Hyperaktivität zentraler auditorischer Kerngebiete hervorrufen und ganz in Analogie zum Menschen, Phantomgeräuschwahrnehmungen auslösen, ist ein Tiermodell entwickelt worden (Penner and Jastreboff, 1996, Bauer et al., 1999), bei dem ein Salicylat-induzierter Tinnitus durch Konditionierung eine Verhaltensänderung im Tier hervorruft (Penner and Jastreboff, 1996; Bauer et al., 1999).Between 6% and 8% of the population in the United States, England or Germany suffers under phantom noise perceptions, the so-called tinnitus. Currently is Tinnitus with psychosomatic treatment, relaxation therapy, biofeedback, Hypnotherapy, electrical stimulation, lidocaine iontophoresis or masking treated, an exclusively symptomatic therapy concept. A causal attacking therapy is still completely absent today. On the basis of the knowledge that tinnitus in the Humans can be induced by the addition of salicylates, that in animals salicylate additions cause a hyperactivity of central auditory core areas and completely in analogy to humans, triggering phantom noise perceptions is an animal model have been developed (Penner and Jastreboff, 1996, Bauer et al., 1999), in which a Salicylate-induced tinnitus by conditioning a change in animal behavior causes (Penner and Jastreboff, 1996; Bauer et al., 1999).
Im dem Stand der Technik ist bekannt, daß Nervenwachstumsfaktoren nicht nur generelle Überlebensfaktoren für Nervenzellen sind, sondern eine akute Stimulierung der elektrischen Aktivität von Nervenzellen induzieren können und diese auf die Aktivität von Neuronen zurückwirken kann (Thoenen, 1995).It is known in the prior art that nerve growth factors are not only general survival factors for nerve cells are, but an acute stimulation of the can induce electrical activity of nerve cells and this on the activity of neurons can react (Thoenen, 1995).
Zur Familie der Nervenwachstumsfaktoren gehört unter anderem das Protein BDNF (brain-derived nerve growth factor), das mit hoher Affinität einen Proto-Oncogen-, Rezeptor, den Tyrosin Kinase Rezeptor (TrkB), bindet. Es ist insbesondere das BDNF- Protein, das über die Aktivierung unterschiedlicher Promotoren auf die Effizienz und den Erhalt von Synapsen und Neuronen zurückwirkt und so unter anderem auch den Phänotyp von distinkten Neuronen aufrechterhalten kann (Rutherford et al., 1997). Das BDNF-Gen besteht aus vier 5' Exonen (Exon I bis Exon IV), die an separate Promotoren gekoppelt sind, und aus einem gemeinsamen 3' Exon (full-length BDNF), das für das reife BDNF-Protein kodiert (Timmusk et al., 1993).The protein BDNF belongs to the family of nerve growth factors (brain-derived nerve growth factor), which has a high affinity for a proto-oncogene, Receptor that tyrosine kinase receptor (TrkB) binds. It is in particular the BDNF Protein that activates different promoters on the efficiency and the Preservation of synapses and neurons, and thus among other things Phenotype of distinct neurons can be maintained (Rutherford et al., 1997). The BDNF gene consists of four 5 'exons (exon I to exon IV) that are attached to separate Promoters are coupled, and from a common 3 'exon (full-length BDNF), which codes for the mature BDNF protein (Timmusk et al., 1993).
Aufgabe der vorliegenden Erfindung ist die Bereitstellung von Arzneimitteln zur therapeutischen Behandlung von Tinnitus, die auf die molekularen Ursachen von Tinnitus ausgerichtet sind und deshalb die bisher bekannten Behandlungsverfahren hinsichtlich ihrer therapeutischen Wirkung übertreffen und ergänzen.The object of the present invention is to provide medicaments for Therapeutic treatment for tinnitus that addresses the molecular causes of tinnitus are aligned and therefore regarding the previously known treatment methods surpass and complement their therapeutic effects.
Eine Lösung dieser Aufgabe besteht in der Bereitstellung von Substanzen der eingangs genannten Art, die dadurch gekennzeichnet sind, daß sie die Transkription der Exone III und IV des BDNF-Gens (Synonym: BDNF Exon III/IV) stimulieren und demzufolge für den Einsatz als Wirkstoff(e) von Arzneimitteln bzw. pharmazeutischen Zubereitungen für die therapeutische Behandlung von Tinnitus geeignet sind.One solution to this problem is to provide substances of the beginning mentioned type, which are characterized in that they the transcription of exons III and IV of the BDNF gene (synonym: BDNF exon III / IV) stimulate and consequently for the use as active ingredient (s) of pharmaceuticals or pharmaceutical preparations for the therapeutic treatment of tinnitus are suitable.
