WO2007019880A1 - Utilisation d'un inhibiteur sélectif du recaptage de la norépinéphrine pour traiter des troubles respiratoires qui résultent du syndrome de rett - Google Patents

Utilisation d'un inhibiteur sélectif du recaptage de la norépinéphrine pour traiter des troubles respiratoires qui résultent du syndrome de rett Download PDF

Info

Publication number
WO2007019880A1
WO2007019880A1 PCT/EP2005/009893 EP2005009893W WO2007019880A1 WO 2007019880 A1 WO2007019880 A1 WO 2007019880A1 EP 2005009893 W EP2005009893 W EP 2005009893W WO 2007019880 A1 WO2007019880 A1 WO 2007019880A1
Authority
WO
WIPO (PCT)
Prior art keywords
mecp2
mice
respiratory
breathing
rett syndrome
Prior art date
Application number
PCT/EP2005/009893
Other languages
English (en)
Inventor
Laurent Villard
Jean-Christophe Roux
Gérard Hilaire
Original Assignee
Inserm (Institut National De La Sante Et De La Recherche Medicale)
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Inserm (Institut National De La Sante Et De La Recherche Medicale) filed Critical Inserm (Institut National De La Sante Et De La Recherche Medicale)
Priority to PCT/EP2005/009893 priority Critical patent/WO2007019880A1/fr
Publication of WO2007019880A1 publication Critical patent/WO2007019880A1/fr

