EP2136777A2 - Use of citrulline for the treatment of conditions linked to an increase in protein carbonylation - Google Patents
Use of citrulline for the treatment of conditions linked to an increase in protein carbonylationInfo
- Publication number
- EP2136777A2 EP2136777A2 EP08787826A EP08787826A EP2136777A2 EP 2136777 A2 EP2136777 A2 EP 2136777A2 EP 08787826 A EP08787826 A EP 08787826A EP 08787826 A EP08787826 A EP 08787826A EP 2136777 A2 EP2136777 A2 EP 2136777A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- treatment
- citrulline
- composition
- intended
- nutrition
- Prior art date
- Legal status (The legal status 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 status listed.)
- Ceased
Links
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 title claims abstract description 81
- 229960002173 citrulline Drugs 0.000 title claims abstract description 54
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- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 title description 27
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Classifications
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- protein carbonylation refers to a chemical modification of proteins related to the production of CO groups. This carbonylation (which may be a special case of protein oxidation) then leads to a loss of protein function (see Nystrom, The EMBO Journal (2005) 24, 1311-1317 and Dalle-Donne et al, J. Mol. Med, Vol.10, No. 2, 2006, pp. 389-406). Although the body has a number of defense systems (glutathione, catalase, SOD, etc.), these can be out of date and insufficient in certain situations. Carbonyl compounds are an interesting marker that accompanies aging and many pathologies.
- Citrulline is used to date in some pharmaceutical applications.
- EP 1 495 755 relates to the use of citrulline for the preparation of a medicament for the treatment of pathologies related to intestinal insufficiency. More particularly, the pathologies mentioned in this application are as follows: short bowel syndrome following intestinal resection, celiac disease, inflammatory bowel diseases, age-related intestinal insufficiency and intestinal insufficiency related to irradiation.
- this application does not mention the carbonylation of proteins.
- compositions comprising a statin associated with citrulline for the preparation of a medicament used in the treatment of primary or secondary atherosclerosis, and in that of degenerative diseases such as Alzheimer's disease.
- the use of these compositions is synergistic compared to compositions comprising a statin or citrulline alone.
- Application FR 2691359 describes the use of citrulline malate in a patient suffering from chronic obstructive pulmonary disease (COPD) and in a patient suffering from REYE-JOHNSON myopathy (mitochondrial myopathy). This beneficial effect of citrulline malate would be due to a better muscle utilization of fats leading to an economy of muscle proteolysis.
- COPD chronic obstructive pulmonary disease
- REYE-JOHNSON myopathy mitochondrial myopathy
- United States Patent Application US 2001/0056068 relates to the use of L-citrulline for the treatment of diseases related to nitrogen oxide deficiency such as atherosclerosis, cerebral ischemia and Alzheimer's disease. Alzheimer.
- European Patent Application EP 1752156 discloses an oxygen scavenger containing a wild watermelon extract containing citrulline and its use especially in Alzheimer's dementia, cataract problems, and cutaneous lesions.
- a pharmaceutical composition intended to inhibit the increase of the carbonylation of the responsible proteins observed in certain pathologies therefore especially intended for the treatment of neurodegenerative diseases such as Alzheimer's or Parkinson's diseases, for the treatment of retinopathy, rheumatoid arthritis, atherosclerosis, amyotrophic lateral sclerosis, cerebral ischemia, the treatment of cataract problems or generalized infections (sepsis), the treatment of pathologies related to skin aging such as wrinkles, hypo and hyperpigmented spots and loss of elasticity and more particularly to the senescence of tissues such as eye, muscle and brain, to the treatment of pathologies related to the dysfunction of mitochondria, namely the myopathies resulting from mitochondriopathies, the treatment of cachexia linked to undernutrition and increase n the longevity of mammals, especially that of pets.
- neurodegenerative diseases such as Alzheimer's or Parkinson's diseases
- retinopathy retinopathy, rheumatoid arthritis, atherosclerosis, amyotrophic lateral
- the present invention also relates to the use of a composition comprising L-citrulline or a nutraceutically acceptable salt thereof, for the nutraceutical treatment of disorders related to the increase in the carbonylation of proteins, by inhibition of the increase of the carbonylation of the responsible proteins, thus especially intended for the treatment of neurodegenerative diseases such as Alzheimer's or Parkinson's diseases, the treatment of retinopathy, rheumatoid arthritis, atherosclerosis, sclerosis amyotrophic lateral, from cerebral ischemia, to the treatment of cataract problems or generalized infections (sepsis), to the treatment of diseases related to skin aging such as wrinkles, hypo and hyperpigmented spots and loss of elasticity and more particularly to the senescence of the tissues such as eye, muscle and brain, to the treatment of the pathologies l Mitochondrial dysfunction, namely myopathies from mitochondriopathies, treatment of cachexia related to malnutrition and increased mammalian longevity.
- neurodegenerative diseases such as Alzheimer's or
- pharmaceutically acceptable salt means citrulline salts such as citrulline malate, citrulline ⁇ -ketoglutarate, citrulline citrate or citrulline paracetoisocaproate. .
- L-citrulline as defined above, for the preparation of a composition for the cosmetic treatment in a form that can be administered topically. It also relates to the use of L-citrulline as defined above, for the preparation of a composition for the nutraceutical treatment in an orally administrable form.
- the enteral administration corresponds in particular to administration by nasogastric or naso-intestinal tube, by gastrostomy or jejunostomy; the parenteral administration corresponds in particular to administration by central, peripheral or subcutaneous intravenous infusion.
- L-citrulline is used in the context of the invention for the preparation of a pharmaceutical composition, a composition for the cosmetic treatment, a composition for a food supplement or a health food for the nutraceutical treatment also comprising one or more other compounds intended for the treatment of malnutrition-related cachexia such as leucine, glutamine, arginine, restroomthine and their various usable salts such as ⁇ -ketoglutarate or ⁇ -ketoisocaproate.
- the compounds can be used alone or in a nutritional mixture for oral nutrition.
- the processes of oxidation of proteins affecting the structure of the amino acids that compose them are complex and all give rise to the formation of carbonyl groups. This is why it was chosen to evaluate overall the oxidation of muscle proteins by quantifying the carbonyl derivatives from a 300 mg sample of tibialis anterior.
- the method used is therefore a non-specific technique of the amino acid type which is based on the spectrophotometric assay of the complex formed by the binding of a compound called dinitrophenyl hydrazine (DNPH) on the carbonyl groups.
- DNPH dinitrophenyl hydrazine
- the solubilized proteins are separated into two equal fractions so as to have two wells containing the same amount of protein (1-1.5 mg / ml).
- One of the cups serves as a blank and the other to quantify the carbonyl groups.
- 500 ⁇ l of 12.5 mM DNPH are added to the measuring cup and 500 ⁇ l of 2M HCl to the white cup. After incubation for 15 minutes at room temperature, the samples are precipitated with 500 ⁇ l of 30% TCA and centrifuged for 10 minutes at 15,000 rpm. The pellet is taken up in 1 ml of 10% TCA and centrifuged again for 10 min at 15,000 rpm. 4 successive washes are then carried out with ethanolethylacetate.
- CIT group (n 5): the animals receive a standard diet enriched in CIT (lg / kg / d) for 1 month
- the animals were euthanized and the brain was removed, weighed, frozen with liquid nitrogen and stored at -80 ° C until the tests were performed.
- the samples are precipitated with 500 ⁇ l of 30% TCA and centrifuged for 10 minutes at 15,000 rpm.
- the pellet is taken up in 1 ml of 10% TCA and centrifuged again for 10 min at 15,000 rpm. 4 successive washes are then carried out with ethanolethylacetate.
- the final pellet is heated for 30 min in a water bath at 50 ° C. After a new centrifugation of 5 min at 15000 rpm, the spectrophotometric reading is performed on 800 ⁇ l of supernatant at 280 nm (protein assay) and at 380 nm (DNPH assay). The carbonyl content is expressed in ⁇ mol / g of organ.
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Abstract
The invention relates to the use of L-citrulline of the formula (I) for preparing a cosmetic composition, a food or nutraceutic composition or a pharmaceutical composition for treating diseases related to an increase in protein carbonylation, in particular for treating neurodegenerative diseases such as Alzheimer's or Parkinson's disease.
