WO2017017363A1

WO2017017363A1 - Xenon-based inhalable drug to fight memory impairment caused by a loss of cholinergic neuron function

Info

Publication number: WO2017017363A1
Application number: PCT/FR2016/051920
Authority: WO
Inventors: Etienne Hirsch; Jérémie LAVAUR; Marc Lemaire; Patrick Michel
Original assignee: L'air Liquide, Societe Anonyme Pour L'etude Et L'exploitation Des Procedes Georges Claude; L'institut Du Cerveau Et De La Moelle Epiniere
Priority date: 2015-07-30
Filing date: 2016-07-22
Publication date: 2017-02-02
Also published as: FR3039403B1; FR3039403A1

Abstract

The invention relates to a gaseous drug including xenon gas for use in treating impaired cholinergic synaptic transmission in humans. Impaired cholinergic synaptic transmission causes disease of the central nervous system of said humans, more particularly memory impairment during normal or premature aging of the brain in said humans. The proportion of xenon is between 10 and 80% by volume, preferably between at least 20% by volume and/or no more than 75% by volume. The invention also relates to a drug combination including such a xenon-gas-based drug and at least one NMDA receptor antagonist in liquid or solid form, such as memantine, nitromemantine, amantadine or ifenprodil.

Description

Inhalable xenon drug to fight memory deficits caused by loss of functionality of cholinergic neurons

The invention relates to the use of xenon gas as an inhalable drug, used alone or in combination with an N-methyl-D-Aspartate (NMDA) glutamate receptor antagonist, to treat neurological degradation characterized by deficits. memory due to a loss of functionality of cholinergic neurons, during normal or premature cerebral aging, as in cases of dementia, particularly in the case of Alzheimer's disease.

Cholinergic neurotransmission, which is involved in the propagation of nerve impulses at the brain level, involves a specific neurotransmitter, namely acetylcholine.

In some cases, cholinergic neurotransmitter may become dysfunctional and result in synthesis and / or synaptic release of the neurotransmitter acetylcholine during normal brain aging (Casu et al., Cereb Cortex, 2002, Grothe et al., Neurobiol. Aging, 2013) or, to a greater extent, during premature cerebral aging, in particular premature cerebral aging generated by a pathology such as dementia, especially of the Alzheimer's disease type (Terry and Buccafusco, J. Pharmacol. Exp Ther., 2003).

In addition, the NMDA receptors of the plasma membrane of neuronal cells are glutamate receptors / channels. These molecular entities are the target of the glutamate molecules released in the synaptic and extra-synaptic space, glutamate being an excitatory neurotransmitter ensuring communication from one nerve cell to another. These receptors are also involved in neural plasticity including learning and memory (Danysz and Parsons, Br. J. Pharmacol, 2012).

However, it is known that the acquisition of cholinergic properties is promoted during neuronal development by pharmacological compounds that act as NMDA receptor antagonists. Thus, a reduction in NMDA receptor activation induces and stimulates synaptic cholinergic activity (Liu et al., J. Neurophysiol, 2008).

The cholinergic neurons of the basal forebrain, which are located at the level of the septum and the nucleus and basalis of Meynert, and which project, respectively, to the level of the hippocampus and cortex, become progressively dysfunctional during normal brain aging or premature aging.

The loss of function of these neurons is also responsible for memory deficits and learning in animals in lesional models of the cholinergic pathways of the anterior basal brain (Terry et al., J. Pharmacol Exp Ther. 2003) and pharmacological models in which cholinergic neurotransmission is reversibly blocked by acetylcholine receptor antagonists (Buccafusco et al., Psychopharmacology (Berl), 2008; Prohovnik et al., J. Cerebral Blood Flow Metab., 1997).

This explains why treatments consisting in reducing and / or delaying the synaptic degradation of acetylcholine are generally tested, during the installation of memory deficits in humans.