Links

Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to the treatment or prevention of the breathing disturbances of Rett Syndrome.
  • Rett Syndrome is a severe neurological disorder which may account for up to 10% of severe mental retardation of genetic origin in women (Armstrong, 1997). Although a few familial cases have been reported, most of the cases are sporadic with frequent (80-90 %) mutations in the methyl-CpG binding protein2 (MECP2) gene (Van den Veyver and Zoghbi, 2000). The disorder typically commences with an apparently normal development until 6 to 18 months of age.
  • MECP2 methyl-CpG binding protein2
  • Breathing is regular during sleep and can switch from highly irregular to regular even during wakefulness (Marcus et al., 1994; Kerr and Witt-Engerstrom, 2001). Because breathing can be regular many clinicians believe that breathing problems are a consequence of disturbed cortical rather than brainstem mechanisms (Marcus et al., 1994) and may thus be behaviourally determined (Elian and Rudolf, 1991).
  • NE plays a key role in the maturation and modulation of the respiratory network (Viemari et al., 2004), and that 5HT and substance P affect respiratory rhythm (Bou-Flores et al., 2000; Pena and Ramirez, 2002, , 2004).
  • 5HT and substance P affect respiratory rhythm
  • no link between these neuromediators and the respiratory disorders observed in Rett Syndrome has been demonstrated.
  • the present invention thus relates to the use of a selective inhibitor of norepinephrine reuptake for preparing a medicament for treating or preventing respiratory disorders resulting from Rett Syndrome.
  • the present invention also includes a method for treating or preventing respiratory disorders resulting from Rett Syndrome, wherein said method comprises administering to a patient suffering of said disorder an effective amount of a selective inhibitor of norepinephrine reuptake.
  • a “selective inhibitor of norepinephrine reuptake” is defined herein as a compound having an inhibition constant (Ki, nmol/1) for norepinephrine uptake by the norepinephrine transporter (NET) of less than 100 nM, preferably less than 5O nM, and also having at least a 5-fold, preferably at least a 10-fold, and more preferably at least a 20-fold selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT), and over the dopamine transporter (DAT).
  • Ki inhibition constant
  • NET norepinephrine transporter
  • Selectivity of a compound refers to the ratio of its Ki for serotonin or dopamine uptake by SERT or DAT, respectively, to its Ki for norepinephrine uptake by the norepinephrine transporter (NET).
  • the selectivity of a coumpond for NET over SERT or over DAT would be expressed as Ki for SERT (or Ki for DAT)/Ki for NET.
  • the Ki of a compound for a given monoamine transporter can be obtained by methods known in themselves, for instance by competition assays using membranes obtained from cell lines transfected with human gene for the specific monoamine transporter, such as those disclosed by Frazer (1997), Owens et al (1997), or Leonard and Richelson (2000).
  • Selective inhibitors of norepinephrine reuptake include, by way of non limitative examples, antidepressants such as imipramine, clomipramine, opipramol, prozapine, quinupramine, trimipramine, reboxetine, atomoxetine, amoxepine, carpipramine, doxepine and maprotiline.
  • antidepressants such as imipramine, clomipramine, opipramol, prozapine, quinupramine, trimipramine, reboxetine, atomoxetine, amoxepine, carpipramine, doxepine and maprotiline.
  • the selective inhibitor of norepinephrine reuptake may be administered orally or parenterally, by any suitable means known to one of ordinary skill in the art.
  • Formulations of suitable for oral administration may be in the form of discrete units, such as capsules, cachets, or tablets, or in the form of
  • Formulations suitable for oral or parenteral administration may be in the form of a solution or a suspension or an emulsion in an aqueous liquid or nonaqueous liquid. All these formulations may be prepared by any of the methods known in the art of pharmacology.
  • the doses of selective inhibitor of norepinephrine reuptake effective for alleviating respiratory disorders resulting from Rett Syndrome are generally of the same order as the doses used in the treatment of depression.
  • doses of 10 to 30 mg a day are generally suitable for children, and 100 to 200 mg a day are generally suitable for adults.