Description
UTILISATION DE LA CITRULLINE POUR LA PREVENTION DE L'AUGMENTATION DE LA CARBONYLATION DES PROTÉINES ET DU TRAITEMENT DES PATHOLOGIES QUI EN DECOULENT USE OF CITRULLINE FOR THE PREVENTION OF INCREASED CARBONYLATION OF PROTEINS AND THE TREATMENT OF DISEASES THEREFROM
La présente invention a pour objet une nouvelle utilisation de la citrulline, à savoir son utilisation dans le cadre d'une augmentation de la carbonylation des protéines et du traitement de pathologies qui en découlent.The subject of the present invention is a new use of citrulline, namely its use in the context of an increase in the carbonylation of proteins and the treatment of pathologies resulting therefrom.
Il est clairement établi que les protéines des milieux extra- et intracellulaires sont, in vivo, une cible privilégiée pour les espèces réactives de l'oxygène et les espèces réactives de l'azote. Il a été estimé que les protéines peuvent capter jusqu'à 50 à 70% des espèces radicalaires synthétisées par la cellule. Les dommages observés sont de plusieurs types : oxydation (ou nitration) des chaînes latérales des acides aminés, ou oxydation de la chaîne polypeptidique (dont un cas particulier est la carbonylation) suivie d'une fragmentation et/ou de la formation de liaisons inter- ou intra-chaînes.It is clearly established that the proteins of the extra- and intracellular media are, in vivo, a preferred target for the reactive species of oxygen and the reactive species of nitrogen. It has been estimated that proteins can capture up to 50 to 70% of the radical species synthesized by the cell. The observed damages are of several types: oxidation (or nitration) of the side chains of the amino acids, or oxidation of the polypeptide chain (of which a particular case is the carbonylation) followed by fragmentation and / or the formation of inter- or intra-chains.
La carbonylation des protéines est un phénomène qui peut être indépendant d'un phénomène d'oxydation.The carbonylation of proteins is a phenomenon that can be independent of an oxidation phenomenon.
L'ensemble de ces modifications des protéines peut entraîner des modifications de structures dont les conséquences peuvent être leur inactivation, cette dernière pouvant avoir des conséquences dommageables pour la cellule. Par ailleurs, dans l'état actuel des connaissances, il ne semble pas exister de système de réparation des protéines carbonylées.All these modifications of the proteins can lead to structural modifications whose consequences can be their inactivation, the latter having potentially damaging consequences for the cell. Moreover, in the current state of knowledge, there does not seem to be a carbonyl protein repair system.
L'expression "carbonylation des protéines" désigne une modification chimique des protéines liée à la production de groupes CO. Cette carbonylation (qui peut être un cas particulier d'oxydation des protéines) entraîne alors une perte de la fonction de la protéine (voir Nystrôm, The EMBO Journal (2005) 24, 1311-1317 et Dalle-Donne et al, J CeIl Mol Med, Vol. 10, n° 2, 2006, pp. 389-406). Bien que l'organisme possède un certain nombre de systèmes de défenses (glutathion, catalase, SOD etc.), ceux-ci peuvent dans certaines situations être dépassés et se révéler insuffisants. Les composés carbonylés constituent un marqueur intéressant qui accompagne le vieillissement et de nombreuses pathologies. En effet, ces situations physiopathologiques (maladies neurodégénératives, maladies inflammatoires, etc.) sont caractérisées par une augmentation des protéines carbonylées au niveau tissulaire. Il est donc essentiel de développer des stratégies visant à diminuer la carbonylation des protéines.
La citrulline (ou acide 2-amino-5-(carbamoyl amino)pentanoïque) est un acide α.- aminé et a été isolée pour la première fois à partir de la pastèque. La citrulline est un acide aminé non essentiel que l'organisme produit à partir d'autres nutriments. Par exemple, la citrulline joue un rôle particulièrement important, avec Pornithine et l'arginine, dans le cycle de l'urée. Enfin, la citrulline joue un rôle majeur dans l'homéostasie de l'arginine et du monoxyde d'azote.The term "protein carbonylation" refers to a chemical modification of proteins related to the production of CO groups. This carbonylation (which may be a special case of protein oxidation) then leads to a loss of protein function (see Nystrom, The EMBO Journal (2005) 24, 1311-1317 and Dalle-Donne et al, J. Mol. Med, Vol.10, No. 2, 2006, pp. 389-406). Although the body has a number of defense systems (glutathione, catalase, SOD, etc.), these can be out of date and insufficient in certain situations. Carbonyl compounds are an interesting marker that accompanies aging and many pathologies. Indeed, these physiopathological situations (neurodegenerative diseases, inflammatory diseases, etc.) are characterized by an increase of carbonyl proteins at the tissue level. It is therefore essential to develop strategies to reduce the carbonylation of proteins. Citrulline (or 2-amino-5- (carbamoyl amino) pentanoic acid) is an α-acid . - amine and was isolated for the first time from the watermelon. Citrulline is a non-essential amino acid that the body produces from other nutrients. For example, citrulline plays a particularly important role, with Pornithine and arginine, in the urea cycle. Finally, citrulline plays a major role in the homeostasis of arginine and nitric oxide.
La citrulline est utilisée à ce jour dans le cadre de certaines applications pharmaceutiques. Ainsi, la demande de brevet européen EP 1 495 755 concerne l'utilisation de la citrulline pour la préparation d'un médicament destiné au traitement de pathologies liées à une insuffisance intestinale. Plus particulièrement, les pathologies mentionnées dans cette demande sont les suivantes : le syndrome du grêle court faisant suite à une résection intestinale, la maladie coeliaque, les maladies inflammatoires chroniques de l'intestin, l'insuffisance intestinale liée au vieillissement et l'insuffisance intestinale liée à une irradiation. Cependant, cette demande ne mentionne pas la carbonylation des protéines.Citrulline is used to date in some pharmaceutical applications. Thus, the European patent application EP 1 495 755 relates to the use of citrulline for the preparation of a medicament for the treatment of pathologies related to intestinal insufficiency. More particularly, the pathologies mentioned in this application are as follows: short bowel syndrome following intestinal resection, celiac disease, inflammatory bowel diseases, age-related intestinal insufficiency and intestinal insufficiency related to irradiation. However, this application does not mention the carbonylation of proteins.
La demande internationale WO 2005/115371 décrit des compositions pharmaceutiques comprenant une statine associée à de la citrulline pour la préparation d'un médicament utilisé dans le traitement de l'athérosclérose primaire ou secondaire, et dans celui des maladies dégénératives comme la maladie de Alzheimer. L'utilisation de ces compositions présente une synergie comparativement à des compositions comprenant une statine ou de la citrulline seule.International Application WO 2005/115371 describes pharmaceutical compositions comprising a statin associated with citrulline for the preparation of a medicament used in the treatment of primary or secondary atherosclerosis, and in that of degenerative diseases such as Alzheimer's disease. The use of these compositions is synergistic compared to compositions comprising a statin or citrulline alone.
La demande FR 2691359 décrit l'utilisation du malate de citrulline chez un malade atteint de broncho-pneumopathie chronique obstructive (BPCO) et chez un malade atteint d'une myopathie de REYE- JOHNSON (myopathie mitochondriale). Cet effet bénéfique du malate de citrulline serait dû à une meilleure utilisation musculaire des graisses conduisant à une économie de la protéolyse musculaire.Application FR 2691359 describes the use of citrulline malate in a patient suffering from chronic obstructive pulmonary disease (COPD) and in a patient suffering from REYE-JOHNSON myopathy (mitochondrial myopathy). This beneficial effect of citrulline malate would be due to a better muscle utilization of fats leading to an economy of muscle proteolysis.
La demande de brevet américain décrit l'utilisation orale de la L-citrulline en tant que complément alimentaire dans les cas de maladies neurodégénératives (démences, maladie d'Alzheimer, maladie' de Parkinson), de rétinopathies (dégénérescence maculaire liée à l'âge) et de la sclérose latérale amyotrophique. Cet apport en citrulline augmente la concentration plasmatique en arginine donc . la disponibilité de cette dernière dans la génération du monoxyde d'azote. Dans ces indications, la citrulline est associée à du phytate et à du carbonate de calcium.
La demande de brevet américain US 2004/0235953 décrit et revendique une méthode de prévention et de traitement thérapeutique de pathologies liées à la diminution de la formation du monoxyde d'azote, notamment le sepsis (infection généralisée), ladite méthode comprenant l'administration d'un précurseur du monoxyde d'azote qui peut-être de la citrulline.US patent application describes the oral use of L-citrulline as a food supplement in the case of neurodegenerative diseases (dementia, Alzheimer's disease, disease 'Parkinson), retinopathies (macular degeneration ) and amyotrophic lateral sclerosis. This intake of citrulline increases the plasma concentration of arginine therefore. the availability of the latter in the generation of nitric oxide. In these indications, citrulline is associated with phytate and calcium carbonate. United States Patent Application US 2004/0235953 describes and claims a method for the prevention and therapeutic treatment of pathologies related to the reduction of the formation of nitric oxide, in particular sepsis (generalized infection), said method comprising the administration of a precursor of nitric oxide which may be citrulline.