For example, memantine, nitromantantin, amantadine and ifenprodil are compounds that antagonize NMDA receptors carried by neuronal cells (Olivares et al., Curr Alzheimer Res., 2012). . The action of these compounds is beneficial and leads to a preservation of nerve transmission between neuronal cells in a pathological context (McShane et al., Cochrane Database

Syst. Rev., 2006; Hu et al., Proc. Natl. Acad. Sci., USA, 2009).

However, this positive effect of the NMDA receptor antagonists, in particular memantine, is limited because these molecules are not devoid of undesirable effects for patients treated with these compounds, in particular of the confounding, vertigo-like side effects. drowsiness, headache, insomnia, agitation, hallucinations, vomiting, anxiety ... which counteract their positive effect.

To date, therefore, there is no completely satisfactory treatment for treating a neurological degradation characterized by memory deficits consecutive to a loss of functionality of cerebral cholinergic neurons.

The problem is therefore to propose a medicament for treating, that is, treating, slowing down, attenuating or minimizing, a neurological degradation characterized by memory deficits consecutive to, that is to say generated by, a loss of functionality of cholinergic neurons, during normal or premature cerebral aging, as in cases of dementia, particularly in the case of Alzheimer's disease The solution according to the present invention is a gaseous drug comprising xenon gas for use in treating a dysfunction of cholinergic synaptic transmission in a human.

In the context of the invention, the term "treat" is understood in the broad sense and encompasses not only "cure" but also "slow evolution", "mitigate" or "minimize" the disease. The treatment is total or partial.

Depending on the case, the gaseous drug according to the invention may have one or more of the following characteristics:

- It is inhalable, that is to say, administered by inhalation via the airways of the patient.

the xenon contained in the drug is in a form that can be administered by inhalation, that is to say that it is intended and able to be inhaled by the patient.

the dysfunction of cholinergic synaptic transmission causes a disease of the central nervous system of said human being.

dysfunction of cholinergic synaptic transmission causes or results in one or more mnemic deficits in said human being.

dysfunction of cholinergic synaptic transmission causes memory deficits during normal or premature cerebral aging in said human being.

dysfunction of cholinergic synaptic transmission results from an attrition of cholinergic cell bodies, a reduction of the neuritic arborization of said cholinergic cell bodies and / or a decrease in the content of said cholinergic cell bodies, to the enzyme which produces acetylcholine.

the disease caused by dysfunction of cholinergic synaptic transmission is selected from among the dementias.

Central nervous system disease is Alzheimer's disease or arises from Alzheimer's disease.

- the patient is a man or a woman, whether an adult or a child.

the drug contains an effective amount of xenon.

the drug contains a non-anesthetic amount of xenon, i.e., sub-anesthetic.

the proportion of xenon is between 10 and 80% by volume.

the proportion of xenon is between 15 and 80% by volume. the proportion of xenon is at least 20% by volume.

the proportion of xenon is at most 75% by volume.

the proportion of xenon is at most 60% by volume.

the proportion of xenon is between 20 and 50% by volume.

the proportion of xenon is between 20 and 40% by volume.

the medicament contains xenon mixed with oxygen, just before or at the time of inhalation by the patient, or is in the form of a "ready-to-use" gas mixture premixed with oxygen; 'oxygen.

the drug optionally contains another gaseous compound, for example nitrogen.

the drug contains xenon mixed with gaseous oxygen and nitrogen gas.

the drug contains at least 21% by volume of oxygen.

the mixture consisting of xenon and oxygen.

a mixture consisting of xenon, nitrogen and oxygen is used.

the gaseous mixture is administered to the patient for an inhalation period of a few minutes to a few hours, typically between 15 minutes and 6 hours, preferably less than 4 hours.

the duration, the dosage and the frequency of administration depend on the evolution of the neurological state of the patient considered, and will preferably be fixed by the doctor or the nursing staff, according to the neurological state of the patient considered.

the gaseous drug containing the gaseous xenon is packaged in a gas bottle having a capacity (water equivalent) of up to 50 liters, typically of the order of 0.5 to 15 liters and / or at a lower pressure or equal to 350 bars absolute, typically a pressure of between 2 and 300 bars.

the gaseous drug containing the gaseous xenon is packaged in a gas cylinder equipped with a tap or an integrated pressure reducing valve, making it possible to control the flow rate and possibly the pressure of the gas delivered.