Diese erfindungsgemäße Lösung beruht auf der überraschenden Erkenntnis, daß die im Säugetier und Mensch durch Salicylatgaben induzierten Tinnitussymptome mit einer signifikanten Reduktion der BDNF Exon III- und BDNF Exon IV-Aktivität im peripheren auditorischen System einhergehen, nämlich mit einer Erniedrigung der BDNF Exon III/IV-mRNA-Konzentration im Innenohr und im Inferioren Colliculus, und daß durch eine Stimulierung der BDNF Exon III/IV Aktivität, d. h. durch eine Erhöhung der BDNF Exon III/IV-mRNA-Konzentration die Tinnitus-Symptome beseitigt oder zumindest verringert werden können.This solution according to the invention is based on the surprising finding that the im Mammals and humans induced by salicylate administration with a tinnitus symptoms significant reduction in BDNF exon III and BDNF exon IV activity in peripheral auditory system, namely with a lowering of the BDNF Exon III / IV mRNA concentration in the inner ear and in the inferior colliculus, and that by stimulating BDNF exon III / IV activity, d. H. by increasing the BDNF exon III / IV mRNA concentration eliminates or tinnitus symptoms can at least be reduced.
In einer bevorzugten Ausführungsform der Erfindung ist die BDNF Exon III/IV stimulierende Substanz ein Analogon von BDNF Exon III- und/oder BDNF Exon IV-Transkriptionsfaktoren oder deren Regulatoren. Ebensogut kann die Substanz aber auch ein AMPA-Glutamat-Transmitter-Rezeptor-Agonist sein, insbesondere ein Kainate-Derivat, oder auch ein NMDA-Glutamat-Rezeptor-Agonist, insbesondere Quinolin Säure-Derivate und/oder Derivate von L-trans-2,3-PDC. In a preferred embodiment of the invention, the BDNF is exon III / IV stimulating substance an analogue of BDNF exon III and / or BDNF Exon IV transcription factors or their regulators. The substance can just as well but can also be an AMPA glutamate transmitter receptor agonist, especially one Kainate derivative, or an NMDA glutamate receptor agonist, in particular Quinolin acid derivatives and / or derivatives of L-trans-2,3-PDC.
Bei einer weiteren bevorzugten Ausführungsform der Erfindung ist die BDNF Exon III /IV regulierende Substanz ein Aktivator der Transmitter-Rezeptor-medierten Signaltransduktionskaskade, die im menschlichen Innenohr und/oder in peripheren zentralen auditorischen Projektionen die Genaktivität der BDNF Exone III und IV reguliert. Als solche Aktivatoren kommen erfindungsgemäß vor allem Regulatoren von Immediately Early Genen (WO) wie z. B. Agonisten spannungsabhängiger Ca2+ Kanäle, insbesondere Bay K 8644-Derivate, und Agonisten des CREB- Signaltransduktionsweges, insbesondere Forskolin-Derivate, zum Einsatz.In a further preferred embodiment of the invention, the BDNF is exon III / IV regulating substance an activator of the transmitter-receptor-mediated Signal transduction cascade in the human inner ear and / or in peripheral central auditory projections the gene activity of BDNF exons III and IV regulated. According to the invention, such activators are primarily regulators Immediately early genes (WO) such as B. agonists of voltage-dependent Ca2 + channels, especially Bay K 8644 derivatives, and agonists of the CREB Signal transduction pathway, especially forskolin derivatives, are used.
Sämtlich vorstehen genannten BDNF Exon III/IV-stimulierenden Substanzen sind als Ausgangsmaterialien bzw. Wirkstoffe von Therapeutika zur langfristigen und/oder akuten Behandlung von Tinnitus geeignet. Die vorliegende Erfindung umfaßt daher auch die Verwendung dieser erfindungsgemäßen Substanzen - allein oder in Kombination - zur Herstellung von Arzneimitteln bzw. pharmazeutischen Zubereitungen für die therapeutische Behandlung von Tinnitus.All of the above-mentioned BDNF exon III / IV stimulating substances are as Starting materials or active ingredients of therapeutic agents for long-term and / or suitable for acute treatment of tinnitus. The present invention therefore also includes the use of these substances according to the invention - alone or in combination - for the production of pharmaceuticals or pharmaceutical preparations for the therapeutic treatment of tinnitus.