La demande de brevet américain US 2001/0056068 a trait à l'utilisation de la L- citrulline pour le traitement de maladies liées à un déficit en monoxyde d.'azote telles que l'athérosclérose, l'ischémie cérébrale et la maladie d'Alzheimer.United States Patent Application US 2001/0056068 relates to the use of L-citrulline for the treatment of diseases related to nitrogen oxide deficiency such as atherosclerosis, cerebral ischemia and Alzheimer's disease. Alzheimer.
XP 00 24 56 361 divulgue des formulations ophtalmiques contenant de la citrulline et leur utilisation en médecine chinoise dans le traitement de la cataracte. Ces formulations agissent sur le système vasculaire ciliaire et sur le vasoganglion péricornéal.XP 00 24 56 361 discloses ophthalmic formulations containing citrulline and their use in Chinese medicine in the treatment of cataracts. These formulations act on the ciliary vascular system and on the pericorneal vasoganglion.
La demande de brevet européen EP 1752156 décrit un agent piégeur d'oxygène contenant un extrait de pastèque sauvage contenant de la citrulline et son utilisation notamment dans la démence de type Alzheimer, les problèmes de cataracte, et les lésions cutanées.European Patent Application EP 1752156 discloses an oxygen scavenger containing a wild watermelon extract containing citrulline and its use especially in Alzheimer's dementia, cataract problems, and cutaneous lesions.
Bien que ces documents décrivent l'utilisation de la citrulline seule ou en combinaison pour la préparation de médicaments utiles dans le traitement de maladies neurodégénératives telles que la maladie d'Alzheimer, de l'athérosclérose, des problèmes de cataracte ou des infections généralisées (sepsis) et au traitement des myopathies mitochondriales, et des compositions nutraceutiques aptes à être utilisées dans le cadre de maladies neurodégénératives (démences, maladie d'Alzheimer, maladie de Parkinson), de rétinopathies (dégénérescence maculaire liée à l'âge) et de la sclérose latérale amyotrophique, aucun de ces documents ne décrit l'effet direct de la citrulline sur la carbonylation des protéines.Although these documents describe the use of citrulline alone or in combination for the preparation of medicaments useful in the treatment of neurodegenerative diseases such as Alzheimer's disease, atherosclerosis, cataract problems or generalized infections (sepsis). ) and the treatment of mitochondrial myopathies, and nutraceutical compositions suitable for use in neurodegenerative diseases (dementia, Alzheimer's disease, Parkinson's disease), retinopathies (age-related macular degeneration) and sclerosis amyotrophic lateral, none of these documents describes the direct effect of citrulline on the carbonylation of proteins.
Aussi, un des buts de la présente invention est de fournir un moyen de prévenir et traiter l'augmentation de la carbonylation des protéines et les pathologies qui en découlent.Also, it is an object of the present invention to provide a means of preventing and treating the increase of carbonylation of proteins and the pathologies that result therefrom.
La présente invention concerne l'utilisation de L-citrulline de formule (I) suivante :The present invention relates to the use of L-citrulline of formula (I) below:
ou d'un sel pharmaceutiquement acceptable de celle-ci,
pour la préparation d'une composition pharmaceutique destinée à inhiber l'augmentation de la carbonylation des protéines responsables observée dans certaines pathologies donc notamment destinée au traitement des maladies neurodégénératives telles que les maladies d'Alzheimer ou de Parkinson, au traitement de la rétinopathie, de la polyarthrite rhumatoïde, de l'athérosclérose, de la sclérose latérale amyotrophique, de l'ischémie cérébrale, au traitement des problèmes de cataracte ou des infections généralisées (sepsis), au traitement des pathologies liées au vieillissement cutané comme par exemple les rides, les taches hypo et hyper- pigmentées et la perte d'élasticité et plus particulièrement à la sénescence des tissus tels que œil, muscle et cerveau, au traitement des pathologies liées au dysfonctionnement des mitochondries, à savoir les myopathies issues des mitochondriopathies, au traitement de la cachexie liée à la dénutrition et à l'augmentation de la longévité des mammifères, en particulier celle des animaux de compagnie. or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition intended to inhibit the increase of the carbonylation of the responsible proteins observed in certain pathologies, therefore especially intended for the treatment of neurodegenerative diseases such as Alzheimer's or Parkinson's diseases, for the treatment of retinopathy, rheumatoid arthritis, atherosclerosis, amyotrophic lateral sclerosis, cerebral ischemia, the treatment of cataract problems or generalized infections (sepsis), the treatment of pathologies related to skin aging such as wrinkles, hypo and hyperpigmented spots and loss of elasticity and more particularly to the senescence of tissues such as eye, muscle and brain, to the treatment of pathologies related to the dysfunction of mitochondria, namely the myopathies resulting from mitochondriopathies, the treatment of cachexia linked to undernutrition and increase n the longevity of mammals, especially that of pets.
La présente invention a également pour objet l'utilisation d'une composition comprenant de la L-citrulline ou d'un sel cosmétiquement acceptable de celle-ci, pour le traitement cosmétique des troubles liés à la carbonylation des protéines responsables, notamment dans le cas des pathologies liées au vieillissement cutané comme par exemple les rides, les taches hypo et hyper- pigmentées et la perte d'élasticité.The present invention also relates to the use of a composition comprising L-citrulline or a cosmetically acceptable salt thereof, for the cosmetic treatment of disorders related to the carbonylation of the responsible proteins, especially in the case pathologies related to skin aging such as wrinkles, hypo and hyperpigmented spots and loss of elasticity.
La présente invention a également pour objet l'utilisation d'une composition comprenant de la L-citrulline ou d'un sel nutraceutiquement acceptable de celle-ci, pour le traitement nutraceutique des troubles liés à l'augmentation de la carbonylation des protéines, par inhibition de l'augmentation de la carbonylation des protéines responsables, donc notamment destinée au traitement des maladies neurodégénératives telles que les maladies d'Alzheimer ou de Parkinson, au traitement de la rétinopathie, de la polyarthrite rhumatoïde, de l'athérosclérose, de la sclérose latérale amyotrophique, de l'ischémie cérébrale, au traitement des problèmes de cataracte ou des infections généralisées (sepsis), au traitement des pathologies liées au vieillissement cutané comme par exemple les rides, les taches hypo et hyper- pigmentées et la perte d'élasticité et plus particulièrement à la sénescence des tissus tels que œil, muscle et cerveau, au traitement des pathologies liées au dysfonctionnement des mitochondries, à savoir les myopathies issues des mitochondriopathies, au traitement de la cachexie liée à la dénutrition et à l'augmentation de la longévité des mammifères.The present invention also relates to the use of a composition comprising L-citrulline or a nutraceutically acceptable salt thereof, for the nutraceutical treatment of disorders related to the increase in the carbonylation of proteins, by inhibition of the increase of the carbonylation of the responsible proteins, thus especially intended for the treatment of neurodegenerative diseases such as Alzheimer's or Parkinson's diseases, the treatment of retinopathy, rheumatoid arthritis, atherosclerosis, sclerosis amyotrophic lateral, from cerebral ischemia, to the treatment of cataract problems or generalized infections (sepsis), to the treatment of diseases related to skin aging such as wrinkles, hypo and hyperpigmented spots and loss of elasticity and more particularly to the senescence of the tissues such as eye, muscle and brain, to the treatment of the pathologies l Mitochondrial dysfunction, namely myopathies from mitochondriopathies, treatment of cachexia related to malnutrition and increased mammalian longevity.
Par nutraceutique, on entend tout produit décrivant des allégations santé (aliment santé, alicament, produits frontières etc.).