- the gas cylinder is made of steel, aluminum or composite materials.

during the treatment, the administration to the patient of the gaseous drug containing xenon gas is carried out by inhalation by means of a facial or nasal mask, nasal goggles or through any other inhalable gas administration system. The invention also relates to a drug combination comprising a drug based on xenon gas as described above, and at least one NMDA receptor antagonist in liquid or solid form.

Depending on the case, the drug combination of the invention may comprise one or more of the following technical characteristics:

the NMDA receptor antagonist is in solid form, in particular in tablet or capsule form.

the NMDA receptor antagonist is memantine, nitromantantine, amantadine or ifenprodil

the NMDA receptor antagonist is memantine or nitromanthine, preferably memantine.

the NMDA receptor antagonist is preferably memantine, or any other analogous compound.

the daily dose of NMDA receptor antagonist administered to the patient is less than or equal to 20 mg / day.

the xenon gas is administered to the patient before, concomitantly or after administration of the NMDA receptor antagonist, preferably after administration of the NMDA receptor antagonist.

Furthermore, the invention also relates to a use of gaseous xenon to manufacture a gaseous drug or drug combination, as described above, for treating a disease caused by a dysfunction of cholinergic synaptic transmission in a human being.

In general, the inhalable gaseous drug according to the invention contains gaseous xenon which can be used, that is to say administered, alone or in combination with a glutamate NMDA receptor antagonist in liquid or solid form, for treating central nervous system disease resulting from dysfunction of cholinergic synaptic transmission in a human patient, such as dementia, particularly Alzheimer's disease.

In other words, the invention relates to xenon gas or a drug combination comprising xenon gas and at least one NMDA receptor antagonist, in liquid or solid form, for treating a disease caused by a dysfunction of cholinergic synaptic transmission in a human patient. .

Indeed, as shown in the examples below, it has been demonstrated, in the context of the present invention, that to treat a disease caused by dysfunction of cholinergic synaptic transmission leading to memory deficits resulting from normal or premature cerebral aging:

on the one hand, the effects of xenon, used alone, are greater than those of an NMDA receptor reference antagonist, such as memantine (MEM), and

on the other hand, memantine increases the efficacy of xenon, that is, acts synergistically with xenon.

It follows that xenon alone as a single active product or used in combination with or in combination with an NMDA receptor antagonist, such as memantine, is a promising treatment for cholinergic synaptic transmission dysfunction. at the origin of memory deficits which result from normal or premature cerebral aging, as in the case of dementia, in particular of Alzheimer's disease type.

The effects of inhaled xenon administered alone or in combination with memantine or other NMDA receptor antagonists are related to the modes of action of these compounds. Thus, xenon has an inhibitory action on excitatory glutamatergic signaling pathways (Dinse et al., Br. J. Anaesth., 2005), via its antagonistic action on NMDA receptors, while memantine also acts as an antagonist of these receptors (Bormann, Europ.J. Pharmacol., 1989).

In general, xenon alone or in combination with memantine or an analogue makes it possible, in the context of the present invention, to restore the synaptic transmission of cholinergic neurons whose functioning is impaired.

Hence, the invention also provides a method of therapeutic treatment for treating or slowing central nervous system disease resulting from dysfunction of cholinergic synaptic transmission, wherein:

i) identifying a human patient suffering from a disease of the central nervous system resulting from a dysfunction of cholinergic synaptic transmission, ii) administering by inhalation, to said patient, a gaseous drug according to the invention containing xenon or a combination medicinal product according to the invention comprising xenon gas and at least one NMDA receptor antagonist, in liquid or solid form, so as to treat said disease of the central nervous system.