  • This quantity may be administered once a day, of if desired it may be divided into two or more administrations.
  • the appropriate daily dosage, route of administration, and administration regimen can easily be determined for each patient by the physician, taking in account all the particulars of the patient, such as the age, the weight, and general medical condition of the patient, and the severity of the respiratory disorders.
  • all of the above formulations may contain other therapeutically-active substances, for instance antagonists of presynaptic ⁇ .2 adrenergic autoreceptors, such as Mirtazapine.
  • A-D The traces show typical plethysmography recordings of breathing (inspiration upward) performed in the same unanesthetized, quiet Mecp2-/y adult mice at different ages, i.e. at 30 days (A), 45 days (B), 55 days (C) and 59 days (D). This animal died when 60 days old; (d-30), (d-15), (d-5) and (d-1) refer to the number of days before death.
  • E Sequential plot of cycle period values (TTOT in s) of 80 consecutive respiratory cycles recorded in the unanesthetized Mecp2-/y mouse shown in A-D at 30 days (lozenges), 5 days (open squares) and 1 day (triangles) before death.
  • A-D Plethysmography recordings of breathing (inspiration upward) at about 6 weeks of age in unanesthetized, quiet wt (A) and Mecp2-/y adult mice (B-D). Mecp2-/y mice show a mixture of slow and fast respiratory rhythm (B) and periods of short- lasting (C) and long-lasting apneas (D).
  • E-F Sequential plot of TTOT values (in s) of 80 consecutive respiratory cycles recorded in wt (E) and Mecp2-/y (F) adult mice reveal that TTOT values are regular in the wt mouse but scattered in the Mecp2-/y mouse.
  • Figure 3
  • Frequency histograms represent the number of occurrences (ordinate) of TTOT (Al, A2, abscissa) and VT/B (Bl, B2, abscissa) values on 100 consecutive respiratory cycles during quiet breathing in the wt mouse (Al, Bl) and the Mecp2-/y mouse (A2, B2) from one pair of litter mates.
  • A Plethysmography recordings obtained from the same Mecp2-/y mouse when unanesthetized (Al) and anesthetized (A2).
  • B-C Frequency histograms present the number of occurrences of T ⁇ o ⁇ (Bl, B2) and V ⁇ /B (Cl, C2) values on 100 consecutive respiratory cycles during awake (Bl, Cl) and anesthetized (B2, C2) conditions in the same Mecp2-/y mouse.
  • A Schematic of a transverse brainstem slice that spontaneously generates respiratory rhythmic activity.
  • Upper trace Extracellular population activity recorded from the VRG.
  • Lower trace Integrated activity obtained from the extracellular population activity.
  • X vagus nuclei
  • XII hypoglossal nuclei
  • PBC Pre- B ⁇ tzinger complex area
  • SP5 spinal trigeminal nucleus
  • VRG ventral respiratory group
  • IO inferior olive
  • Bl Integrated regular respiratory activity from a wt mouse.
  • B2 Mecp2-/y mouse with an irregular respiratory rhythm.
  • C-D Sequential plot (C) and frequency histograms (D) of cycle period (s) obtained for 80 consecutive VRG bursts recorded in brainstem slices from wt (Cl, Dl) and Mecp2-/y (C2, D2) mice. Note cycle period variability in the Mecp2-/y mouse.
  • Al Integrated population activity from a wt slice preparation before application of NE.
  • A2 In the same animal, exogenous application of NE [20 ⁇ M] increases the respiratory rhythmic frequency.
  • Bl Integrated population activity from a Mecp2-/y mouse before application of NE.
  • B2 Exogenously applied NE [20 ⁇ M] significantly increases the regularity and frequency of respiratory rhythmic activity.
  • A-D Schematic representation of a medullary slice of adult wt mice and enlargements showing neurons of the X and XII motor nuclei that express the synthesis enzyme choline acetyltransferase (A), 5HT neurons (C) and neurons of the dorsal A2/C2 (B- B') and ventral Al/Cl (D) groups that express Tyrosine Hydroxylase (TH).
  • Mecp2-/y mice present a significant decrease of TH neurons in Al/Cl (not shown) and A2/C2 cell group (B- B').
  • Amb ambiguus nucleus
  • Ap area postrema
  • Cu cuneate nucleus
  • LRt lateral reticular nucleus
  • Py pyramidal tract
  • SoIM nucleus solitary tract
  • Sp5 spinal trigeminal nucleus
  • X dorsal vagal motor nucleus
  • XII hypoglossal motor nucleus.
  • mice Experiments were performed on mice using the mouse model (strain B6 ⁇ 29?2(C)-Mecp2 tmMBird ) for Rett Syndrome developed by A. Bird (Guy et al., 2001). The mice were obtained from the Jackson Laboratory and maintained on a C57BL/6 background. Hemizygous mutant males were generated by crossing heterozygous knockout females to C57BL/6 males. All our experiments were performed in hemizygous Mecp2 deficient male. Although Rett syndrome in humans affects female patients, most researchers use Mecp2-/y male mice for their studies.
