WO2024024395A1 - Composition pharmaceutique ou sous forme d'aliment et de boisson pour la prévention ou le traitement d'un trouble du nerf optique - Google Patents

Composition pharmaceutique ou sous forme d'aliment et de boisson pour la prévention ou le traitement d'un trouble du nerf optique Download PDF

Info

Publication number
WO2024024395A1
WO2024024395A1 PCT/JP2023/024440 JP2023024440W WO2024024395A1 WO 2024024395 A1 WO2024024395 A1 WO 2024024395A1 JP 2023024440 W JP2023024440 W JP 2023024440W WO 2024024395 A1 WO2024024395 A1 WO 2024024395A1
Authority
WO
WIPO (PCT)
Prior art keywords
diosgenin
optic nerve
pharmaceutical
food
treatment
Prior art date
Application number
PCT/JP2023/024440
Other languages
English (en)
Japanese (ja)
Inventor
千尋 東田
省吾 渋江
Original Assignee
国立大学法人富山大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 国立大学法人富山大学 filed Critical 国立大学法人富山大学
Publication of WO2024024395A1 publication Critical patent/WO2024024395A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present invention relates to a pharmaceutical or food/beverage composition for the prevention or treatment of optic nerve disorders such as glaucoma.
  • Glaucoma has been described as ⁇ a disease characterized by functional and structural abnormalities of the eye that have characteristic changes in the optic nerve and visual field, and which can usually improve or suppress optic nerve damage by sufficiently lowering intraocular pressure.'' has been defined (see Non-Patent Document 1).
  • Lowering the intraocular pressure is the standard treatment for patients with normal-tension glaucoma, but lowering the intraocular pressure is a way to protect the optic nerve and suppress the progression of visual field damage, and it is possible to restore lost visual field. cannot be expected. Therefore, glaucoma treatment strategies other than lowering intraocular pressure are desired.
  • optic nerve damage such as glaucoma.
  • problems such as visual field defects occur due to optic nerve damage such as death of retinal ganglion cells for some reason or atrophy of the optic nerve, which is the axon of the retinal ganglion cells. If the optic nerve re-projects correctly to its projection sites, such as the lateral geniculate body and superior colliculus, and the pathway that transmits signals to the visual cortex is repaired, it is thought that visual field defects can be restored, and this is possible. Methods and drugs have not yet been established.
  • an object of the present invention is to provide a pharmaceutical or food/beverage composition for the prevention or treatment of optic nerve disorders such as glaucoma.
  • the present invention provides a pharmaceutical or food/beverage composition for the prevention or treatment of optic nerve disorders, which contains diosgenin or a diosgenin derivative as an active ingredient.
  • Such pharmaceutical or food/beverage compositions can contribute to an increase in retinal ganglion cells and/or elongation of optic nerves, and therefore are effective in preventing or treating optic nerve disorders, regardless of whether or not they reduce intraocular pressure.
  • the pharmaceutical or food/beverage composition of the present invention preferably contains a plant extract containing diosgenin or a diosgenin derivative. Plant extracts containing diosgenin or diosgenin derivatives are desirable because they are inexpensive and easily available.
  • the above-mentioned plant extract is preferably a plant extract with an increased content of diosgenin through at least one treatment selected from acid hydrolysis treatment, fermentation treatment, and enzyme treatment. This makes it easier to improve the medicinal efficacy of the medicine or food/beverage composition.
  • the pharmaceutical or food/beverage composition of the present invention can prevent or treat optic neuropathy, for example, by suppressing the death of retinal ganglion cells.
  • the pharmaceutical or food/beverage composition of the present invention is particularly effective when the optic nerve disorder is glaucoma. Furthermore, the pharmaceutical or food/beverage composition of the present invention is particularly effective in preventing or treating normal-tension glaucoma, since it can be prevented or treated regardless of whether or not there is a decrease in intraocular pressure.