La présente invention a également pour objet l'utilisation d'une composition comprenant de la L-citrulline, ladite composition étant destinée à être un complément alimentaire apte à être utilisé dans le cadre des maladies neurodégénératives telles que les maladies d'Alzheimer ou de Parkinson, de la rétinopathie, de la polyarthrite rhumatoïde, de l'athérosclérose, de la sclérose latérale amyotrophique, de l'ischémie cérébrale, des problèmes de cataracte ou des infections généralisées (sepsis), du vieillissement cutané comme par exemple les rides, les taches hypo et hyper- pigmentées et la perte d'élasticité et plus particulièrement de la sénescence des tissus tels que œil, muscle et cerveau, des pathologies liées au dysfonctionnement des mitochondries, à savoir les myopathies issues des mitochondriopathies, au traitement de la cachexie liée à la dénutrition et à l'augmentation de la longévité des mammifères, en particulier celle des animaux de compagnie.Nutraceutical means any product describing health claims (health food, food, border products, etc.). The present invention also relates to the use of a composition comprising L-citrulline, said composition being intended to be a dietary supplement suitable for use in the context of neurodegenerative diseases such as Alzheimer's or Parkinson's diseases. , retinopathy, rheumatoid arthritis, atherosclerosis, amyotrophic lateral sclerosis, cerebral ischemia, cataract problems or generalized infections (sepsis), skin aging such as wrinkles, stains hypo and hyperpigmented and the loss of elasticity and more particularly of the senescence of the tissues such as eye, muscle and brain, pathologies related to the dysfunction of the mitochondria, namely the myopathies resulting from the mitochondriopathies, the treatment of the cachexia related to undernutrition and increased longevity of mammals, particularly that of c OMPANY.
Dans le cadre de l'invention on entend par L-citrulline le produit disponible dans le commerce, notamment fourni par Sigma, Biocodex ou Kyowa Hakko ou le produit naturel issu de végétaux, notamment de la pastèque, ou melon d'eau (Citruîlus lanatus), sous forme notamment de jus, de pulpe ou d'extrait.In the context of the invention, L-citrulline is understood to mean the product commercially available, in particular provided by Sigma, Biocodex or Kyowa Hakko, or the natural product derived from plants, in particular watermelon, or watermelon (Citruilus lanatus). ), especially in the form of juice, pulp or extract.
On désigne par "sel pharmaceutiquement acceptable", par sel cosmétiquement acceptable » et par « sel nutraceutiquement acceptable » les sels de citrulline tels que le malate de citrulline, l'α-cétoglutarate de citrulline, le citrate de citrulline ou Pa- cétoisocaproate de citrulline.The term "pharmaceutically acceptable salt", "cosmetically acceptable salt" and "nutraceutically acceptable salt" means citrulline salts such as citrulline malate, citrulline α-ketoglutarate, citrulline citrate or citrulline paracetoisocaproate. .
Dans ma mode de réalisation avantageux de l'invention, la L-citrulline, telle que définie ci-dessus, est utilisée pour la préparation d'une composition pharmaceutique, d'une composition destinée au traitement cosmétique, d'une composition destinée à être un complément alimentaire, et d'une composition destinée au traitement nutraceutique ou aliment santé de manière à ce que la dose unitaire en L-citrulline soit d'environ 2 g à environ 20 g, notamment environ 10 g, pour une posologie d'environ 0,1 g/kg/jour à environ 0,5 g/kg/jour, notamment environ 0,25 g/kg/jour.In my advantageous embodiment of the invention, L-citrulline, as defined above, is used for the preparation of a pharmaceutical composition, a composition intended for the cosmetic treatment, a composition intended to be a dietary supplement, and a composition for the nutraceutical treatment or health food such that the unit dose of L-citrulline is from about 2 g to about 20 g, in particular about 10 g, for a dosage of about 0.1 g / kg / day to about 0.5 g / kg / day, especially about 0.25 g / kg / day.
Dans un mode avantageux de réalisation de l'invention, la L-citrulline est apportée en une à trois doses quotidiennes, préférablement en une dose.In an advantageous embodiment of the invention, L-citrulline is provided in one to three daily doses, preferably in one dose.
Selon un autre mode de réalisation avantageux de l'invention, la composition pharmaceutique et la composition pour le traitement nutraceutique (ou aliment santé) se présentent sous forme sèche, sous forme de solution aqueuse, sous forme hydroalcoolique ou huileuse, sous forme d'une émulsion huile-dans Peau ou eau-dans-
huile ou multiple, d'un gel aqueux ou huileux. Pour la composition pour le traitement cosmétique on peut utiliser tout véhicule approprié c'est-à-dire tout excipient, véhicule ou support cosmétiquement, notamment dermatologiquement, acceptable. De tels supports sont bien connus de l'homme de l'art et résultent également de compositions cosmétiques ou dermatologiques qui ont une portée générale. En exemple, les mélanges, les formules, les encapsulations monolamellaires (micelles), bilamellaires (liposomes), multilamellaires (sphémlites), et tout autre support connu en cosmétique peuvent être employés.According to another advantageous embodiment of the invention, the pharmaceutical composition and the composition for the nutraceutical treatment (or health food) are in dry form, in the form of an aqueous solution, in hydroalcoholic or oily form, in the form of a oil-in-water or water-in-emulsion oil or multiple, an aqueous or oily gel. For the composition for the cosmetic treatment it is possible to use any suitable vehicle, that is to say any excipient, vehicle or carrier cosmetically, in particular dermatologically, acceptable. Such carriers are well known to those skilled in the art and also result from cosmetic or dermatological compositions which have a general scope. As an example, mixtures, formulas, monolamellar (micelles), bilamellar (liposomes), multilamellar (sphémlites) encapsulations, and any other medium known in cosmetics may be used.
La présente invention concerne l'utilisation de la L-citrulline telle que définie ci-The present invention relates to the use of L-citrulline as defined above.
' dessus, pour la préparation d'une composition pharmaceutique se présentant sous une forme administrable par voie orale, entérale ou parentérale. Dans le cas de nutrition entérale ou de nutrition parentérale, elle peut être mélangée à la nutrition ou, préférentiellement, administrée en bolus dans la sonde de nutrition entérale ou en Y dans la nutrition parentérale.above, for the preparation of a pharmaceutical composition in an orally, enterally or parenterally administrable form. In the case of enteral nutrition or parenteral nutrition, it can be mixed with nutrition or, preferentially, administered as a bolus in the enteral nutrition tube or in Y in parenteral nutrition.
Elle concerne également l'utilisation de la L-citrulline telle que définie ci-dessus, pour la préparation d'une composition pour le traitement cosmétique sous une forme administrable par voie topique. Elle concerne également l'utilisation de la L-citrulline telle que définie ci-dessus, pour la préparation d'une composition pour le traitement nutraceutique sous une forme administrable par voie orale.It also relates to the use of L-citrulline as defined above, for the preparation of a composition for the cosmetic treatment in a form that can be administered topically. It also relates to the use of L-citrulline as defined above, for the preparation of a composition for the nutraceutical treatment in an orally administrable form.
L'administration par voie entérale correspond notamment à une administration par sonde naso-gastrique ou naso-intestinale, par gastrostomie ou jéjunostomie ; l'administration par voie parentérale correspond notamment à une administration par perfusion intraveineuse centrale, périphérique ou sous-cutanée.The enteral administration corresponds in particular to administration by nasogastric or naso-intestinal tube, by gastrostomy or jejunostomy; the parenteral administration corresponds in particular to administration by central, peripheral or subcutaneous intravenous infusion.
Selon un mode de réalisation préféré, la L-citrulline est utilisée dans le cadre de l'invention pour la préparation d'une composition pharmaceutique, d'une composition pour le traitement cosmétique, d'une composition pour complément alimentaire ou aliment santé pour le traitement nutraceutique comprenant également un ou plusieurs autres composés destinés au traitement de la cachexie liée à la dénutrition tel que la leucine, la glutamine, l'arginine, Pornithine et leurs différents sels utilisables tels que Pα-cétoglutarate ou l'α-cétoisocaproate. Dans le cadre d'une composition pour le traitement nutraceutique, les composés peuvent être utilisés seuls ou au sein d'un mélange nutritionnel destiné à la nutrition orale.According to a preferred embodiment, L-citrulline is used in the context of the invention for the preparation of a pharmaceutical composition, a composition for the cosmetic treatment, a composition for a food supplement or a health food for the nutraceutical treatment also comprising one or more other compounds intended for the treatment of malnutrition-related cachexia such as leucine, glutamine, arginine, pornithine and their various usable salts such as α-ketoglutarate or α-ketoisocaproate. In the context of a composition for the nutraceutical treatment, the compounds can be used alone or in a nutritional mixture for oral nutrition.