  • Mecp2 gene is X-linked in mouse and in humans, and females will thus have a different amount of normally Mecp2- expressing cells depending on their X-chromosome inactivation profile. Since the proportion of Mecp2 -deleted X chromosomes that will be inactivated in a given female animal is unpredictable, we decided to use Mecp2-/y male mice that correspond to a complete absence of the Mecp2 gene product in all cells (i.e. a real null phenotype). Genotyping was performed by routine PCR technique according to Jackson Laboratory protocols.
  • the breathing pattern was recorded from unrestrained mice by whole-body barometric plethysmography.
  • the animal and reference chambers 200 ml and 25 ml for adult and young mice, respectively) were immersed in a temperature-regulated water bath, and maintained at 26 - 28 0 C (temperature sensor Checktemp 1, Hanna Instruments, Lingolsheim, France).
  • the spirogram was obtained by recording the pressure difference between the two chambers (Validyne CD 15, frequency response: DC to 1000 Hz, Northbridge, CA, USA).
  • the signal was amplified, filtered (DC-50 Hz), fed to an analog-to-digital converter (sampling frequency 1 kHz), and stored on a PC disk via Spike 2 interface and software (Cambridge Electronic Design, Ltd, Cambridge, UK). For each mouse, successive 3-minute plethysmographic measurements were performed until the animal was quiet (i.e. without limb, body and head movements). Only the recording periods during which the animals were quiet were analyzed. The total respiratory cycle duration (TTOT) and the tidal volume (VT) were measured for each cycle of a recording of a 100 consecutive respiratory cycles. In the figures, VT values were normalized and expressed as the ratio of the VT divided by the body weight (VT/B).
  • Mecp2-/y mice To test the effect of anesthesia on breathing of Mecp2-/y mice, some plethysmographic recordings were performed in slightly anesthetized Mecp2-/y mice which received half surgical doses of sodium pentobarbitone (30 mg kg "1 i.p., Sanofi, France).
  • the brainstem was glued rostral end-up onto an agar block, was mounted into a vibratome (Leica Microsystems, Waukegan, IL) and serially sliced until disappearance of the facial nucleus, and appearance of the inferior olive, the nucleus ambiguus and the hypoglossal nucleus.
  • a single 650 ⁇ m thick slice was then taken and used for study.
  • Slices were transferred into a recording chamber, continuously superfused with oxygenated ACSF and maintained at a temperature of 29 ⁇ 0.5oC.
  • norepinephrine was added to carbogenated ACSF.
  • the normal ACSF was changed to ACSF containing NE for 5 * 10 min and the resulting alterations in frequency and stability of VRG bursts were analyzed as reported below.
  • mice and eighteen wt mice were killed with a lethal pentobarbitone injection (300 mg kg "1 i.p.), and their brains were dissected out within 5 minutes of their last breaths.
  • the forebrain, pons and medulla were separated, weighted, and kept at -80°C until biochemical analysis.
  • Each sample was homogenized in cold trichloroacetic acid (5% in H 2 O; 200 ⁇ l for pons and medulla and 1000 ⁇ l for forebrain) with a micropotter.
  • the cellular suspension was then centrifuged (10 minutes, 600 g, 5 0 C), the supernatant was collected and diluted by adding a volume of an antioxidant solution (0.65 mM of ascorbic acid and 0.35 mM of EDTA in H 2 O) corresponding to one-fifth of the supernatant volume.
  • an antioxidant solution (0.65 mM of ascorbic acid and 0.35 mM of EDTA in H 2 O) corresponding to one-fifth of the supernatant volume.
  • High Performance Liquid Chromatography UVK Lab., Paris, France
  • electrochemical detection was used to measure the endogenous concentrations of norepinephrine, dopamine and serotonin.
  • the carbon electrode was at a potential of + 650 mV against the Ag/ AgCl reference electrode of the electrochemical detector (Model 105, Precision Instruments, France) and the sensitivity of the detection was set up to 0.05 nA V "1 .
  • the compound concentrations were also measured in l ⁇ l standard samples injected by an autosampler Biotek 565 (UVK Lab) into an hypersil ODS Column (200 x 3 mm; 3 ⁇ m) (Phymep, Paris, France) in which the polar mobile phase (in mM: citric acid 120, potassium hydrogenophosphate 430, heptane sulfonic acid 4.2, EDTA 1.7, and 10 % methanol in H 2 O) was delivered at a rate of 0.2 ml min "1 .