  • a pharmaceutical or food/beverage composition for the prevention or treatment of optic nerve disorders such as glaucoma.
  • FIG. 2 is a micrograph of a region fluorescently immunostained with pNF-H (phosphorylated NF-H) and a region fluorescently immunostained with MAP2 in Example 1.
  • FIG. 3 is a diagram showing the measurement results of axon length ( ⁇ m) per retinal ganglion cell in Example 1.
  • FIG. 3 is a diagram showing the measurement results of dendrite length per retinal ganglion cell in Example 1.
  • 3 is a diagram showing the results of intraocular pressure measurement in Example 2.
  • FIG. FIG. 2 is a diagram showing representative photographs proximal to the injury site and quantitative values of the CTB-488 positive area in Example 2.
  • FIG. 2 is a diagram showing representative photographs distal to the injury site and quantitative values of the CTB-488 positive area in Example 2.
  • FIG. 2 is a diagram showing the results of LC-MS analysis of a standard substance (diosgenin).
  • FIG. 7 is a diagram showing the analysis results for the retina in Example 3.
  • FIG. 7 is a diagram showing the analysis results for the optic nerve in Example 3.
  • FIG. 7 is a diagram showing the analysis results for the brain in Example 3.
  • FIG. 7 is a diagram showing the results of intraocular pressure measurement in Example 4. This is a representative micrograph in Example 4 when a solvent, 0.1.1 ⁇ mol/kg diosgenin olive oil solution, was administered.
  • FIG. 4 is a diagram showing retinal ganglion cell densities when the optic nerve was not crushed and when the optic nerve was crushed in Example 4.
  • FIG. 4 is a diagram showing the retinal ganglion cell density after oral administration of a solvent, 0.1, 1, and 10 ⁇ mol/kg diosgenin olive oil solution in Example 4.
  • FIG. 4 is a representative micrograph of a case where a diosgenin olive oil solution was orally administered in Example 4.
  • FIG. 7 is a diagram showing the CTB area in the lateral geniculate body in Example 4 when the optic nerve was not crushed and when the optic nerve was crushed.
  • FIG. 4 is a diagram showing the overlapping area of the CTB area and the Fluoro-Gold positive area in the lateral geniculate body when the optic nerve was not crushed and when the optic nerve was crushed in Example 4.
  • FIG. 4 is a diagram showing the CTB area in Example 4 when a solvent was administered and when a diosgenin olive oil solution was administered.
  • FIG. 4 is a diagram showing the overlap area between the CTB area and the Fluoro-Gold positive area in the case of administering a solvent and the case of administering a diosgenin olive oil solution in Example 4.
  • the pharmaceutical or food/beverage composition of this embodiment contains diosgenin or a diosgenin derivative as an active ingredient.
  • Diosgenin is a compound represented by the following chemical formula (I).
  • Diosgenin derivative refers to a compound that can be an equivalent of diosgenin.
  • Diosgenin and diosgenin derivatives are not particularly limited, and may be commercially available products, those manufactured according to known methods, methods known per se, or methods analogous thereto, and extracts from natural products. Good too.
  • diosgenin derivatives may be equivalents that can be achieved by chemical modification such as introducing or converting substituents into diosgenin, or may be diosgenin glycosides (such as dioscine) extracted from natural products. It's okay.
  • diosgenin derivatives include, for example, replacing the hydroxyl group in diosgenin with an alkoxy group, ester group (e.g. acetate ester), amino acid ester group (e.g. glycine ester), aminosulfonic acid ester group, carbamate group, halogen atom (e.g. fluorine atom). ).
  • the pharmaceutical or food/beverage composition of the present embodiment preferably contains a plant extract containing diosgenin or a diosgenin derivative.
  • Plant extracts include, for example, Dioscorea rhizome, Trigonella spp., Polygonatum spp., and Smilax, which are known to contain diosgenin (or its glycosides). Extracts of plants such as herbal medicines such as spp.) can be used. Extraction can be performed by a conventional method using an extraction solvent such as water, ethanol, 1,3-butylene glycol, or the like.
  • the plant extract is preferably a plant extract with increased diosgenin content through further processing.