Da es bisher keine befriedigend wirksame ursächlich angreifende Therapie für Tinnitus gibt, und die Folgekosten von nicht-therapiertem Tinnitus - durch psychosomatische Behandlungen, Arbeitsunfähigkeit bis hin zum Suizid - ein immenses gesellschaftspolitisches Problem darstellen, liefert die vorliegende Erfindung mit der Möglichkeit der Bereitstellung solcher Arzneimitteln/pharmazeutischen Zubereitungen einen Lösungsweg auch für dieses Problem.Since so far there has been no satisfactory effective causal attack therapy for tinnitus there, and the consequential costs of untreated tinnitus - through psychosomatic Treatments, incapacity to work to suicide - an immense represent sociopolitical problem, the present invention provides with the Possibility of providing such drugs / pharmaceutical preparations a solution to this problem too.
Eine bevorzugte Verwendungsvariante sieht die Herstellung solcher Arzneimittel bzw. pharmazeutischen Zubereitungen vor, die den Patienten mittels des von Lehner et al. 1996 beschriebenen Mikrodosiersystem verabreicht werden können. Dieses Mikrodosiersystem ist zur langfristigen Applikation der erfindungsgemäßen BDNF Exon III/IV stimulierenden Substanzen geeignet.A preferred use variant sees the production of such medicaments or pharmaceutical preparations, which the patient by means of Lehner et al. 1996 microdosing system can be administered. This Microdosing system is for long-term application of the BDNF exon according to the invention III / IV stimulating substances suitable.
Eine anderen Ausführungsvariante besteht darin, daß die unter Verwendung der erfindungsgemäßen Substanzen hergestellten Arzneimittel bzw. pharmazeutischen Zubereitungen virale Expressionssysteme (virale Genkonstrukte) der Humanmedizin sind, die dazu geeignet sind, einen stabilen Gentransfer von Substanzanaloga ins Innenohr oder ins zentrale Nervensystem zu realisieren (Garrido et al. 1996).Another embodiment variant is that using the Drugs or pharmaceuticals produced according to the invention Preparations of viral expression systems (viral gene constructs) in human medicine are, which are suitable for a stable gene transfer from substance analogues into Realize inner ear or in the central nervous system (Garrido et al. 1996).
Die Erfindung wird im folgenden anhand eines Ausführungsbeispiels näher erläutert.The invention is explained in more detail below using an exemplary embodiment.
Die Untersuchungen wurden am Tiermodell gemäß Penner und Jastreboff (1996) und Bauer et al. (1999) durchgeführt.The investigations were carried out on the animal model according to Penner and Jastreboff (1996) and Bauer et al. (1999).
Ratten (Wistar) wurden von Charles River bezogen. Adulte Ratten (1-3 Monate) wurden in folgende Gruppen aufgeteilt. Eine Kontrollgruppe (I) von Tieren blieb unbehandelt. Eine Testgruppe (II) wurde entsprechend dem Stand der Technik (siehe Bauer et al., 1999) für 3 Monate über das Trinkwasser mit Salicylat behandelt. Eine Testgruppe (III) wurde mit Salicylat und darüberhinaus über eine Mittelohr Drainage (Katheter) lokal mit niedrigsten Dosen von AMPA-Rezeptor Agonist Kainate (0,1 nanomolar, 1 Bolus, 1 × täglich) behandelt. Eine Testgruppe (IV) wurde mit Salicylat und darüber über eine lokale Applikation mit NMDA Rezeptor Agonist Quinolin- Säure (0,1 nanomolar, 1 Bolus, 1 × täglich) behandelt. Eine Testgruppe (V) wurde mit Salicylat und darüber hinaus über eine lokale Applikation mit L-Typ Ca2+ Kanal Agonist Bay-K-8644 (0,1 µ- molar, 1 Bolus, 1 × täglich) behandelt. Die Tiere wurden nach der Salicylatbehandlung zum Zweck der Organentnahme getötet. Rats (Wistar) were purchased from Charles River. Adult rats (1-3 months) were born divided into the following groups. A control group (I) of animals remained untreated. A test group (II) was established in accordance with the prior art (see Bauer et al., 1999) treated with salicylate in drinking water for 3 months. A test group (III) was local with salicylate and also via a middle ear drainage (catheter) lowest doses of AMPA receptor agonist kainates (0.1 nanomolar, 1 bolus, 1 × treated daily. A test group (IV) was treated with salicylate and over a local application with NMDA receptor agonist quinolinic acid (0.1 nanomolar, 1 Bolus, treated once a day). A test group (V) was made with salicylate and above beyond a local application with L-type Ca2 + channel agonist Bay-K-8644 (0.1 µ- molar, 1 bolus, 1 × daily) treated. The animals were treated after the salicylate treatment killed for the purpose of organ removal.