  • the endogenous concentrations were expressed in nM/mg of brain sample.
  • mice One and two months old mice were anesthetized with a lethal pentobarbitone injection (300 mg kg "1 i.p.) and transcardially perfused (chilled saline for 1 min followed by PBS 0.1 M containing 4% paraformaldehyde for 10 min). Brains were postfixed for 5 h and placed overnight in PBS containing 20% sucrose. For neonatal mice, brains were dissected and fixed by immersion during 12 h and placed overnight in PBS containing 20% sucrose. Medullary coronal sections were cut on cryostat (20 ⁇ m) and one every successive five slices was arranged serially on a slide.
  • Sections were permeabilized (0.15% TritonX ⁇ OO), blocked with 7% normal goat serum (NGS), and incubated overnight at 4°C with primary antibody in PBS containing 3.5% serum, 0.15% Triton X -1 OO. Sections were washed, incubated with secondary antibody in PBS containing 3.5% serum, 0.15% Triton X " 1 OO, and re-washed. The sections were subsequently mounted in Prolong antifade (Molecular Probes, Eugene, Oregon). Tyrosine hydroxylase (TH), serotonin (5HT) and choline acetyl transferase (ChAT) were probed with affinity-purified rabbit polyclonal antibodies (1 :1000, Institut J.
  • the IS was defined for each cycle by applying the formula for consecutive cycle period values 100*ABS( Pn-Pn " )/Pn "J , with P being the period of the nth respiratory cycle (Telgkamp et al., 2002); mean IS values for wt and Mecp2-/y mice were compared by Student's T-test. In addition, we also used the one-tailed Moses rank-like test for scale differences followed by the Edgington procedure to compare the distribution of respiratory cycle period between paired wt-Mecp2-/y slices (mice from same litter).
  • results are given as medians ⁇ quartile deviation (i.e., half of the difference between the 75 th and the 25 th percentile) and the statistical differences between the wt and Mecp2-/y mice were analyzed by the non-parametric Mann- Whitney U test.
  • the frequency changes induced by ACSF containing NE were analyzed by one-way ANOVA (experimental conditions: control and NE application) for repeated measures in the same subjects, followed by Tukey's tests as multiple-comparisons procedure.
  • the effect of NE application on the IS was analyzed by a two-way ANOVA, [the factors are strain (wt or Mecp2-/y mice) and experimental conditions (control, NE application and recovery)] for repeated measurements in the same subjects with only one repeated factor (experimental conditions) followed by Tukey's tests as multiple comparisons procedure.
  • EXAMPLE 1 EFFECT OF MECP2 DEFICIENCY ON THE BREATHING PATTERN IN ADULT MECP2-/Y MICE
  • Plethysmography recordings were performed in 25 unrestrained Mecp2-/y mice, 15 young mice that were recorded at least once before one month of age and thereafter sacrificed for other analysis and 10 adult mice that were recorded several times between one and two months of age.
  • Mecp2-/y mice failed to thrive and their lifespan is short (54 days) although some animals survive until three months of age.
  • adult Mecp2-/y mice had a significantly reduced body weight (23 ⁇ 1 g and 15 ⁇ 2 g for wt and Mecp2-/y mice) and a short lifespan.
  • Eight Mecp2-/y mice died before 2 months of age (median 54 days, range 32-60 days), two survived until 67 and 89 days and all presented breathing disturbances that developed during the studied period.
  • the mean breathing frequency was not significantly different in wt and Mecp2-/y mice (3.25 ⁇ 0.28 Hz vs. 2.95 ⁇ 0.50 Hz, respectively) but Mecp2-/y mice displayed alternating periods of fast and slow respiratory frequencies (Fig. 2B) and apneas of variable duration (Fig. IB; Fig. 2C, 2D). (median 6 apneas lasting more than 1 second during 15 min recording sessions; range 3-25). Indeed, the respiratory cycle period was more stable in wt than Mecp2-/y mice (Fig. 2E, 2F).
  • Mecp2-/y mice the apneas were sometimes preceded by an increase in the breathing frequency or by a large inspiration (Fig.2D). However, this was not always the case (Fig. IB) and the occurrence of apneas was therefore unpredictable.
  • a given Mecp2-/y mice that displayed breathing disturbances during 2-3 consecutive recording sessions of 15 min might transiently show an apparently normal breathing during the next recording session.