  • the treatment include acid hydrolysis treatment, fermentation treatment, enzyme treatment, and the like. These treatments may be used alone or in combination of two or more. Conventionally known treatment methods can be applied to these treatments, but for example, as acid hydrolysis treatment, the method described in T Herrera et al., J Sci Food Agric 2019; 99: 3157-3167, For fermentation treatment, the methods described in Y. Chen et al., Steroids 136 (2016) 40-46 and J. Dong et al., Indian J Microbiol (Apr-June 2015) 55(2):200-206 are used.
  • the enzyme treatment the methods described in W. Huang et al., Bioresource Technology 99 (2008) 7407-7411 can be applied.
  • the form of the medicament of this embodiment is not particularly limited, and diosgenin or a diosgenin derivative may be used as it is (for example, a powder), or may be formulated with other ingredients.
  • components include components that are generally used as raw materials for pharmaceutical preparations, and are not particularly limited. Specific examples include carriers, excipients, binders, disintegrants, lubricants, coating agents, colorants, flavoring agents, stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, Examples include preservatives and antioxidants. These may be used alone or in combination of two or more.
  • the pharmaceutical or food/beverage composition of this embodiment may be administered orally or parenterally.
  • Parenteral administration forms include topical ocular administration (intravitreal administration, eye drops, intraconjunctival sac administration, subconjunctival administration, sub-Tenon's administration, etc.), intravenous administration, transdermal administration, and the like.
  • dosage forms for oral administration include solutions, suspensions, capsules, soft capsules, tablets, granules, powders, syrups, jellies, orally disintegrating tablets, and chewable tablets.
  • diosgenin or diosgenin derivative is preferably suspended or dissolved in an oil or fat.
  • oils and fats examples include soybean oil, rapeseed oil (rapeseed oil, canola oil), high oleic acid rapeseed oil, corn oil, sesame oil, sesame salad oil, Taihaku sesame oil, perilla oil, linseed oil (linseed oil), peanut oil, safflower oil ( safflower oil), high oleic safflower oil, sunflower oil, high oleic sunflower oil, cottonseed oil, grape seed oil, macadamia nut oil, hazelnut oil, peanut oil, almond oil, nut oil, walnut oil, pumpkin seed oil, walnut oil , lemon oil, camellia oil, tea seed oil, perilla oil, borage oil, olive oil (olive oil), rice oil, rice bran oil, wheat germ oil, palm oil, palm olein, palm stearin, palm kernel oil, coconut oil, cocoa butter Vegetable oils such as beef tallow, pork fat (lard), chicken fat, milk fat, animal oils such as
  • sardine oil mackerel oil, cod oil, whale oil, liver oil, etc.
  • fatty acids docosahexaenoic acid (DHA), eicosapentaene, etc.
  • examples include edible oils such as acid (EPA), fat-soluble vitamins (vitamin A, vitamin E, etc.); synthetic oils such as medium-chain fatty acid triglycerides, and iodized poppy seed fatty acid esters. These may be used alone or in combination of two or more.
  • dosage forms for parenteral administration include injections, eye drops, eye ointments, patches, gels, and inserts.
  • the food and drink composition of this embodiment can be provided in the form of drinks, foods, supplements, and the like.
  • beverages include water, soft drinks, fruit juice drinks, carbonated drinks, milk drinks, alcoholic drinks, sports drinks, nutritional drinks, and the like.
  • foods include breads, noodles, rice, tofu, dairy products, soy sauce, miso, and sweets.
  • Food and drink compositions include, for example, health foods, foods with health claims, foods with functional claims, foods for special uses, nutritional supplements, and foods for specified health uses.
  • the content of diosgenin or a diosgenin derivative as an active ingredient in the pharmaceutical or food/beverage composition of the present embodiment is not particularly limited, but is a sufficient amount to treat, improve, alleviate, or recover the symptoms associated with the disease. It is preferable to do so.