Klick-evozierte und frequenzabhängige Stammhirn-Potential-Messungen wurden gemäß Knipper et al., 2000 durchgeführt. Distorsionsprodukte otoakustischer Emissionen (DPOAEs) wurden wie bei Knipper et al., 2000 beschrieben durchgeführt.Click-evoked and frequency-dependent brainstem potential measurements were made according to Knipper et al., 2000. Products of otoacoustic distortion Emissions (DPOAEs) were performed as described in Knipper et al., 2000.
Die Präparation der Cochlea und des Colliculus Inferior erfolgte gemäß den im Stand der Technik bekannten Methoden (Knipper et al., 2000). Die zentralen auditorischen Kerngebiete bzw. die Cochleae wurden mittels der im Stand der Technik (Knipper et al. 2000) bekannten Verfahren isoliert und dessektiert. Die Cochleae wurden in 0,1 molar EDTA oder Calex (Fisher Diagnostic, Fair Lawn, NJ, USA) zum entkalken inkubiert und abschließend in O. C. T. Compound (Miles Laboratories, Elkhart, Ind., USA) eingebettet.The preparation of the cochlea and the colliculus inferior was carried out in accordance with the state of the art Techniques known (Knipper et al., 2000). The central auditory Core areas or the cochleae were identified using the methods described in the prior art (Knipper et al. 2000) known methods isolated and detected. The cochleae were in 0.1 molar Incubated for EDTA or Calex (Fisher Diagnostic, Fair Lawn, NJ, USA) for decalcification finally embedded in O.C.T. Compound (Miles Laboratories, Elkhart, Ind., USA).
Von im Handel erhältlichen (z. B. Firma Regeneron, USA), in pBluescript II SK(-) Vektoren klonierte Vollängensequenzen (Full-length Sequenzen) der Tyrosinekinase Rezeptoren trkB (Rezeptor für BDNF), (pSK-rTrkB(C1), 3.3 kb) und BDNF (pSK- rB(C1), 1.1 kb) wurden komplementäre Sense und Antisense Stränge mit den im Stand der Technik bekannten und geläufigen Methoden in vitro transkribiert (Wiechers et al., 1999). BDNF-Exon I-IV cDNAs wurden auf fachübliche Weise kloniert und zur Verifizierung sequenziert. Riboproben wurden mit im Stand der Technik bekannten Methoden in vitro transkribiert (Timmusk et al., 1993).From commercially available (e.g. from Regeneron, USA), in pBluescript II SK (-) Vectors cloned full-length sequences of the tyrosine kinase Receptors trkB (receptor for BDNF), (pSK-rTrkB (C1), 3.3 kb) and BDNF (pSK- rB (C1), 1.1 kb) were complementary sense and antisense strands with those in the stand methods known and known in the art are transcribed in vitro (Wiechers et al., 1999). BDNF exon I-IV cDNAs were cloned in the usual manner and used Verification sequenced. Ribo samples have been known in the art Methods transcribed in vitro (Timmusk et al., 1993).
Die Riboproben wurden in entsprechenden Konzentrationen im Hybridisierungspuffer verdünnt (RPN3310, Amersham). Die Hybridisierung mit mRNA auf Cochlea- und Inferior-Colliculus-Schnitten erfolgte über Nacht in einer 50%-Formamid-haltigen Feuchtekammer bei 5°C. Die Wasch- und Detektionsprozedur erfolgte wie bei Gestwa et al., 1999 beschrieben. The riboprobes were in appropriate concentrations in the hybridization buffer diluted (RPN3310, Amersham). Hybridization with mRNA on cochlear and Inferior colliculus cuts were made overnight in a 50% formamide-containing Humidity chamber at 5 ° C. The washing and detection procedure was the same as for Gestwa et al., 1999.