According to this method of therapeutic treatment, xenon alone or in combination with the NMDA receptor antagonist, leads to a restoration of normal cholinergic synaptic functioning, thus leading to treatment, especially at least a slowing of the evolution of the disease, especially when it is a disease selected from dementia, including Alzheimer's disease type.

Preferably, in step i) of the therapeutic treatment method:

- the human patient is a man or a woman, whether an adult or a child.

- the identification of the patient is done by a doctor or the like.

- The identification of the patient is done by screening technical examination.

- The abnormal synaptic functioning of cholinergic neurons in the patient is likely to cause neurological dysfunction.

Preferably, in step ii) of the therapeutic treatment method:

the duration, the dosage and the frequency of administration of the xenon are chosen and / or fixed according to the evolution of the neurological state of the patient considered.

an effective amount of xenon is administered.

a non-anesthetic quantity of xenon is administered.

from 10 to 75% by volume of xenon, preferably from 20 to 50% by volume of xenon, are administered.

xenon is mixed with oxygen before or at the moment of its inhalation by the patient, preferably with at least 21% by volume of oxygen.

a gaseous mixture ready for use consisting of xenon and oxygen (binary mixture) is administered.

a gaseous mixture ready for use consisting of xenon, oxygen and nitrogen (ternary mixture) is administered.

the xenon gas is administered one or more times a day to the patient.

the xenon gas is administered to the patient for an inhalation duration of a few minutes to a few hours, typically between 15 minutes and 6 hours, preferably less than 4 hours.

xenon gas is administered by means of a facial or nasal mask, nasal goggles or through any other gas delivery system or device to a patient.

at least one NMDA receptor antagonist in solid form is administered to said patient.

at least one NMDA receptor antagonist is administered, preferably enterally, ie, orally. at least one NMDA receptor antagonist in the form of a tablet or capsule is administered to said patient.

the patient is administered memantine or a compound derived from memantine, as an NMDA receptor antagonist.

the patient is administered nitromantantin as an NMDA receptor antagonist.

the patient is administered amantadine or Pifenprodil as an NMDA receptor antagonist.

the patient is administered a daily dose of NMDA receptor antagonist, less than or equal to 20 mg / day.

at least one NMDA receptor antagonist is administered to said patient before, concomitantly, or after inhalation of xenon by the patient.

The invention will now be better understood thanks to the following examples and to the appended figures, which are given by way of illustration but without limitation, where:

1 represents the size of the cell bodies containing the synthetic enzyme of acetylcholine or choline acetyltransferase (ChAT), after exposure to the gases tested, with or without the presence of memantine, and shows digitized images representative of the size cell bodies and the neurite network of these ChAT neurons under the same treatment conditions,

FIG. 2 represents the intensity of the ChAT immuno fluorescence signal in cell bodies containing this enzyme, after exposure to the gases tested, with or without the presence of memantine, and

3 represents the number of ChAT ⁺ neurons / culture wells after exposure to the gases tested, with or without the presence of memantine.

Examples

In order to demonstrate the efficacy of xenon alone or in combination with an NMDA receptor antagonist, according to the present invention, a cellular model has been established in which the dysfunction of cholinergic synaptic transmission is spontaneously demonstrated.

This dysfunction is characterized by attrition of the cell body, a decrease in neuritic arborization, as well as a reduction of synaptic functioning, under the culture conditions used. The technique used for the production of the cultures is described below and the results obtained are summarized in Tables 1, 2, 3 and illustrated by FIGS. 1, 2 and 3, appended hereto, showing the effects of xenon alone. , or associated with memantine, in a cell model mimicking a neuronal attrition, a decrease in neuritic arborization, related to a dysfunction of cholinergic synaptic transmission.

Primary cultures of cholinergic septal neurons

The cultures are prepared from septum of rat embryos, taken from Wistar rats, at day 15.5 gestation (January LABS, Genest St Isles, France).