  • the dosage of the pharmaceutical or food/beverage composition of the present embodiment is appropriately selected depending on, for example, the severity of symptoms of the subject to be administered, age, sex, body weight, dosage form, type of salt, specific type of disease, etc.
  • the molar amount of diosgenin or diosgenin derivative per unit body weight of the subject to be administered may be, for example, usually about 0.001 to about 1000 ⁇ mol/kg/day, Preferably about 0.01 to about 10 ⁇ mol/kg/day, more preferably 0.01 to about 1 ⁇ mol/kg/day.
  • the subject to whom the medicine or food/beverage composition of the present embodiment is administered is not particularly limited, but is preferably a mammal including a human.
  • Mammals including humans include, but are not particularly limited to, humans, monkeys, baboon, chimpanzees, mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, sheep, goats, pigs, cows, horses, etc. .
  • the pharmaceutical or food/beverage composition of this embodiment is effective for preventing or treating optic nerve disorders.
  • Optic nerve disorders include optic nerve diseases such as glaucoma, optic neuropathy, and optic neuritis, and the pharmaceutical or food/beverage composition of the present embodiment may be particularly effective in preventing or treating glaucoma, particularly normal-tension glaucoma. .
  • Diosgenin (Tokyo Kasei) was dissolved in 99.5% ethanol (Fujifilm, Wako Pharmaceutical) to prepare a high concentration solution of diosgenin, and diluted with physiological saline to prepare a diosgenin ethanol solution.
  • diosgenin olive oil solution was prepared by dissolving 9.6 mg of diosgenin (Tokyo Kasei) in 790 ⁇ l of Japanese Pharmacopoeia olive oil (Maruishi Pharmaceutical).
  • mice All mice were housed in plastic cages (23 x 16 x 12 cm) in an environment with a 12-hour light/dark cycle (light period: 7:00 am to 7:00 pm) and constant temperature and humidity (22°C ⁇ 2°C, 55 ⁇ 10%). bred. Water and chow were available ad libitum.
  • mice Male 6-week-old ddY mice (Japan SLC) were used in the experiment. The animal was anesthetized by intraperitoneally administering a triple-mixed anesthesia. While pulling out the eyeball, the optic nerve in the immediate vicinity of the eyeball was compressed for one second with forceps. Optic nerve compression was performed in both eyes. Antisedan was administered intraperitoneally, and the mice were left on a hot plate at 37°C to wake up while preventing a drop in body temperature.
  • ⁇ Intraocular pressure measurement method> Immediately before exsanguination and perfusion of the mouse, intraocular pressure was measured under anesthesia. Using a Tonolab hand-held tonometer (M-E Technica for mice and rats), the average value of the values obtained by measuring 5 times per eye was used.
  • Frozen brains were wrapped in aluminum foil and stored at -30°C.
  • the washed eyeballs were placed in a PBS solution and a small hole was made in the eyeballs using a 21G injection needle under a stereomicroscope (SZ61, Olympus), and one blade of scissors was inserted through the hole to cut off the cornea. After carefully removing the lens and gel-like vitreous body, only the retina was isolated. Thereafter, the optic nerve was cut from the eyeball with microscissors, and the retina and optic nerve were each replaced with a 30% sucrose solution.
  • the secondary antibody solution [0.5% TritonX-100-PBS solution, Alexa Fluor647-labeled goat anti-rabbit IgG antibody] (1:600, Thermo Fisher Scientific)] was added at 100 ⁇ l/well, and the reaction was allowed to occur overnight at 4°C with shaking in the dark. After the reaction, the secondary antibody solution was removed and washed with PBS. Four incisions were made in the cup-shaped retina and the plate was transferred onto a slide glass. After being flat mounted, Aqua poly Mount (Polysciences, Warrington , PA, USA).
  • ⁇ Preparation of optic nerve section> The sucrose-substituted optic nerve was implanted into Tissue Tek OCT (Sakura Finetech Japan) using Cryomold No. 3 (Sakura Finetech Japan) as a mold. Sagittal sections with a thickness of 12 ⁇ m were successively prepared using a cryostat (CM3050SL, Leica). At that time, the temperature inside the chamber and on the stage was set to -22°C. The sections were attached to coated glass slides (Matsunami Glass Industries) and stored at -30°C.
  • CM3050SL a cryostat