Die Detektion von BDNF-, Exon I-V- und trkB-mRNA im Northern Blot erfolgte mit den im Stand der Technik bekannten Methoden (Knipper et al., 1998; Wiechers et al., 1999; Gestwa et al., 1999).The detection of BDNF, exon I-V and trkB mRNA in the Northern blot was carried out with the methods known in the prior art (Knipper et al., 1998; Wiechers et al., 1999; Gestwa et al., 1999).
Ratten werden in Analogie zu Penner und Jastreboff, 1996 und Bauer et al. 1999 so konditioniert, daß sich eine Salicylat-induzierte Phantomgeräusch-wahrnehmung in einer messbaren Verhaltensänderung demonstrieren läßt. Käfig- und Versuchsaufbau sind in Analogie zu Penner und Jastreboff, 1996 und Bauer et al. 1999 durchgeführt. 10 Ratten werden über 10 Trainingseinheiten in täglich 20 Minuten Trainungsitzungen konditioniert, so dass sie einen 70 dB/3 kHz Ton mit Zuckerwasserbelohnung koppeln. Der Ton wird in Grenzen und Breitbandigkeit variiert. Bei Stille verbringen die Tiere typischerweise nach ca. 10 Konditionierungs - Sitzungen keine sinnlose Zeit mehr am Belohnungsspender. Bei Bedarf wird Fehlverhalten mit negativem Stimulus (Strompuls) bestraft.Rats are used in analogy to Penner and Jastreboff, 1996 and Bauer et al. 1999 so conditioned that a salicylate-induced phantom noise perception in one demonstrable measurable behavior change. Cage and experimental setup are in Analogy to Penner and Jastreboff, 1996 and Bauer et al. Carried out in 1999. 10 rats are over 10 training sessions in 20 minute training sessions daily conditioned so that they couple a 70 dB / 3 kHz tone with sugar water reward. The tone is varied within limits and broadband. The animals spend in silence typically after 10 conditioning sessions no more pointless time on Reward donors. If necessary, misconduct with a negative stimulus (current pulse) fined.
Salicylat-induzierter Tinnitus im Tier resultiert in einer meßbaren Verweildauer am Belohnungspender.Salicylate-induced tinnitus in animals results in a measurable length of stay on Reward donors.
Die Untersuchung der Hörfähigkeit der Tiere mit Hilfe der Klick- und frequenzabhängigen BERA und mit Hilfe von DPOAE Messungen jeweils vor und nach der Salicylat-Behandlung zeigten (in Übereinstimmung mit Kujawa et al., 1992), daß eine kurzfristige Salicylat Behandlung die Hörschwelle nicht meßbar verändert, die Distorsionsprodukte otoakustischer Emissionen (DPOAE) jedoch signifikant reduziert. Nach chronischen Salicylatgaben war mit der Klick-induzierten Stammhirn-Potential-Messung und mit der frequenzabhängigen Stammhirn-Potential- Ableitung ein geringer aber dennoch signifikanter Hörschwellenverlust im hochfrequenten Bereich nachweisbar, der (in Analogie zu Bauer et al. 1999) mit einer konditionierten Verhaltensänderung des Tieres korrelierte. Examination of the hearing of the animals with the help of the click and frequency-dependent BERA and with the help of DPOAE measurements before and after salicylate treatment showed (in accordance with Kujawa et al., 1992) that a Short-term salicylate treatment does not measurably change the hearing threshold However, distortion products of otoacoustic emissions (DPOAE) significantly reduced. After chronic salicylate administration was click-induced Stem brain potential measurement and with the frequency-dependent brain stem potential Derivation of a small but significant hearing loss in the high-frequency range detectable, which (in analogy to Bauer et al. 1999) with a conditioned animal behavior change correlated.
Die molekulare Analyse der Konzentration von BDNF-Exon I- bis V-mRNA sowie trkB-mRNA in der Cochlea und im Inferioren Colliculus mittels in situ Hybridisierung und Northern Blot Technik zeigte, daß der BDNF Exon III- und IV-mRNA-Spiegel sowohl in den Spiralganglien der Cochlea als auch im gesamten Inferioren Colliculus (Northern Blot) und im zentralen, dorsalen und externen Nukleus des Inferioren Colliculus (In Situ Hybridisierung) nach chronischer Salicylat-Applikation im Vergleich zur Kontrolle signifikant niedriger war.The molecular analysis of the concentration of BDNF exon I to V mRNA as well trkB mRNA in the cochlea and inferior colliculus using in situ hybridization and Northern blot technique showed that the BDNF exon III and IV mRNA levels both in the spiral ganglia of the cochlea and in the entire inferior colliculus (Northern blot) and in the central, dorsal and external nucleus of the inferior Colliculus (in situ hybridization) after chronic salicylate application in comparison control was significantly lower.