Selon un mode de réalisation préféré, la L-citrulline est utilisée dans le cadre de . l'invention pour la préparation d'une composition pharmaceutique, d'une composition
destinée au traitement cosmétique, d'un complément alimentaire bu d'une composition destinée au traitement nutraceutique (aliment santé) comprenant également un ou plusieurs autres composés destinés au traitement de la cachexie liée à la dénutrition tels que la leucine, la glutamine, l'arginine, l'ornithine et leurs différents sels utilisables tels que l'α-cétoglutarate ou Pα-cétoisocaproate, seuls ou au sein d'un mélange nutritionnel destiné à la nutrition orale.According to a preferred embodiment, L-citrulline is used in the context of. the invention for the preparation of a pharmaceutical composition, a composition for the cosmetic treatment, a dietary supplement bu a composition for nutraceutical treatment (health food) also comprising one or more other compounds for the treatment of cachexia related to malnutrition such as leucine, glutamine, the arginine, ornithine and their various usable salts such as α-ketoglutarate or Pα-ketoisocaproate, alone or in a nutritional mixture for oral nutrition.
Selon un autre mode de réalisation l'invention concerne des produits comprenant : - de la L-citrulline ou un sel pharmaceutiquement acceptable ou mitraceutiquement de celle-ci, - et au moins un autre composé destiné au traitement de la cachexie liée à la dénutrition tels que la leucine, la glutamine, l'arginine, l'ornithine et leurs différents sels utilisables tels que l'α-cétoglutarate ou l'α-cétoisocaproate, seuls ou au sein d'un mélange nutritionnel destiné à la nutrition parentérale, ou d'un mélange destiné à la nutrition entérale ou d'un mélange destiné à la nutrition orale, comme produits de combinaison pour une utilisation simultanée, séparée, ou étalée dans le temps, dans le cadre du traitement de pathologies liées à une augmentation de la carbonylation des protéines, lesdites pathologies étant telles que définies ci-dessus. Les exemples 1 et 2 qui suivent et la figure 1 illustrent l'invention. La Figure 1 représente la carbonylation des protéines musculaires chez le rat. L'axe des ordonnées correspond à la quantité de protéines carbonylées en μmol/g. La colonne "1 " correspond aux rats sains ; la colonne "2" correspond aux rats dénutris ; la colonne "3" correspond aux rats renourris avec un régime standard et la colonne "4" correspond aux rats renourris et ayant eu un régime enrichi en citrulline.According to another embodiment the invention relates to products comprising: - L-citrulline or a pharmaceutically acceptable or mitraceutical salt thereof, - and at least one other compound intended for the treatment of malnutrition-related cachexia such as leucine, glutamine, arginine, ornithine and their various usable salts such as α-ketoglutarate or α-ketoisocaproate, alone or in a nutritional mixture intended for parenteral nutrition, or a mixture intended for enteral nutrition or a mixture intended for oral nutrition, as combination products for simultaneous, separate or spreading use in the context of the treatment of pathologies related to an increase in carbonylation proteins, said pathologies being as defined above. Examples 1 and 2 which follow and Figure 1 illustrate the invention. Figure 1 shows the carbonylation of muscle proteins in the rat. The ordinate axis corresponds to the amount of carbonyl proteins in μmol / g. Column "1" corresponds to healthy rats; column "2" corresponds to undernourished rats; Column "3" corresponds to rats renounced with a standard diet and Column "4" corresponds to rats renaturated and having had a diet enriched with citrulline.
EXEMPLE 1 : Influence de la citrulϋne chez Ie rat dénutri-renourriEXAMPLE 1 Influence of Citrene in Undrained Rats
Matériels et Méthodes I - MatérielsMaterials and Methods I - Materials
Tous les réactifs chimiques utilisés proviennent de chez Sigma (Saint-Quentin- Fallavier, France). La L-citrulline a été gracieusement fourme par les Laboratoires Biocodex (Compiègne, France).All the chemical reagents used come from Sigma (Saint-Quentin-Fallavier, France). L-citrulline was donated by Laboratoires Biocodex (Compiègne, France).
H - Entretien des animauxH - Animal Care
Les rats mâles Sprague-Dawley (Charles River Laboratories, L'arbresles, France) âgés de 19 mois sont placés dans des cages individuelles, en ambiance thermostatée
(23° ± 1°C), et soumis à un cycle lumière-obscurité de 12h (obscurité de 8h à 2Oh). Le responsable du programme est autorisé (n° 75.522), par le Ministère de l'Agriculture et de la Forêt, à pratiquer ce type d'expériences. De plus l'utilisation ainsi que l'entretien des animaux de laboratoires sont respectueux de la législation (D2001-486) et sont en accord avec la législation européenne (Journal Officiel de la Communauté EuropéenneMale Sprague-Dawley rats (Charles River Laboratories, L'Arbre, France) aged 19 months are placed in individual cages, in a thermostated environment. (23 ° ± 1 ° C), and subjected to a light-dark cycle of 12h (darkness from 8h to 20h). The program manager is authorized (No. 75.522) by the Ministry of Agriculture and Forestry to perform such experiments. In addition, the use and maintenance of laboratory animals are compliant with the legislation (D2001-486) and are in accordance with European legislation (Official Journal of the European Community
L358 12/18/1986).L358 12/18/1986).
L'acclimatation des rats est effectuée pendant 2 semaines, au cours desquelles la consommation alimentaire spontanée est mesurée. Ils sont nourris avec un régime standard (A(M, UAR, Villemoisson-sur-Orge, France) contenant 17% de protéines, 3% de lipides, 59% de glucides et 21% d'eau, fibres, vitamines et minéraux. La prise alimentaire moyenne, durant cette période est de 34,4 g/ jour.Acclimation of rats is carried out for 2 weeks, during which spontaneous food consumption is measured. They are fed a standard diet (A (M, UAR, Villemoisson-sur-Orge, France) containing 17% protein, 3% lipids, 59% carbohydrates and 21% water, fiber, vitamins and minerals. The average food intake during this period is 34.4 g / day.
III - Protocole expérimentalIII - Experimental Protocol
Après la période d'acclimatation, les rats sont randomisés en 4 groupes : Un groupe contrôle formé de rats (n=10) nourri ad libitum (AL) pendant 12 semaines et 3 autres groupes soumis à une restriction alimentaire durant la même période : nourris avec seulement 50% des ingesta spontanés (soit 17,2 g), avec le régime standard (UARAfter the acclimation period, the rats are randomized into 4 groups: A control group consisting of rats (n = 10) fed ad libitum (AL) for 12 weeks and 3 other groups subjected to a food restriction during the same period: fed with only 50% of spontaneous ingesta (17.2 g), with the standard diet (UAR
A04). A la fin de la période de restriction, les animaux (n=10) d'un groupe sont sacrifiésA04). At the end of the restriction period, the animals (n = 10) of a group are sacrificed
(groupe R) et les rats des deux groupes restants sont renourris pendant une semaine avec 90% des ingesta spontanés (soit 30,9 g), soit avec un régime enrichi en acides aminés non essentiels (groupe AANE : alanine, asparagine, glycine, serine, histidine, et proline apportés de façon équimolaire) ou un régime enrichi en citrulline (5g/kg/j)(groupe citrulline). Les apports des deux groupes sont isoazotés et isocaloriques. La limitation à(group R) and the rats of the two remaining groups are renourished for one week with 90% of spontaneous ingesta (or 30.9 g), or with a diet enriched in non-essential amino acids (AANE group: alanine, asparagine, glycine, serine, histidine, and proline provided equimolarly) or a diet enriched with citrulline (5g / kg / day) (citrulline group). The contributions of the two groups are iso-nitrogenated and isocaloric. The limitation to
90 % des apports spontanés permet d'être certain que les rats consomment l'intégralité des aliments qui leur sont offerts.90% of spontaneous intake makes it possible to be sure that the rats consume all the food offered to them.