  • breathing disturbances were almost permanent and very severe (Fig. 1C, ID), with a significantly reduced mean breathing frequency (3.33 ⁇ 0.23 Hz vs. 1.55 ⁇ 0.38 Hz, for wt and Mecp2-/y mice, respectively) and very frequent long lasting apneas (median 10 apneas lasting more than 1 second during 15 min recording sessions; range 5-75).
  • Mecp2 deficiency significantly alters the breathing pattern in adult mice, inducing a highly variable cycle period.
  • Mecp2-/y mice were however capable of generating regular breathing in the presence of light anesthesia. This effect was analyzed in 5 Mecp2-/y adult mice that displayed breathing disturbances (Fig. 4Al). Ten minutes following anesthesia onset, breathing activity became regular and stable with no apneas (Fig. 4A2). The distributions of T ⁇ o ⁇ and Vx were significantly different in unanesthetized (Fig. 4Bl and 4Cl) and anesthetized conditions (Fig. 4B2 and 4C2). The significance was confirmed with the Edgington procedure.
  • EXAMPLE 2 EFFECT OF MECP2 DEFICIENCY ON IN VITRO RESPIRATORY RHYTHMOGENESIS IN BRAINSTEM SLICES FROM YOUNG MECP2-/Y MICE
  • This slice contains neurons of the ventral respiratory group (VRG, Fig. 5A) that are thought to form a network that generates the basic respiratory rhythm.
  • the spontaneous generated bursts of population activity of this region correspond to fictive inspiratory activity.
  • NE application in slices from wt mice had no effects on CVd and IS values.
  • slices from wt and Mecp2-/y mice produced rhythmic VRG bursts with a statistically similar frequency and regularity.
  • Mecp2-/y mice have a deficiency in NE systems that could contribute to their breathing disturbances.
  • TH-neurons were found in the ventral Al/Cl (Fig. 7D) and dorsal A2/C2 (Fig. 7B-B 1 ) catecholaminergic groups of wt and Mecp2-/y mice.
  • Neuron counting revealed a significantly reduced number of TH-neurons in Mecp2-/y mice.
  • the number of TH-neurons was significantly reduced in the Al/Cl group of Mecp2-/y mice (302 ⁇ 70 and 211 ⁇ 48 neurons for wt and Mecp2-/y mice, respectively).
  • the number of TH-neurons was also significantly reduced in Mecp2-/y mice (325 ⁇ 19 and 204 ⁇ 9 TH-neurons for wt and Mecp2-/y mice, respectively).
  • the number of immuno-labeled neurons expressing 5HT in the median B1-B2 groups and the lateral B3 group was not significantly different between wt and Mecp2-/y mice (244 ⁇ 26 and 228 ⁇ 26, respectively; Fig. 7C).
  • the number of immuno-labeled neurons expressing ChAT in the X and XII motor nuclei (Fig.
  • Mecp2 deficiency induces a specific reduction of the medullary NE contents in adult mice with a reduction of number of medullary NE neurons that occurs postnatally during the first month of age and precedes the occurrence of drastic breathing alterations.
  • EXAMPLE 5 EFFECT OF DESIPRAMINE ON THE ALTERATIONS OF THE BREATHING PATTERN INDUCED MECP2 DEFICIENCY.
  • Mecp2-/y mice were separated in 2 groups, and the breathing pattern of the mice of both groups was recorded by barometric plethysmography.
  • mice of both groups were recorded by barometric plethysmography, up to 80 days after the beginning of the treatment.
  • mice treated with desipramine is 48% higher than the mean survival of control mice (* P>0,05).
  • Kerr AM JuIu PO, Hansen S, Apartopoulos F (1998) Serotonin and breathing dysrhythmia in Rett syndrome.
  • Perat MV, edn New Developments in child neurology Bologna : Monduzzi Editore: 191 -195.
  • Kerr AM Armstrong DD, Prescott RJ, Doyle D, Kearney DL (1997) Rett syndrome: analysis of deaths in the British survey. Eur Child Adolesc Psychiatry 6 Suppl 1 :71-74.
  • Woodyatt GC, Murdoch BE (1996) The effect of the presentation of visual and auditory stimuli on the breathing patterns of two girls with Rett syndrome. J Intellect Disabil Res 40 ( Pt 3):252-259.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Pulmonology (AREA)
  • Emergency Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention porte sur le traitement ou la prévention de troubles respiratoires du syndrome de Rett par l’utilisation d'un inhibiteur sélectif du recaptage de la norépinéphrine.
PCT/EP2005/009893 2005-08-18 2005-08-18 Utilisation d'un inhibiteur sélectif du recaptage de la norépinéphrine pour traiter des troubles respiratoires qui résultent du syndrome de rett WO2007019880A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP2005/009893 WO2007019880A1 (fr) 2005-08-18 2005-08-18 Utilisation d'un inhibiteur sélectif du recaptage de la norépinéphrine pour traiter des troubles respiratoires qui résultent du syndrome de rett