  • Leica the brain was serially sectioned into 12- ⁇ m-thick coronal sections in a region ranging from Bregma -1.70 mm to -2.92 mm.
  • the temperature inside the warehouse and on the stage was set to -20°C.
  • the sections were attached to coated glass slides (Matsunami Glass Industries) and stored at -30C.
  • a fluorescent inverted microscope KEYENCE BZ-X800 (Keyence) and an objective lens (PlanApo10x, Nikon) were used to photograph the left and right lateral geniculate bodies.
  • Example 1 We investigated the effect of diosgenin on axonal elongation in cultured retinal ganglion cells. Details are shown below.
  • ⁇ Retinal ganglion cell primary culture> The eyeballs of 4-day-old ddY mice (Japan SLC) were removed under isoflurane anesthesia. The eyeballs were placed in Neurobasal-A medium (Life Technologies) containing B-27 [2mM L-glutamine, 1X B-27 added], and the retinas were isolated under a stereomicroscope. Thereafter, the supernatant was removed by centrifugation at 700 rpm for 3 minutes, and 2 ml of 0.05 trypsin-0.53 mM EDTA solution (Life Technologies) was added to the pellet to suspend it. It was left standing at 37°C for 7 minutes, and tapped once after 5 minutes.
  • the number of living cells was counted while separating them from dead cells by Trypanblue staining, and the cells were seeded in an 8-well chamber slide at a density of 1.0 ⁇ 10 5 cells/well/300 ⁇ l. All culture dishes were incubated with 5 ⁇ g/ml poly-D-lysin-PBS solution at 37°C for 16 hours, washed twice with PBS, and further incubated with 20 ⁇ g/ml laminin-PBS solution at 37°C for 16 hours. , and those washed twice with PBS were used. After seeding, culture was performed under 10% CO 2 at 37° C. and saturated steam, and the entire amount of the medium was replaced 24 hours after seeding. After medium exchange, culture was performed under 5% CO 2 at 37°C and saturated steam.
  • ⁇ Drug treatment on retinal ganglion cells The above-mentioned 0.1 ⁇ M and 1 ⁇ M diosgenin ethanol solutions were each dissolved in Neurobasal-A medium containing B-27 (ethanol final concentration: 9.95 ⁇ 10 ⁇ 2 %) to prepare a culture medium of each concentration. After replacing the entire volume with the medium 4 days after the start of retinal ganglion cell culture, the culture was continued for an additional 4 days.
  • Triton100-PBS solution 1% normal goat serum (Fujifilm Wako Pure Chemical Industries), rabbit anti-MAP2 antibody (1:1000, Abcam), mouse anti-phosphorylated neurofilament-H (pNF-H) monoclonal antibody ( 1:200, Convance)
  • Triton100-PBS solution 1% normal goat serum (Fujifilm Wako Pure Chemical Industries), rabbit anti-MAP2 antibody (1:1000, Abcam), mouse anti-phosphorylated neurofilament-H (pNF-H) monoclonal antibody ( 1:200, Convance)
  • pNF-H mouse anti-phosphorylated neurofilament-H
  • FIG. 1A shows micrographs of the areas fluorescently immunostained by pNF-H (corresponding to axons) and the areas fluorescently immunostained by MAP2 (corresponding to dendrites).
  • FIG. 1B shows the measurement results of the dendrite length ( ⁇ m) per retinal ganglion cell
  • FIG. 1C shows the measurement results of the dendrite length ( ⁇ m) per retinal ganglion cell.
  • Example 2 We used an optical nerve crush (ONC) model as a glaucoma mouse model to reliably evaluate optic nerve crush and reprojection, and investigated the effects of intravitreal administration of diosgenin on the optic nerve. Details are shown below.
  • OOC optical nerve crush
  • ⁇ Intravitreal drug administration> The above-mentioned 0.1 ⁇ M and 1 ⁇ M diosgenin solutions (2.5% ethanol, 97.5% physiological saline) were each administered into the vitreous body of a normal-tension glaucoma model mouse under anesthesia by intraperitoneally administering a triple-mixed anesthesia. Diosgenin concentration was expressed as the final intravitreal concentration. Under a stereomicroscope (SZ61, Olympus), the eyeball of the mouse was picked out with tweezers, and a sterilized glass syringe (Narishige, Tokyo) with an outer diameter of 0.15 mm at the tip was inserted from the ciliary body toward the vitreous body. .
  • SZ61 stereomicroscope