HI.l Evaluation du niveau de carbonylation des protéinesHI.l Evaluation of the carbonylation level of proteins
Les processus d'oxydation des protéines affectant la structure des acides aminés qui les composent sont complexes et donnent tous lieu à la formation de groupements carbonyles. C'est pourquoi il a été choisi d'évaluer de manière globale l'oxydation des protéines musculaires en quantifiant les dérivés carbonyles à partir d'un échantillon de 300 mg de tibialis anterior. La méthode utilisée est donc une technique non spécifique du type d'acide aminé qui repose sur le dosage spectrophotométrique du complexe formé par la fixation d'un composé appelé dinitrophényl-hydrazine (DNPH) sur les
groupements carbonyles. Les protéines musculaires sont isolées. Le culot protéique est repris dans 600 μl de tampon SET. Les protéines solubilisées sont séparées en deux fractions égales de façon à avoir deux cupules contenant la même quantité de protéines (1-1,5 mg/ml). Une des cupules sert de blanc et l'autre à quantifier les groupements carbonyles. 500 μl de DNPH 12,5 mM sont ajoutés à la cupule de mesure et 500 μl d'HCl 2M à la cupule du blanc. Après 15 min d'incubation à température ambiante, les échantillons sont précipités avec 500 μl de TCA 30% et centrifugés 10 min à 15000 tpm. Le culot est repris par 1 ml de TCA 10% et centrifugé à nouveau 10 min à 15000 tpm. 4 lavages successifs sont ensuite réalisés à Péthanoléthylacétate. Le culot final est chauffé pendant 30 min au bain-marie à 5O0C. Après une nouvelle centrifugation de 5 min à 15000 tpm, la lecture spectrophotométrique est effectuée sur 800 μl de surnageant à 280 nm (dosage des protéines) et à 380 nm (dosage du DNPH). La teneur en carbonyles est exprimée en nmol/mg de protéines.The processes of oxidation of proteins affecting the structure of the amino acids that compose them are complex and all give rise to the formation of carbonyl groups. This is why it was chosen to evaluate overall the oxidation of muscle proteins by quantifying the carbonyl derivatives from a 300 mg sample of tibialis anterior. The method used is therefore a non-specific technique of the amino acid type which is based on the spectrophotometric assay of the complex formed by the binding of a compound called dinitrophenyl hydrazine (DNPH) on the carbonyl groups. The muscle proteins are isolated. The protein pellet is taken up in 600 μl of SET buffer. The solubilized proteins are separated into two equal fractions so as to have two wells containing the same amount of protein (1-1.5 mg / ml). One of the cups serves as a blank and the other to quantify the carbonyl groups. 500 μl of 12.5 mM DNPH are added to the measuring cup and 500 μl of 2M HCl to the white cup. After incubation for 15 minutes at room temperature, the samples are precipitated with 500 μl of 30% TCA and centrifuged for 10 minutes at 15,000 rpm. The pellet is taken up in 1 ml of 10% TCA and centrifuged again for 10 min at 15,000 rpm. 4 successive washes are then carried out with ethanolethylacetate. The final pellet is heated for 30 min in a water bath at 50 ° C. After a new centrifugation of 5 min at 15000 rpm, the spectrophotometric reading is performed on 800 μl of supernatant at 280 nm (protein assay) and at 380 nm (DNPH assay). The carbonyl content is expressed in nmol / mg of protein.
III.2 RésultatsIII.2 Results
Les résultats obtenus sont représentés dans la Figure 1.The results obtained are shown in Figure 1.
Il apparaît clairement que la dénutrition induit une augmentation de la carbonylation des protéines par rapport aux rats sains (colonne 2 versus colonne 1). La renutrition augmente encore ce phénomène et le phénomène de dénutrtion-renutrition s'accompagne d'une forte augmentation de la carbonylation des protéines musculairesIt is clear that undernutrition induces an increase in protein carbonylation compared with healthy rats (column 2 versus column 1). Renutrition further increases this phenomenon and the phenomenon of malnutrition-renutrition is accompanied by a sharp increase in the carbonylation of muscle proteins
(colonne 3 versus colonne 2). En revanche, lorsque l'alimentation est enrichie en citrulline, ce phénomène est complètement aboli (colonne 4 versus colonne 3), la carbonylation des protéines étant similaire à celle observée chez les rats sains.(column 3 versus column 2). On the other hand, when the diet is enriched with citrulline, this phenomenon is completely abolished (column 4 versus column 3), the carbonylation of proteins being similar to that observed in healthy rats.
EXEMPLE 2 .Effet de Ia citrulline chez le rat âgéEXAMPLE 2 Effect of citrulline in the elderly rat
Matériels et MéthodesMaterials and methods
I - MatérielsI - Materials
Tous les réactifs chimiques utilisés proviennent de chez Sigma (Saint-Quentin- Fallavier, France). La L-citrulline a été gracieusement fournie par les Laboratoires Biocodex (Compiègne, France).All the chemical reagents used come from Sigma (Saint-Quentin-Fallavier, France). L-Citrulline was provided free of charge by Laboratoires Biocodex (Compiègne, France).
II - Entretien des animauxII - Animal care
Les rats mâles Sprague-Dawley (Charles River Laboratories, L'arbresles, France) âgés de 25 mois sont placés dans des cages individuelles, en ambiance thermostatée
(23° ± 1°C), et soumis à un cycle lumière-obscurité de 12h (obscurité de 8h à 2Oh). Le responsable du programme est autorisé (n° 75.522), par le Ministère de l'Agriculture et de la Forêt, à pratiquer ce type d'expériences. De plus l'utilisation ainsi que l'entretien des animaux de laboratoires sont respectueux de la législation (D2001-486) et sont en accord avec la législation européenne (Journal Officiel de la Communauté EuropéenneMale Sprague-Dawley rats (Charles River Laboratories, The trees, France) aged 25 months are placed in individual cages, in a thermostated environment (23 ° ± 1 ° C), and subjected to a light-dark cycle of 12h (darkness from 8h to 20h). The program manager is authorized (No. 75.522) by the Ministry of Agriculture and Forestry to perform such experiments. In addition, the use and maintenance of laboratory animals are compliant with the legislation (D2001-486) and are in accordance with European legislation (Official Journal of the European Community
L358 12/18/1986).L358 12/18/1986).
L'acclimatation des rats est effectuée pendant 2 semaines, au cours desquelles la consommation alimentaire spontanée est mesurée. Ils sont nourris avec un régime standard (A(M, UAR, Villemoisson-sur-Orge, France) contenant 17% de protéines, 3% de lipides, 59% de glucides et 21% d'eau, fibres, vitamines et minéraux. La prise alimentaire moyenne, durant cette période est de 34,4 g/ jour.Acclimation of rats is carried out for 2 weeks, during which spontaneous food consumption is measured. They are fed a standard diet (A (M, UAR, Villemoisson-sur-Orge, France) containing 17% protein, 3% lipids, 59% carbohydrates and 21% water, fiber, vitamins and minerals. The average food intake during this period is 34.4 g / day.
HI - Protocole expérimentalHI - Experimental Protocol
Après la période d'acclimatation, les rats sont randomisés en 2 groupes :After the acclimation period, the rats are randomized into 2 groups:
Groupe CIT (n=5) : les animaux reçoivent une alimentation standard enrichie en CIT (lg/kg/j) pendant 1 moisCIT group (n = 5): the animals receive a standard diet enriched in CIT (lg / kg / d) for 1 month
Groupe AANE (n-4) : les animaux reçoivent une alimentation standard rendue isoazotée au groupe CIT par l'ajout d'acides aminés non essentiels (alanine, asparagine, glycine, serine, histidine, et proline apportés de façon équimolaire) pendant 1 mois.AANE group (n-4): the animals receive a standard diet rendered iso-nitrogenated to the CIT group by the addition of non-essential amino acids (alanine, asparagine, glycine, serine, histidine, and proline brought equimolarly) for 1 month .
Au terme de l'étude, les animaux ont été euthanasiés et le cerveau a été prélevé, pesé, congelé à l'azote liquide et conservé à -80°C jusqu'à la réalisation des analyses.At the end of the study, the animals were euthanized and the brain was removed, weighed, frozen with liquid nitrogen and stored at -80 ° C until the tests were performed.