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2005/009893 WO2007019880A1 (fr) 2005-08-18 2005-08-18 Utilisation d'un inhibiteur sélectif du recaptage de la norépinéphrine pour traiter des troubles respiratoires qui résultent du syndrome de rett

Publications (1)

Publication Number Publication Date
WO2007019880A1 true WO2007019880A1 (fr) 2007-02-22

Family

ID=36123569

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2005/009893 WO2007019880A1 (fr) 2005-08-18 2005-08-18 Utilisation d'un inhibiteur sélectif du recaptage de la norépinéphrine pour traiter des troubles respiratoires qui résultent du syndrome de rett

Country Status (1)

Country Link
WO (1) WO2007019880A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010020585A1 (fr) * 2008-08-18 2010-02-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la recapture de la sérotonine destinés au traitement du syndrome de rett
US10603272B2 (en) 2015-02-27 2020-03-31 Kindred Biosciences, Inc. Stimulation of appetite and treatment of anorexia in dogs and cats

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001034124A2 (fr) * 1999-11-08 2001-05-17 Diethelm Wolfgang Richter Utilisation d'agonistes des recepteurs 5ht-1a a la serotonine pour le traitement de troubles respiratoires genetiques ou fonctionnels
DE10130168A1 (de) * 2001-06-22 2003-01-23 Richter Diethelm Wolfgang Verwendung von 5-HT¶4¶-oder 5-HT¶7¶-Serotoninrezeptor-Agonisten
EP1336406A1 (fr) * 2002-02-14 2003-08-20 Solvay Pharmaceuticals B.V. Agonistes partiels du récepteur D2 de la dopamine et inhibiteurs de la sérotonine et/ou de la noradrénaline
WO2005020976A2 (fr) * 2003-08-27 2005-03-10 Eli Lilly And Company Traitement des troubles profonds du developpement au moyen d'inhibiteurs de la recapture de la norepinephrine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001034124A2 (fr) * 1999-11-08 2001-05-17 Diethelm Wolfgang Richter Utilisation d'agonistes des recepteurs 5ht-1a a la serotonine pour le traitement de troubles respiratoires genetiques ou fonctionnels
DE10130168A1 (de) * 2001-06-22 2003-01-23 Richter Diethelm Wolfgang Verwendung von 5-HT¶4¶-oder 5-HT¶7¶-Serotoninrezeptor-Agonisten
EP1336406A1 (fr) * 2002-02-14 2003-08-20 Solvay Pharmaceuticals B.V. Agonistes partiels du récepteur D2 de la dopamine et inhibiteurs de la sérotonine et/ou de la noradrénaline
WO2005020976A2 (fr) * 2003-08-27 2005-03-10 Eli Lilly And Company Traitement des troubles profonds du developpement au moyen d'inhibiteurs de la recapture de la norepinephrine