The method for obtaining septum cultures comprises producing a homogenous cell suspension by mechanical, i.e. non-enzymatic, dissociation of the embryonic tissue using Leibovitz's L15 medium (Traver et al., Mol. Pharmacol, 2005).

Aliquots of this suspension are added to 48-well Nunc plates, which have been previously coated with a thin layer of polyethylenimine (1 mg / ml, borate buffer pH 8.3) to allow adhesion of the neuronal cells (Toulorge et al., Faseb J., 2011).

The septum cultures are maintained in Neurobasal culture medium, containing an antioxidant-free B27 cocktail, N2 supplement, glutamine (2 mM) and a penicillin / streptomycin cocktail. Medium and supplement are available from Life Technologies.

The cultures are treated with 0.5 μl of the antimitotic cytosine arabinoside (Sigma Aldrich) to limit glial proliferation. Nerve growth factor, called "Nerve Growth Factor" or "NIF" (NGF 2.5S; 50 ng / ml; Sigma-Aldrich) is added to the cultures, the ^1st day of culture, 7 days later and just before start of incubation under controlled gaseous atmosphere.

Until the moment when the effects of the tested gases are evaluated, the cultures are placed in a conventional chamber thermostated at 37 ° C., in which the gaseous atmosphere is saturated with water and the content of C0 ₂ maintained at 5% in volume.

The process of cholinergic neuron dysfunction that occurs spontaneously results from neuronal attrition, reduced neuritic arborization, and synaptic transmission deficiency. Pharmacological treatment of cultures

An NMD A receptor blocker, namely memantine (10 μl), is added to certain culture wells, just before the gaseous atmosphere is controlled, and the treatment is then prolonged until the cultures are fixed.

Maintaining cultures under controlled gaseous atmosphere

Once the pharmacological treatments have been carried out, the multi-well dishes containing the cells in culture and the box used for humidifying the internal compartment of the chamber are placed on a metal base which receives the Plexiglas incubation chamber, which is fixed by screwing, contiguously.

The incubation chamber, whose inlet and outlet valves are open, and whose output flow rate is controlled by means of a flowmeter, is then injected with several gaseous mixtures of interest comprising (% by volume):

- 20% of 02,

- 5% C02

and 75% of a test gas, namely either nitrogen (N ₂ ) or xenon (Xe). The reference output flow rate (set at 10 liters / min for air) is corrected according to the density of the gaseous mixture of interest thus formed. When the CO 2 measurement reaches 5% at the exit, the injection of the gaseous mixture is stopped and the chamber is made completely watertight by closing the inlet and outlet valves. The exposure chamber is then placed in a chamber at 37 ° C for the duration of the experimental protocol.

Immunodetection of choline acetyltransferase

After rupture of the seal by opening the inlet and outlet valves and unscrewing the chamber from its base, the cultures are fixed with 4% formaldehyde in PBS buffer for 12 minutes and then incubated at 4 ° C. with a anti-choline acetyltransferase antibody (ChAT) produced in the goat (Merck Millipore, Darmstadt, Germany) diluted 1/100 in PBS containing 0.2% Triton X-100, to reveal the presence of cholinergic neurons.

The revelation of this antibody is obtained with a secondary antibody anti-goat coupled to fluorochrome Alexa Fluor-555 (Life Technologies, dilution 1/1000). The intensity of the ChAT immuno fluorescence signal at the cell body level is considered a marker of phenotypic differentiation of cholinergic neurons.

Counting jittery choliner neurons

Digitized images generated by an automated Arrayscan imager

XTi (Thermoscientific) equipped with a 10X objective, are used to produce composite images of each culture well. The estimation of the number of cholinergic neurons is done by manual counting of ChAT ⁺ neurons on the composite images.