Evaluation du niveau de carbonylation des protéinesEvaluation of the carbonylation level of proteins
Les processus d'oxydation des protéines affectant la structure des acides aminés qui les composent sont complexes et donnent tous lieu à la formation de groupements carbonyles. C'est pourquoi il a été choisi d'évaluer de manière globale l'oxydation des protéines musculaires en quantifiant les dérivés carbonyles à partir d'un échantillon deThe processes of oxidation of proteins affecting the structure of the amino acids that compose them are complex and all give rise to the formation of carbonyl groups. This is why it was decided to evaluate the oxidation of muscle proteins globally by quantifying the carbonyl derivatives from a sample of
Ig de cerveau. La méthode utilisée est donc une technique non spécifique du type d'acide aminé qui repose sur le dosage spectrophotométrique du complexe formé par la fixation de dinitrophényl-hydrazine (DNPH) sur les groupements carbonyles. Les protéines cérébrales sont isolées. Le culot protéique est repris dans 600 μl de tampon
SET. Les protéines solubilisées sont séparées en deux fractions égales de façon à avoir deux cupules contenant la même quantité de protéines (1-1,5 mg/ml). Une des cupules sert de blanc et l'autre à quantifier les groupements carbonyles. 500 μl de DNPH 12,5 mM sont ajoutés à la cupule de mesure et 500 μl d'HCl 2M à la cupule du blanc. Après 15 min d'incubation à température ambiante, les échantillons sont précipités avec 500 μl de TCA 30% et centrifugés 10 min à 15000 tpm. Le culot est repris par 1 ml de TCA 10% et centrifugé à nouveau 10 min à 15000 tpm. 4 lavages successifs sont ensuite réalisés à l'éthanoléthylacétate. Le culot final est chauffé pendant 30 min au bain-marie à 5O0C. Après une nouvelle centrifugation de 5 min à 15000 tpm, la lecture spectrophotométrique est effectuée sur 800 μl de surnageant à 280 nm (dosage des protéines) et à 380 nm (dosage du DNPH). La teneur en carbonyles est exprimée en μmol/g d'organe.Brain Ig. The method used is therefore a non-specific technique of the amino acid type which is based on the spectrophotometric assay of the complex formed by the binding of dinitrophenyl hydrazine (DNPH) to the carbonyl groups. Brain proteins are isolated. The protein pellet is taken up in 600 μl of buffer SET. The solubilized proteins are separated into two equal fractions so as to have two wells containing the same amount of protein (1-1.5 mg / ml). One of the cups serves as a blank and the other to quantify the carbonyl groups. 500 μl of 12.5 mM DNPH are added to the measuring cup and 500 μl of 2M HCl to the white cup. After incubation for 15 minutes at room temperature, the samples are precipitated with 500 μl of 30% TCA and centrifuged for 10 minutes at 15,000 rpm. The pellet is taken up in 1 ml of 10% TCA and centrifuged again for 10 min at 15,000 rpm. 4 successive washes are then carried out with ethanolethylacetate. The final pellet is heated for 30 min in a water bath at 50 ° C. After a new centrifugation of 5 min at 15000 rpm, the spectrophotometric reading is performed on 800 μl of supernatant at 280 nm (protein assay) and at 380 nm (DNPH assay). The carbonyl content is expressed in μmol / g of organ.
IV- RésultatsIV- Results
Protéines carbonylées (μmol/g)Carbonyl proteins (μmol / g)
AANE 180 ± 28 CIT 164 ± 12AANE 180 ± 28 CIT 164 ± 12
Moyenne ± ESMMean ± ESM
Les résultats obtenus sont représentés dans le tableau ci dessus. Il apparaît qu'une nutrition enrichie en CIT chez le rat âgé sain s'accompagne d'une diminution de la carbonylation des protéines cérébrales de l'ordre de 10%.
The results obtained are shown in the table above. It appears that nutrition enriched with CIT in the healthy elderly rat is accompanied by a decrease in the carbonylation of brain proteins of the order of 10%.
Claims
1. Utilisation de L-citrulline de formule (I) suivante1. Use of L-citrulline of the following formula (I)
ou d'un sel pharmaceutiquement, cosmétiquement ou nutraceutiquement acceptable de celle-ci, pour la préparation d'une composition destinée à inhiber l'augmentation de la carbonylation des protéines responsables observées dans certaines pathologies, donc notamment destinée au traitement des maladies neurodégénératives, telles que les maladies d'Alzheimer ou de Parkinson, au traitement de la rétinopathie, de la polyarthrite rhumatoïde, de l'athérosclérose, de la sclérose latérale amyotrophique, de l'ischémie cérébrale, au traitement des problèmes de cataracte ou des infections généralisées (sepsis), au traitement des pathologies liées au vieillissement cutané et plus particulièrement à la sénescence des tissus tels que œil, muscle et cerveau, au traitement des pathologies liées au dysfonctionnement des mitochondries, à savoir les myopathies issues des mitochondriopathies, au traitement de la cachexie liée à la dénutrition et à l'augmentation de la longévité des mammifères.or a pharmaceutically, cosmetically or nutraceutically acceptable salt thereof, for the preparation of a composition intended to inhibit the increase of the carbonylation of the responsible proteins observed in certain pathologies, and therefore especially intended for the treatment of neurodegenerative diseases, such as Alzheimer's or Parkinson's disease, treatment of retinopathy, rheumatoid arthritis, atherosclerosis, amyotrophic lateral sclerosis, cerebral ischemia, treatment of cataract problems or generalized infections (sepsis) ), the treatment of pathologies related to skin aging and more particularly to the senescence of tissues such as eye, muscle and brain, to the treatment of pathologies related to mitochondrial dysfunction, namely the myopathies resulting from mitochondriopathies, the treatment of linked cachexia to undernutrition and the increase of the long ity mammals.
2. Utilisation selon la revendication 1 caractérisée en ce que la composition est une composition pharmaceutique comprenant de la L-citrulline ou un de ses sels pharmaceutiquement acceptable, une composition pour le traitement cosmétique comprenant de la L-citrulline ou un de ses sels cosmétiquement acceptable, un complément alimentaire comprenant de la L-citrulline ou une composition pour le traitement nutraceutique comprenant de la L-citrulline ou un de ses sels nutraceutiquement acceptable.2. Use according to claim 1 characterized in that the composition is a pharmaceutical composition comprising L-citrulline or a pharmaceutically acceptable salt thereof, a composition for the cosmetic treatment comprising L-citrulline or a cosmetically acceptable salt thereof a dietary supplement comprising L-citrulline or a composition for the nutraceutical treatment comprising L-citrulline or a nutraceutically acceptable salt thereof.
3. Utilisation selon l'une quelconque des revendications 1 ou 2, caractérisée en ce que la L-citrulline est utilisée de manière à ce que la dose unitaire en L-citrulline soit d'environ 2 g à environ 20 g, notamment environ 10 g,- pour une posologie d'environ 0,1 g/kg/jour à environ 0,5 g/kg/jour, notamment environ 0,25 g/kg/jour à raison de une à trois doses quotidiennes, préférablement en une dose. 3. Use according to any one of claims 1 or 2, characterized in that the L-citrulline is used so that the unit dose of L-citrulline is from about 2 g to about 20 g, including about 10 g. g, for a dosage of about 0.1 g / kg / day to about 0.5 g / kg / day, in particular about 0.25 g / kg / day at one to three doses daily, preferably in one dose.
4. Utilisation selon l'une quelconque des revendications 1 à 3 caractérisée en ce que la composition se présente sous forme sèche, sous forme de solution aqueuse, sous forme hydroalcoolique ou huileuse, sous forme d'une émulsion huile-dans l'eau ou eau- dans-huile ou multiple, d'un gel aqueux ou huileux.4. Use according to any one of claims 1 to 3 characterized in that the composition is in dry form, in the form of an aqueous solution, in hydroalcoholic or oily form, in the form of an oil-in-water emulsion or water-in-oil or multiple, an aqueous or oily gel.
5. Utilisation selon l'une quelconque des revendications 1 à 4 caractérisée en ce que la composition pharmaceutique se présente sous une forme administrable par voie orale, topique, entérale ou parentérale, la composition cosmétique sous une forme administrable par voie topique, la composition nutraceutique et le complément alimentaire sous forme administrable par voie orale.5. Use according to any one of claims 1 to 4 characterized in that the pharmaceutical composition is in a form that can be administered orally, topically, enterally or parenterally, the cosmetic composition in a form that can be administered topically, the nutraceutical composition. and the dietary supplement in orally administrable form.
6. Utilisation selon la revendication 5 caractérisée en ce que dans le cas d'une forme administrable par voie entérale ou parentérale, celle-ci peut être mélangée à la nutrition entérale ou parentérale ou administrée en bolus dans la sonde de nutrition entérale ou en Y dans la nutrition parentérale.6. Use according to claim 5 characterized in that in the case of an enterally or parenterally administrable form, it can be mixed with enteral or parenteral nutrition or administered as a bolus in the enteral nutrition probe or in Y in parenteral nutrition.
7. Utilisation selon l'une quelconque des revendications 1 à 6 caractérisée en ce que la composition comprend en outre un ou plusieurs autres composés destinés au traitement de la cachexie liée à la dénutrition tels que la leucine, la glutamine, l'arginine, Pornithine et leurs différents sels utilisables tels que l'α-cétoglutarate ou l'α- cétoisocaproate.7. Use according to any one of claims 1 to 6 characterized in that the composition further comprises one or more other compounds for the treatment of cachexia related to malnutrition such as leucine, glutamine, arginine, Pornithine and their different usable salts such as α-ketoglutarate or α-ketoisocaproate.