  • the glass syringe was connected to a 10 ⁇ l Hamilton syringe (Hamilton Company) via 0.5 mm tubing (MS Equipment) and a 21G injection needle (Terumo), and set in a syringe pump (KD Scientific). After inserting a glass syringe into the vitreous, diosgenin ethanol solution was injected at 1.0 ⁇ l/eye/min. After intravitreal injection, the same amount of antisedan as the anesthetic was administered intraperitoneally, and the mouse was left on a hot plate at 37°C to waken up while preventing a drop in body temperature. In the same manner, intravitreal administration was performed three times in total, every 5 days after the first administration.
  • ⁇ Optic nerve labeling using an antegrade tracer> Anterograde tracer injection was performed 6 days before retinal, optic nerve, and brain extraction under anesthesia using triple anesthesia administered intraperitoneally. Under a stereomicroscope (SZ61, Olympus), the mouse eyeball was picked out with tweezers, and a sterilized glass syringe (Narishige) with an outer diameter of 0.15 mm at the tip was inserted from the ciliary body toward the vitreous body.
  • the glass syringe was connected to a 10 ⁇ l Hamilton syringe (Hamilton Company) via 0.5 mm tubing (MS Equipment) and a 21G injection needle (Terumo), and set in a syringe pump (KD Scientific). After inserting a glass syringe into the vitreous body, 1.0 mg/ml Alexa Fluor 488-conjugated cholera toxin subunit B (CTB) (Molecular probes) was administered into the vitreous body of the mouse at 1.0 ⁇ l/eye/min.
  • CTB Alexa Fluor 488-conjugated cholera toxin subunit B
  • Example 3 In Example 2, intravitreal administration of diosgenin showed a tendency for optic nerve density to increase. If diosgenin acts not only on the retina but also on the optic nerve, which is the axon of retinal ganglion cells, and the lateral geniculate body neurons, which are the destinations of its projection, the neural circuits that form visual function will be strengthened as a whole. It is thought that Therefore, we investigated the migration of diosgenin into the retina, optic nerve, and brain after oral administration. Details are shown below.
  • mice Male 6-week-old ddY mice (Japan SLC) were used in the experiment. The mice were fasted 16 hours before administration, and the above-mentioned diosgenin olive oil solution was orally administered to the mice. After 1, 6, and 12 hours, plasma, retina, optic nerve, and whole brain were removed. A 10-fold volume of methanol (Fujifilm Wako Pharmaceutical) was added to the excised tissue, homogenized for 15 seconds, vortexed for 1 minute, sonicated for 5 minutes, and centrifuged at 4°C at 12,000 g for 10 minutes.
  • methanol Flujifilm Wako Pharmaceutical
  • the supernatant was transferred to a 5 ml tube and evaporated to dryness on a hot plate at 50°C. 100 ⁇ l of 100% methanol was added thereto to dissolve, and the mixture was centrifuged at 13,000 x 5 minutes at 4°C. The supernatant was passed through a 0.45 ⁇ m filter (Merck Millipore) to obtain a sample for LC-MS/MS.
  • Example 4 The effect of oral administration of diosgenin on optic nerve elongation was investigated. Details are shown below.
  • Retrograde tracer injection was performed under anesthesia by intraperitoneal administration of triple anesthesia 7 days before retinal, optic nerve, and brain extraction. The top of the head was shaved, and the scalp was incised to expose the skull. Using an electric microdrill, a hole was made at the position of Lat: 2.5 mm, Bregma: -38 mm, depth: 1.2 mm, and Fluoro-Gold (Fujifilm Wako Pharmaceutical) was injected into the left and right primary visual cortex at 1.0 ⁇ l/min. . After the surgery, antisedan was administered intraperitoneally in the same amount as the anesthetic, and the mice were left on a hot plate at 37°C to wake them up while preventing a drop in body temperature.
  • CTB Alexa Fluor 488-conjugated cholera toxin subunit B
  • FIG. 7A shows the CTB area in the lateral geniculate body when the optic nerve was not crushed and when the optic nerve was crushed
  • Fig. 7C shows the overlap area between the CTB area and the Fluoro-Gold positive area
  • 7D shows the CTB area when a diosgenin olive oil solution of 1,10 ⁇ mol/kg was administered
  • FIG. 7E shows the overlap area between the CTB area and the Fluoro-Gold positive area.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Ophthalmology & Optometry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Food Science & Technology (AREA)
  • Nutrition Science (AREA)
  • Mycology (AREA)
  • Botany (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