Other cholinergic parameters

Digitized images of cholinergic neurons (ChAT ⁺ ), taken randomly in septum cultures with a Nikon Eclipse TE-2000 fluorescence microscope equipped with a 40X objective, are used to estimate the intensity of the immunofluorescence signal of ChAT in immuno-positive cell bodies for this enzyme and to quantify the size of these cell bodies, using MCID software (InterFocus Imaging Ltd, Cambridge). To make them more readable, digitized images of ChAT immuno-labeled neurons are shown in an inverted format. Results

The results obtained in this cellular model of cholinergic synaptic transmission dysfunction are set forth in the following Tables 1, 2, 3 and are represented in the appended FIGS. 1 to 3.

In Tables 1 to 3, a favorable response, in the presence of the treatments of interest, is indicated by a sign "+", "++", "+++", depending on the importance of this response. Conversely, a lack of response is represented by a sign "-".

Table 1

Table 2

Table 2: Typical pheno-differentiation of cholera neurons (Intensity of ChAT immuno fluorescence signal) in rat septum cultures, according to different treatments of interest.

Gas mixture Expression of ChAT

treatments

(20% O2 + 5% CO2 in cell bodies J 12 - J 16 (4 days)

+ 75% gas tested) cholmergic

N2 control group -

Xenon group alone Xe ++

Memantine group (10 μΜ) N2 -

Xenon group + memantine (ΙΟμΜ) Xe ++ Table 3

It can be seen from Tables 1-3 that a favorable response of cholinergic neurons to treatment results in:

an increase in their morphological differentiation: size of the cell bodies and the neurite network; see Table 1,

a stimulation of their phenotypic differentiation: intensity of the immuno-fluorescence signal of ChAT in the immunodepositing cell bodies for this enzyme; see Table 2, and

an overall increase in the number of immuno-positive neurons for this enzyme / culture well; see Table 3.

These results were obtained on rat septum cultures which were placed from day 12 of culture until day 16, under an atmosphere containing 75% nitrogen or 75% xenon, with or without memantine ( MEM), tested at 10 μΜ.

In view of these results, which are illustrated in Figures 1 to 3, it can be said that:

xenon at the concentration of 75% vol., produces effects significantly greater than the memantine (MEM), at the concentration of 10 μΜ, whatever the parameter analyzed, ie the morphological differentiation of the neurons expressing ChAT (Table 1), the intensity of the ChAT immuno fluorescence signal in the immuno-positive cell bodies for this enzyme (Table 2) and the total number of ChAT expressing neurons / culture well (Table 3). ). the combination of xenon 75% and memantine (10 μl) significantly improves the effect of xenon, when the level of morphological differentiation of ChAT ⁺ neurons is used as an evaluation parameter (Table 1).

In other words, the results illustrated in FIGS. 1 to 3 show a significant effect of xenon, even when used alone, in the cellular model of cholinergic synaptic dysfunction, whereas memantine (MEM) acts synergistically with xenon. by significantly potentiating the effect of xenon, when considering the level of morphological differentiation of cholinergic neurons (Figure 1).

In Figure 1 (left), the size of the ChAT ⁺ cell bodies, considered as a morphological differentiation index of cholinergic neurons, is quantified on cultures fixed at D16. The experimental values are expressed in% (+ SEM) values obtained in control cultures grown under an atmosphere containing 75% nitrogen. The data come from the counting of 25 ChAT ⁺ neurons, randomly selected in each culture condition.

An ANOVA statistical study (ANalysis Of Variance) followed by a Student-Newman Keuls test shows that:

- Xenon alone, when it replaces nitrogen or memantine in nitrogen, significantly increases the size of the cell bodies compared to the control condition, that is to say to nitrogen alone ( ^{* **} p <0.001, increased vs control cultures under 75% nitrogen).

a combined xenon-memantine treatment produces a significantly higher effect than that observed with xenon alone or memantine under nitrogen (P <0.05, increased vs cultures receiving xenon alone or treatment with memantine under nitrogen).

In Figure 1 (right part), digitized images illustrate the impact of the test gases (Xe, N ₂ ), in the presence or absence of MEM, on the morphological differentiation of ChAT ⁺ neurons, namely body size. and the importance of the neurite network. The cholinergic cell bodies are indicated by the black arrows (scale bar: 25 μιη).