8. Utilisation selon l'une quelconque des revendications 1 à 7 caractérisée en ce la L-citrulline est utilisée pour la préparation d'une composition pharmaceutique comprenant également un ou plusieurs autres composés destinés au traitement de la cachexie liée à la dénutrition tels que la leucine, la glutamine, l'arginine, l'ornithine et leurs différents sels utilisables tels que l'α-cétoglutarate ou l'α-cétoisocaproate, seuls ou au sein d'un mélange nutritionnel destiné à la nutrition parentérale, ou d'un mélange ' destiné à la nutrition entérale ou d'un mélange destiné à la nutrition orale.8. Use according to any one of claims 1 to 7 characterized in that L-citrulline is used for the preparation of a pharmaceutical composition also comprising one or more other compounds for the treatment of cachexia related to undernutrition such as the leucine, glutamine, arginine, ornithine and their various usable salts such as α-ketoglutarate or α-ketoisocaproate, alone or in a nutritional mixture intended for parenteral nutrition, or a mixture 'intended for enteral nutrition or a mixture intended for oral nutrition.
9. Composition comprenant :9. Composition comprising:
- de la L-citrulline ou un sel pharmaceutiquement acceptable nutraceutiquement de celle-ci, - et au moins un autre composé destiné au traitement de la cachexie liée à la dénutrition tels que la leucine, la glutamine, l'.arginine, Pornithine et leurs, différents sels utilisables tels que l'α-cétoglutarate ou l'α-cétoisocaproate, seuls ou au sein d'un mélange nutritionnel destiné à la nutrition parentérale, ou d'un mélange destiné à la nutrition entérale ou d'un mélange destiné à la nutrition orale, comme produits de combinaison pour une utilisation simultanée, séparée, ou étalée dans le temps, dans le cadre du traitement de pathologies liées à une augmentation de la carbonylation des protéines. - L-citrulline or a pharmaceutically acceptable salt of nutraceutical thereof, and at least one other compound intended for the treatment of malnutrition-related cachexia such as leucine, glutamine, arginine, Pornithine and their various usable salts such as α-ketoglutarate or α-ketoisocaproate , alone or in a nutritional mixture intended for parenteral nutrition, or a mixture intended for enteral nutrition or a mixture intended for oral nutrition, as combination products for simultaneous, separate or spread use in the course of time, in the context of the treatment of pathologies related to an increase in the carbonylation of proteins.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0702090A FR2913885B1 (en) | 2007-03-22 | 2007-03-22 | USE OF CITRULLINE FOR THE TREATMENT OF PATHOLOGIES ASSOCIATED WITH INCREASED CARBONYLATION OF PROTEINS |
| PCT/FR2008/000379 WO2008135661A2 (en) | 2007-03-22 | 2008-03-20 | Use of citrulline for the treatment of conditions linked to an increase in protein carbonylation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2136777A2 true EP2136777A2 (en) | 2009-12-30 |
Family
ID=38561836
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP08787826A Ceased EP2136777A2 (en) | 2007-03-22 | 2008-03-20 | Use of citrulline for the treatment of conditions linked to an increase in protein carbonylation |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US20100093863A1 (en) |
| EP (1) | EP2136777A2 (en) |
| JP (1) | JP2010522146A (en) |
| CN (1) | CN101686919A (en) |
| CA (1) | CA2689608A1 (en) |
| FR (1) | FR2913885B1 (en) |
| IL (1) | IL200830A0 (en) |
| WO (1) | WO2008135661A2 (en) |
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|---|---|---|---|---|
| CN102600260A (en) * | 2010-12-24 | 2012-07-25 | 漆又毛 | Medicinal use of composition of amino acids and extracts for preventing and treating senile dementia |
| MX359453B (en) * | 2011-03-18 | 2018-09-28 | Nestec Sa | Compositions and methods useful for ameliorating age related maladies. |
| US20140037604A1 (en) * | 2011-04-18 | 2014-02-06 | Nestec S.A. | Nutritional compositions comprising alpha-hydroxyisocaproic acid |
| US20140235735A1 (en) * | 2013-02-15 | 2014-08-21 | Mediterranean Institute For Life Sciences | Protein Damage in Aging and Age-Related Diseases |
| CN106137782A (en) * | 2015-04-22 | 2016-11-23 | 捷通国际有限公司 | The topical composition that comprises sinomenine and for the method suppressing protein carbonyl |
| JP7220838B2 (en) * | 2015-09-29 | 2023-02-13 | 学校法人北里研究所 | oral composition |
| CN105147684B (en) * | 2015-09-30 | 2017-12-12 | 暨南大学 | Application of the pipering in the anti-medicine that cures the septicaemia is prepared |
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| US5385938B1 (en) * | 1986-12-23 | 1997-07-15 | Tristrata Inc | Method of using glycolic acid for treating wrinkles |
| FR2691359B1 (en) * | 1992-05-20 | 1995-06-23 | Krempf Michel | NEW THERAPEUTIC APPLICATION OF 1-CITRULLINE MALATE. |
| DE4341000A1 (en) * | 1993-12-02 | 1995-06-08 | Beiersdorf Ag | Use of L-arginine, L-ornithine or L-citrulline and topical preparations with these substances |
| FR2766712B1 (en) * | 1997-08-01 | 1999-10-22 | Aguettant Lab | PREFERABLY COMPOSITION ANTIOXIDANT SOLUTION AND MEDICAMENTS USING THE SAME |
| US20010056068A1 (en) * | 1998-03-04 | 2001-12-27 | Kristof Chwalisz | Method of treatment and prevention of nitric oxide deficiency-related disorders with citrulline and citrulline derivatives |
| US9486429B2 (en) * | 1999-06-01 | 2016-11-08 | Vanderbilt University | Therapeutic methods employing nitric oxide precursors |
| DE19929993C2 (en) * | 1999-06-30 | 2001-07-05 | Sueddeutsche Kalkstickstoff | Creatine alpha ketoglutarate, process for its preparation and its use |
| NL1014380C2 (en) * | 2000-02-14 | 2001-08-15 | Friesland Brands Bv | Intestinal wall-strengthening food. |
| JP3843298B2 (en) * | 2001-02-05 | 2006-11-08 | 国立大学法人 奈良先端科学技術大学院大学 | Active oxygen scavenger containing citrulline |
| US20040087490A1 (en) * | 2002-09-20 | 2004-05-06 | Troup John P. | Nutritional compositions |
| US20060063827A1 (en) * | 2004-09-23 | 2006-03-23 | Yu Ruey J | Systemic administration of therapeutic amino acids and N-acetylamino acids |
| FR2853210B1 (en) * | 2003-04-02 | 2006-12-15 | Neolait Sas | ACTIVATOR COMPOSITION OF DIGESTION |
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| JP3878612B2 (en) * | 2004-03-01 | 2007-02-07 | ピアス株式会社 | Composition for suppressing active oxygen, and external preparation for skin and cosmetic containing the composition |
| FR2869539B1 (en) * | 2004-04-29 | 2008-08-08 | Univ Paris Descartes | PHARMACEUTICAL COMPOSITIONS FOR THE PREVENTION AND TREATMENT OF ATHEROSCLEROSIS |
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-
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- 2008-03-20 US US12/532,299 patent/US20100093863A1/en not_active Abandoned
- 2008-03-20 EP EP08787826A patent/EP2136777A2/en not_active Ceased
- 2008-03-20 JP JP2009554063A patent/JP2010522146A/en active Pending
- 2008-03-20 WO PCT/FR2008/000379 patent/WO2008135661A2/en active Application Filing
- 2008-03-20 CN CN200880009440A patent/CN101686919A/en active Pending
- 2008-03-20 CA CA002689608A patent/CA2689608A1/en not_active Abandoned
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2008135661A3 (en) | 2009-01-15 |
| WO2008135661A2 (en) | 2008-11-13 |
| JP2010522146A (en) | 2010-07-01 |
| CN101686919A (en) | 2010-03-31 |
| CA2689608A1 (en) | 2008-11-13 |
| IL200830A0 (en) | 2010-05-17 |
| FR2913885A1 (en) | 2008-09-26 |
| US20100093863A1 (en) | 2010-04-15 |
| FR2913885B1 (en) | 2012-07-20 |
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