L'invention concerne une composition pharmaceutique ou sous forme d'aliment et de boisson qui est destinée à la prévention ou au traitement d'un trouble du nerf optique et qui comprend de la diosgénine ou un dérivé de diosgénine en tant que principe actif correspondant.
PCT/JP2023/024440 2022-07-29 2023-06-30 Composition pharmaceutique ou sous forme d'aliment et de boisson pour la prévention ou le traitement d'un trouble du nerf optique WO2024024395A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2022-121223 2022-07-29
JP2022121223 2022-07-29

Publications (1)

Publication Number Publication Date
WO2024024395A1 true WO2024024395A1 (fr) 2024-02-01

Family

ID=89706097

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2023/024440 WO2024024395A1 (fr) 2022-07-29 2023-06-30 Composition pharmaceutique ou sous forme d'aliment et de boisson pour la prévention ou le traitement d'un trouble du nerf optique

Country Status (1)

Country Link
WO (1) WO2024024395A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008516972A (ja) * 2004-10-14 2008-05-22 ジョージタウン ユニバーシティー 神経保護作用を有するスピロステノールの薬学的組成物
JP2010500287A (ja) * 2006-08-03 2010-01-07 オンコロジー リサーチ インターナショナル リミテッド 血管新生を抑制するための方法及び組成物
WO2014112145A1 (fr) * 2013-01-21 2014-07-24 レジリオ株式会社 Agent thérapeutique et procédé thérapeutique concernant 1,25d3-marrs pour une maladie neurologique telle que la maladie d'alzheimer
CN104324038A (zh) * 2013-07-24 2015-02-04 四川京华创生物科技有限公司 一种薯蓣皂苷元-3-位衍生物的用途
WO2015163318A1 (fr) * 2014-04-25 2015-10-29 レジリオ株式会社 Agent thérapeutique pour des maladies associées à un dysfonctionnement des axones nerveux, comprenant un agent thérapeutique pour la maladie d'alzheimer
JP2015218134A (ja) * 2014-05-16 2015-12-07 タカラバイオ株式会社 記憶障害の予防及び／又は治療のための組成物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008516972A (ja) * 2004-10-14 2008-05-22 ジョージタウン ユニバーシティー 神経保護作用を有するスピロステノールの薬学的組成物
JP2010500287A (ja) * 2006-08-03 2010-01-07 オンコロジー リサーチ インターナショナル リミテッド 血管新生を抑制するための方法及び組成物
WO2014112145A1 (fr) * 2013-01-21 2014-07-24 レジリオ株式会社 Agent thérapeutique et procédé thérapeutique concernant 1,25d3-marrs pour une maladie neurologique telle que la maladie d'alzheimer
CN104324038A (zh) * 2013-07-24 2015-02-04 四川京华创生物科技有限公司 一种薯蓣皂苷元-3-位衍生物的用途
WO2015163318A1 (fr) * 2014-04-25 2015-10-29 レジリオ株式会社 Agent thérapeutique pour des maladies associées à un dysfonctionnement des axones nerveux, comprenant un agent thérapeutique pour la maladie d'alzheimer
JP2015218134A (ja) * 2014-05-16 2015-12-07 タカラバイオ株式会社 記憶障害の予防及び／又は治療のための組成物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHOGO SHIBUE, CHIHIRO HIGASHIDA: "O-10: Examination of drugs that promote optic nerve elongation in normal-tension glaucoma model mice", 39TH ACADEMIC CONFERENCE OF JAPANESE AND CHINESE MEDICINE SOCIETY; AUGUST 27-28, 2022 WEB EVENT, JAPANESE AND CHINESE MEDICINE SOCIETY, JP, 10 August 2022 (2022-08-10) - 28 August 2022 (2022-08-28), JP, pages 73, XP009553650, ISSN: 2435-4953 *