It is clear that the presence of xenon increases the size of the cell bodies and the size of the neurite network relative to nitrogen alone or to nitrogen associated with memantine (MEM). This is even more noticeable in the case of a combination Xe + MEM. Moreover, in FIG. 2, the intensity of the immunofluorescence signal of ChAT, considered as an index of phenotypic function and differentiation, is quantified on cultures fixed on D16. The experimental values are expressed in% (+ SEM) average values obtained in control cultures, grown under an atmosphere containing 75% nitrogen. The data come from the counting of 25 ChAT ⁺ neurons, randomly selected in each culture condition.

Again, an ANOVA statistical study, followed by a Student-Newman-Keuls test, demonstrates that either xenon alone (when it replaces nitrogen) or xenon in the presence of memantine significantly increases the expression intensity of the ChAT, in comparison with the control condition, that is to say nitrogen alone ( ^*** p <0.001, increased vs control cultures under 75% nitrogen).

Finally, in FIG. 3, the number of ChAT ⁺ neurons / culture well, considered as an index of function and efficiency of cholinergic neurotransmission, is quantified in septum cultures fixed at J16. The experimental values are expressed in% (+ SEM) of the average values obtained in control cultures, grown under an atmosphere containing 75% nitrogen. The data come from 6 independent experiments.

Similarly, an ANOVA statistical study, followed by a Student-Newman-Keuls test, shows that:

- Xenon alone, as well as memantine in a xenon-enriched atmosphere, significantly increase the number of ChAT + neurons / culture well, compared to the control condition, namely nitrogen alone ( ^*** P <0.001, increased vs control cultures under 75% nitrogen).

- Memantine alone significantly increases the number of ChAT + neurons / culture well compared to the control condition under nitrogen (P <0.05, increased vs control cultures under 75% nitrogen).

All the results obtained converge and tend to demonstrate that gaseous xenon used, alone or in combination with an NMDA glutamate receptor antagonist, in particular memantine, is effective for treating, that is, treating, slowing down, to attenuate or minimize a neurological degradation, characterized by memory deficits, following a loss of functionality of cholinergic neurons, during normal or premature cerebral aging, and can therefore be used as medicament for treating the human pathologies that result therefrom, such as cases of dementia, in particular diseases such as Alzheimer's disease.

Claims

claims

A gaseous drug comprising xenon gas for use in treating a dysfunction of cholinergic synaptic transmission in a human.

2. Medicament according to the preceding claim, characterized in that the dysfunction of cholinergic synaptic transmission causes a disease of the central nervous system of said human being.

3. Medicament according to the preceding claim, characterized in that the dysfunction of cholinergic synaptic transmission causes memory deficits during normal or premature cerebral aging in said human being.

4. Medicament according to one of the preceding claims, characterized in that the dysfunction of cholinergic synaptic transmission derives from an attrition of cholinergic cell bodies, a reduction of the neuritic arborization of said cholinergic cell bodies and / or a decrease in the content of said cholinergic cell bodies, to the enzyme which produces acetylcholine.

5. Medicament according to one of the preceding claims, characterized in that the disease of the central nervous system is dementia and / or Alzheimer's disease.

6. Medicament according to one of the preceding claims, characterized in that the proportion of xenon is between 10 and 80% by volume, preferably between at least 20% by volume and / or at most 75% by volume.

7. Medicament according to one of the preceding claims, characterized in that the xenon is mixed with oxygen gas, and optionally with nitrogen gas, preferably at least 21% by volume of oxygen.

8. Drug combination comprising a xenon gas drug according to one of the preceding claims, and at least one NMDA receptor antagonist in liquid or solid form.

9. Drug combination according to claim 8, characterized in that the NMDA receptor antagonist is memantine, nitromemantine, amantadine or ifenprodil.

10. Use of xenon gas to manufacture a gaseous drug according to one of claims 1 to 7, for treating a disease caused by a dysfunction of cholinergic synaptic transmission in a human.