TREATMENT AND/OR PREVENTION OF LESIONS IN THE CENTRAL AUDITORY NERVOUS SYSTEM

Abstract

The therapeutic use of azasetron or an analogue thereof for treating and/or preventing a lesion in the central auditory nervous system (CANS) in an individual. The treatment of lesions in the CANS with azasetron also prevents, inhibits, and/or reduces the loss of the central auditory neuron cells in the brainstem.

Claims

1-15. (canceled)

16. A method for treating and/or preventing a lesion in the central auditory nervous system (CANS) in an individual in need thereof, said method comprising administering to said individual a therapeutically effective amount of azasetron, or an analogue thereof.

17. The method according to claim 16, wherein azasetron, or the analogue thereof, is in the form of a pharmaceutically acceptable salt and/or solvate thereof.

18. The method according to claim 16, wherein azasetron is (R)-azasetron, (S)-azasetron, or a mixture thereof.

19. The method according to claim 16, wherein azasetron is (R)-azasetron or a pharmaceutically acceptable salt and/or solvate thereof.

20. The method according to claim 19, wherein the pharmaceutically acceptable salt of (R)-azasetron is selected from the group consisting of (R)-azasetron besylate, (R)-azasetron malate, and (R)-azasetron hydrochloride.

21. The method according to claim 16, wherein azasetron, or the analogue thereof, is administered at a dose ranging from about 0.01 mg/kg of body weight to about 100 mg/kg of body weight.

22. The method according to claim 16, wherein azasetron, or the analogue thereof, is administered systemically.

23. The method according to claim 16, wherein azasetron, or the analogue thereof, is administered transdermally.

24. The method according to claim 16, wherein azasetron, or the analogue thereof, is administered orally.

25. The method according to claim 16, wherein said lesion in the CANS is a lesion localized in the cochlear nucleus, the superior olive, the trapezoid body, the lateral lemniscus, the inferior colliculus, the medial geniculate body, and/or the auditory cortices.

26. The method according to claim 16, wherein said lesion in the CANS is a lesion observed in a disorder selected from the group consisting of a central auditory processing disorder, a stroke of the central auditory pathway, a seizure, a brain trauma, a bacterial or viral infection, a demyelinating disorder, a neurodegenerative disorder, a neoplasm, a brain malformation, learning disabilities, dyslexia, autism, depression, alcoholism, anorexia, schizophrenia, epilepsy, an infantile mental retardation, an attention deficit disorder, and aged-related degeneration.

27. The method according to claim 16, wherein said central auditory processing disorder is an auditory processing deficit and/or a loss of speech recognition.

28. The method according to claim 16, wherein azasetron, or the analogue thereof, is administered in combination with at least one pharmaceutically acceptable excipient in a pharmaceutical composition.

29. A method for preventing and/or inhibiting and/or reducing the loss of central auditory neuronal cells in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of azasetron or an analogue thereof.

30. The method according to claim 29, wherein azasetron, or the analogue thereof, is in the form of a pharmaceutically acceptable salt and/or solvate thereof.

31. The method according to claim 29, wherein azasetron is (R)-azasetron, (S)-azasetron, or a mixture thereof.

32. The method according to claim 29, wherein azasetron is (R)-azasetron or a pharmaceutically acceptable salt and/or solvate thereof.

33. The method according to claim 32, wherein the pharmaceutically acceptable salt of (R)-azasetron is selected from the group consisting of (R)-azasetron besylate, (R)-azasetron malate, and (R)-azasetron hydrochloride.

34. The method according to claim 29, wherein said individual is susceptible to undergo or have undergone an acoustic trauma.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0170] FIG. 1 is a graph showing the hearing threshold shift of placebo versus (R)-azasetron besylate of young adult NMRI mice having undergone an acoustic trauma and treated for 14 days with placebo (curve 1) or 26.4 mg/kg (R)-azasetron besylate (curve 2) peroral.

[0171] FIG. 2 is a graph (cochleogram) showing a number of lost outer hair cells (OHC) with respect to the distance from the cochlear apex in NMRI mice treated with placebo (plain circles) or (R)-azasetron besylate (plain triangles) as in FIG. 1.

[0172] FIG. 3 is a photograph showing a hematoxylin and eosin (H&E) staining of ventral cochlear nucleus (VCN) slices obtained from NMRI mice treated as in FIG. 1.

[0173] FIG. 4 is a histogram showing the number of normalized cell densities per grid, after 14 days of treatment with either (R)-azasetron besylate initiated at immediately or 24/48/72 hours after acoustic trauma or placebo, calculated from the VCN slices obtained in FIG. 3. Histogram bar 1: placebo. Histogram bars 2-5: (R)-azasetron besylate.

[0174] FIG. 5 is a histogram showing the number of normalized cell densities per grid from sample of the inferior colliculus (IC) from mice treated as described in the legend of

[0175] FIG. 4. Histogram bar 1: placebo. Histogram bars 2-5: (R)-azasetron besylate.