Similar Documents

Publication Publication Date Title
Kijlstra et al. Lutein: more than just a filter for blue light
JP6408702B2 (ja) 抗酸化点眼薬
JP2017511380A (ja) 脂溶性栄養素の糖尿病性眼疾患への効果
JP7012379B2 (ja) 視神経症を処置するためのトリテルペノイドを含む組成物およびその使用
JP2012515754A (ja) 神経栄養因子介在疾患の治療
Prokopiou et al. Omega-3 fatty acids supplementation protects the retina from age-associated degeneration in aged C57BL/6J mice
KR20120064707A (ko) 리피드 비히클에 9-시스-레티닐 에스테르를 포함하는 약제 처방
US11173164B2 (en) Compositions comprising triterpenoids
JP6389893B2 (ja) 神経系に対する損傷に関与する疾病を治療するためのオメガ３脂肪酸の組成物
JP5071618B2 (ja) 外分泌腺の機能障害改善剤及び機能障害改善用飲食物
CN108025029A (zh) 用于治疗角膜疾病或结膜疾病的组合物
WO2024024395A1 (fr) Composition pharmaceutique ou sous forme d'aliment et de boisson pour la prévention ou le traitement d'un trouble du nerf optique
CN108135956B (zh) 视神经保护用组合物
JP3778509B2 (ja) 眼の調節機能障害改善剤
US11564962B2 (en) Pharmaceutical composition comprising maple leaf extract for preventing or treating retinal disease
EP2944316A1 (fr) Composition pharmaceutique et aliment fonctionnel comprenant des extraits naturels pour prévenir ou traiter les complications diabétiques ou l'angiodème
CN110691590A (zh) 用于预防和/或改善脑功能障碍的含有叶黄素类或其盐和菱属植物的加工产物的组合物
JP2013501706A (ja) 網膜色素上皮におけるａ２ｅの形成を軽減するための組成物および方法
JPWO2006030907A1 (ja) 網膜保護剤
US20090022757A1 (en) Method for treating photoreceptor cell degeneration
KR20190006925A (ko) 신규한 디하이드로-2'H,3H-스피로[퓨란-2,3'-퓨로[3,2-b]퓨란]-2',5(3a'H,4H,5'H)-디온 유도체 및 이를 포함하는 염증성 안구질환 예방 또는 치료용 약학적 조성물
KR20110078524A (ko) 인삼 열매 추출물을 함유하는 퇴행성 신경장애 치료용 조성물
KR20230140344A (ko) 등검은말벌 유래 말벌독을 유효성분으로 포함하는 인지기능 개선용, 퇴행성 뇌질환 예방 또는 치료용 조성물
JP2022081394A (ja) 女性向け膀胱緊張緩解剤及びこれを含む経口摂取用組成物
KR20190006461A (ko) (7S,8R)-디히드로디히드로디코니페릴 알콜-9-β-D-글루코피라노사이드를 포함하는 염증성 안구질환의 예방 또는 치료용 조성물

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23846128

Country of ref document: EP

Kind code of ref document: A1