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DUNN H G: "Neurons and neuronal systems involved in the pathophysiologies of Rett syndrome.", BRAIN & DEVELOPMENT. DEC 2001, vol. 23 Suppl 1, December 2001 (2001-12-01), pages S99 - S100, XP002376901, ISSN: 0387-7604 *
MATSUISHI T ET AL: "Neurobiology and neurochemistry of Rett syndrome.", BRAIN & DEVELOPMENT. DEC 2001, vol. 23 Suppl 1, December 2001 (2001-12-01), pages S58 - S61, XP002376903, ISSN: 0387-7604 *
SAITO Y ET AL: "Reduced expression of neuropeptides can be related to respiratory disturbances in Rett syndrome.", BRAIN & DEVELOPMENT. DEC 2001, vol. 23 Suppl 1, December 2001 (2001-12-01), pages S122 - S126, XP002376899, ISSN: 0387-7604 *
SEGAWA M: "Discussant--pathophysiologies of Rett syndrome.", BRAIN & DEVELOPMENT. DEC 2001, vol. 23 Suppl 1, December 2001 (2001-12-01), pages S218 - S223, XP002376902, ISSN: 0387-7604 *
SZABO S T ET AL: "Effects of the selective norepinephrine reuptake inhibitor reboxetine on norepinephrine and serotonin transmission in the rat hippocampus.", NEUROPSYCHOPHARMACOLOGY : OFFICIAL PUBLICATION OF THE AMERICAN COLLEGE OF NEUROPSYCHOPHARMACOLOGY. DEC 2001, vol. 25, no. 6, December 2001 (2001-12-01), pages 845 - 857, XP002376900, ISSN: 0893-133X *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010020585A1 (fr) * 2008-08-18 2010-02-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la recapture de la sérotonine destinés au traitement du syndrome de rett
US10603272B2 (en) 2015-02-27 2020-03-31 Kindred Biosciences, Inc. Stimulation of appetite and treatment of anorexia in dogs and cats

Similar Documents

Publication Publication Date Title
Viemari et al. Mecp2 deficiency disrupts norepinephrine and respiratory systems in mice
US10172825B2 (en) Pharmacological treatment of cognitive impairment
CA2693254C (fr) Methodes de traitement de syndrome non metabolique au moyen d'agonistes du recepteur de dopamine
EP3442513B1 (fr) Utilisation d'acide cannabidiolique dans le traitement des troubles du spectre autistique et des troubles associés
EP3442581B1 (fr) Utilisation de cannabidivarine dans le traitement du trouble du spectre autistique, de troubles associés et de la schizophrénie
TW201605443A (zh) 治療ｘ染色體脆折症及相關病症的方法
US20170209425A1 (en) Methods and compositions for treating pathologies associated with bdnf signaling
CN113924087A (zh) 血清素4受体激动剂对抗应激的预防功效
WO2007019880A1 (fr) Utilisation d'un inhibiteur sélectif du recaptage de la norépinéphrine pour traiter des troubles respiratoires qui résultent du syndrome de rett
Chen et al. Role of glutamate and substance P in the amphibian respiratory network during development
Sontheimer et al. Neurodevelopmental disorders
US20210030734A1 (en) Method of treating amyotrophic lateral sclerosis with pridopidine
US20240148708A1 (en) Method of treating amyotrophic lateral sclerosis with pridopidine
Tuinier et al. Neuropsychiatric and biological characteristics of X-linked MAO-A deficiency syndrome. A single case intervention study
US20230190724A1 (en) Method of treating amyotrophic lateral sclerosis with pridopidine
AU2016219678B2 (en) Pharmacological treatment of cognitive impairment
Der-Ghazarian A Mouse Model of Serotonin 1B Receptor Modulation of Cocaine and Methamphetamine Craving
Green Environmental tauopathies
AU2013204190B2 (en) Pharmacological treatment of cognitive impairment
Ádám et al. Second Joint Meeting of the LXXIV Annual Meeting of the Hungarian Physiological Society and the Hungarian Society for Experimental and Clinical Pharmacology
US20040176467A1 (en) Method of preventing or reducing the occurrence of symptoms of psychosis
Calvey et al. Proceeding of the British Pharmacological Society, Clinical Pharmacology Section, 16‐18th December, 1980, University of London. Abstracts.
Lioy et al. Effect of sarizotan, a 5-HT1a and D2-like receptor agonist, on respiration in three mouse models of Rett syndrome
Reguilón et al. Progress in Neuropsychopharmacology & Biological Psychiatry
Schweimera et al. Serotonin Club Satellite Meeting Posters

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 05787399

Country of ref document: EP

Kind code of ref document: A1