EXAMPLES

[0176] The present invention is further illustrated by the following examples.

1—Materials and Methods

In Vivo Treatment And Audiometry (12 Months)

[0177] 12 animals per group (young adult Naval Medical Research Institute (NMRI) mice), 96 animals in total.

[0178] day 0:

[0179] Treatment groups 1-4 +Placebo groups 1-4:

[0180] Frequency specific ABR-thresholds at 4; 8; 12; 16; 20; 24; 28; 32 kHz under anesthesia (Ketamine/Xylazine). At least 3 measurements per frequency were performed.

[0181] day 1:

Treatment and Placebo Groups

[0182] Noise application was performed for 3 h under anesthesia, using a broad band noise 4-20 kHz, 115 dB SPL, free-field.

Treatment and Placebo Groups

[0183] Post-traumatic (0; 24 h; 48 h or 72 h after noise exposure) initiation of oral administration of 26.4 mg/kg (R)-azasetron besylate or of the related placebo formulation, respectively, was performed once daily. Treatments were continued daily for 14 days. [0184] Treatment (T) group 1 +Placebo (P) group 1: Treatment from d1-d14 [0185] Treatment (T) group 2 +Placebo (P) group 2: Treatment from d2-d15 [0186] Treatment (T) group 3 +Placebo (P) group 3: Treatment from d3-d16 [0187] Treatment (T) group 4 +Placebo (P) group 4: Treatment from d4-d17

[0188] day 0-18:

[0189] Animals were kept in housings in a quiet surrounding at normal light/dark regime (12h/12h) and with free access to food and water. Cages were equipped with enrichment. Animals were kept in small groups.

[0190] days 15 (T/P groups 1), 16 (T/P groups 2), 17 (T/P groups 3) and 18 (T/P groups 4):

[0191] Treatment groups 1-4 +Placebo groups 1-4:

[0192] Frequency specific ABR-thresholds at 4; 8; 12; 16; 20; 24; 28; 32 kHz under anesthesia (Ketamine/Xylazine). At least 3 measurements per frequency were performed.

Histology (3 Months)

[0193] Six animals per group (48 in total) have been perfused via the left hearth chamber with a fixative solution (paraformaldehyde (4%)) on day 15.

[0194] Cochleae and brains were prepared (cutting, staining), as disclosed in Gröschel et al. (2010). Cochlear hair cell loss and neuronal cell density in the ventral cochlear nucleus (VCN), inferior colliculus (IC) have been quantified.

2—Results

[0195] As seen in FIG. 1, the administration of (R)-azasetron besylate to rats subjected to a noise trauma does not significantly affect the threshold shift of the auditory brainstem response, as compared to the administration of placebo.

[0196] However, FIG. 2 shows that (R)-azasetron besylate affects the loss of outer hair cells (OHC) in the cochlea at growing distances from the apex.

[0197] The further hypothesis that a (R)-azasetron besylate mediated treatment of a noise trauma may likely benefit the auditory structures that are downstream from the inner ear (cochlea) was then assessed.

[0198] In order to confirm this theory, slices of ventral cochlear nucleus (VCN) were prepared for histological analysis (FIG. 3) and the total (neuronal) cells were counted (FIG. 4). FIGS. 3 and 4 show that the treatment with (R)-azasetron besylate reduces the destruction of neuronal cells in the VCN after a noise trauma.

[0199] FIG. 5 similarly shows that (R)-azasetron besylate treatment of the mice subjected to an acoustic trauma also reduces the destruction of neuronal cells in a second structure of the CANS, the IC, as compared to the placebo treatment, irrespective of whether the treatment is initiated 0 h, 24 h, 48 h or 72 h after the acoustic trauma.

[0200] Altogether, these data indicate that a treatment of individuals having experienced a noise trauma with (R)-azasetron besylate will benefit the structures of the central auditory nervous system.

3—Discussion

[0201] To date, there are no models for studying a trauma in the CANS exclusively. Current models to achieve better knowledge on how the brainstem cope with trauma in the CANS are based upon an acoustic trauma. The acoustic trauma often results in lesions in the peripheral system, such as, e.g., the inner ear. Lesions of the peripheral system may be accountable for cochlear hair cell loss.

[0202] Nevertheless, under some controllable conditions, acoustic trauma may also be accountable for lesion in the CANS, in particular in the brainstem, the diencephalon, the mesencephalon, the auditory cortices.

[0203] Experimental data provided herein show that neurons within the ventral cochlear nucleus (VCN) and the inferior colliculus (IC) in the CANS are affected by an acoustic trauma, since cellular loss may be observed, most probably because of an apoptotic process. Administration of azasetron upon the onset of lesions allows to significantly reduce the loss of neurons in the brainstem.

[0204] Altogether, these data show that applying an acoustic trauma is a suitable model for studying lesion occurring in the CANS and that azasetron may promote inhibition or reduction of the apoptotic mechanism that undergoes upon the occurrence of the lesion.