Die gleichzeitige Applikation von Salicylat und Quinolin Säure bzw. Salicylat und Kainate bzw. Salicylat und Bay K 8644 resultierte sowohl in der Cochlea als auch im Inferioren Colliculus in BDNF-Exon-III/IV-mRNA Spiegeln, die mit denen der unbehandelten Kontrolltiere vergleichbar waren. Damit einher ging eine Normalisierung des hochfrequenten Hörverlustes bei den betroffenen Tieren. The simultaneous application of salicylate and quinolin acid or salicylate and Kainate or salicylate and Bay K 8644 resulted in both the cochlea and the Inferior colliculus levels in BDNF exon III / IV mRNA that match those of the untreated control animals were comparable. This was accompanied by normalization of high-frequency hearing loss in the affected animals.
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WO2006079476A1 (en) * | 2005-01-25 | 2006-08-03 | Eberhard-Karls-Universität Tübingen | Phantom phenomena treatment |
DE102007063210A1 (en) | 2007-12-20 | 2009-06-25 | Eberhard-Karls-Universität Tübingen Universitätsklinikum | Medicines for the treatment of phantom phenomena |
US8268866B2 (en) | 2004-03-29 | 2012-09-18 | Matthieu Guitton | Methods for the treatment of tinnitus induced by cochlear excitotoxicity |
US8507525B2 (en) | 2004-03-29 | 2013-08-13 | Auris Medical Ag | Methods for the treatment of tinnitus induced by cochlear excitotoxicity |
US9066865B2 (en) | 2005-09-28 | 2015-06-30 | Auris Medical Ag | Pharmaceutical compositions for the treatment of inner ear disorders |
US9072662B2 (en) | 2004-03-29 | 2015-07-07 | Auris Medical Ag | Methods for the treatment of tinnitus induced by cochlear excitotoxicity |
US10709682B2 (en) | 2011-12-12 | 2020-07-14 | Otolanum Ag | Treatment of tinnitus through modulation of chloride co-transporter NKCC1 in the auditory system |
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WO2000005232A1 (en) * | 1998-07-21 | 2000-02-03 | Pfizer Limited | Heterocyclic compounds as inhibitors of rotamase enzymes |
WO2000073283A1 (en) * | 1999-06-02 | 2000-12-07 | Nps Pharmaceuticals, Inc. | Metabotropic glutamate receptor antagonists and their use for treating central nervous system diseases |
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US8268866B2 (en) | 2004-03-29 | 2012-09-18 | Matthieu Guitton | Methods for the treatment of tinnitus induced by cochlear excitotoxicity |
US8507525B2 (en) | 2004-03-29 | 2013-08-13 | Auris Medical Ag | Methods for the treatment of tinnitus induced by cochlear excitotoxicity |
US9072662B2 (en) | 2004-03-29 | 2015-07-07 | Auris Medical Ag | Methods for the treatment of tinnitus induced by cochlear excitotoxicity |
US9463168B2 (en) | 2004-03-29 | 2016-10-11 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Methods for the treatment of tinnitus induced by cochlear excitotoxicity |
US10966940B2 (en) | 2004-03-29 | 2021-04-06 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Methods for the treatment of tinnitus induced by cochlear excitotoxicity |
WO2006079476A1 (en) * | 2005-01-25 | 2006-08-03 | Eberhard-Karls-Universität Tübingen | Phantom phenomena treatment |
DE102005004343A1 (en) * | 2005-01-25 | 2006-08-10 | Eberhard-Karls-Universität Tübingen Universitätsklinikum | Treatment of phantom phenomena |
EP2196199A1 (en) | 2005-01-25 | 2010-06-16 | Eberhard-Karls-Universität Tübingen | Treatment of phantom phenomena |
US9066865B2 (en) | 2005-09-28 | 2015-06-30 | Auris Medical Ag | Pharmaceutical compositions for the treatment of inner ear disorders |
DE102007063210A1 (en) | 2007-12-20 | 2009-06-25 | Eberhard-Karls-Universität Tübingen Universitätsklinikum | Medicines for the treatment of phantom phenomena |
US10709682B2 (en) | 2011-12-12 | 2020-07-14 | Otolanum Ag | Treatment of tinnitus through modulation of chloride co-transporter NKCC1 in the auditory system |
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