WO2005030189A1 - Nouvelle utilisation therapeutique d'alcool 4-hydroxybenzylique, d'aldehyde de 4-hydroxybenzylique et de vanilline - Google Patents

Nouvelle utilisation therapeutique d'alcool 4-hydroxybenzylique, d'aldehyde de 4-hydroxybenzylique et de vanilline Download PDF

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Publication number
WO2005030189A1
WO2005030189A1 PCT/KR2003/002578 KR0302578W WO2005030189A1 WO 2005030189 A1 WO2005030189 A1 WO 2005030189A1 KR 0302578 W KR0302578 W KR 0302578W WO 2005030189 A1 WO2005030189 A1 WO 2005030189A1
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hydroxybenzyl
group
vanillin
ischemia
aldehyde
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PCT/KR2003/002578
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English (en)
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Hyeon-Ju Kim
Moo-Ho Won
In-Koo Hwang
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C.F. Co., Ltd.
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Priority to AU2003282440A priority Critical patent/AU2003282440A1/en
Publication of WO2005030189A1 publication Critical patent/WO2005030189A1/fr

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    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/11—Aldehydes
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Definitions

  • the present invention relates to a novel therapeutic use of 4- hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin. More particularly, the invention relates to a method for treating ischemic brain disease comprising administering 4-hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin into a subject, a method for inhibiting neuronal injury caused by ischemia and reperfusion comprising administering 4-hydroxybenzyl alcohol, 4- hydroxybenzyl aldehyde and vanillin into a subject, a pharmaceutical composition comprising 4-hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin, and a use thereof.
  • Ischemic brain disease is caused by delayed neuronal death in the ' hippocampus CA1 area which is induced by insufficient supply of oxygen and glucose by the decrease of blood flow in brain (Kirino, Brain Res., 239:57-69, 1982; Petito et al., Neurology, 37:1281-1286, 1987; Pulsinelli et al., Ann. Neurol. , 11:491-498, 1982).
  • ischemic brain disease is developed when blood is not rally supplied to brain during pathological situations such as stroke or heart attack (Nedergaard, Acta. Neurol. Scand., 77:81-101, 1988; White et al., Neurology, 43:1656-1665, 1993).
  • the reversion of active transport caused by the decrease of ATP accelerates accumulation of glutamate in the extracellular area.
  • the accumulation of the glutamate in the extracellular area induces consecutive activations of NMD A (N-methyl-D-aspartic acid), AMPA ( ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole- propionic acid) and metabotropic glutamate receptor, leading to the overflow of calcium into cells (Olney et al., Science, 244:1360-1362, 1989).
  • Such inflow of calcium speeds up the activities of calcium-dependent protease, lipase and modulator, and at last induces the generation of cytotoxic molecules including free radical, by which the cellular structures such as DNA and cell membrane are destroyed to cause neuronal death.
  • the therapeutic agents for ischemic brain disease which have been clinically used are as follows: thrombolytics such as tissue plasminogen activator (TPA) and urokinase; platelet inhibitor such as ticlopidine, cilostazole and prostacycline; antithrombin agent; anticoagulant; cerebrovascular extender; Ca 2+ - channel blocker; cerebral edema suppressor and the like (Sandercock et al., Hosp. Med., 47:731-736, 1992).
  • TPA tissue plasminogen activator
  • urokinase urokinase
  • platelet inhibitor such as ticlopidine, cilostazole and prostacycline
  • antithrombin agent anticoagulant
  • cerebrovascular extender Ca 2+ - channel blocker
  • cerebral edema suppressor and the like andercock et al., Hosp. Med., 47:731-736, 1992.
  • those agents cannot guarantee the treatment effect when they are administered late
  • 4-hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin have been known to have an antioxidant effect that can effectively eliminate DPPH (l,l-diphenyl-2-picryl hydrazyl) radical, superoxide radical and hydroxyl radical (Liu J. and Mori A., Neuropharmacology, 31:1287-1298, 1992; Luo H et al., Hua Hsi IKo Ta Hwuehpao, 23: 53-56, 1992).
  • DPPH l,l-diphenyl-2-picryl hydrazyl
  • 4-hydroxybenzyl alcohol, 4- hydroxybenzyl aldehyde and vanillin are effective for treating and preventing ischemic brain disease.
  • the present invention provides a method for preventing and treating ischemic brain disease comprising administering an effective amount of one or more compounds selected from a group consisting of 4-hydroxybenzyl alcohol represented in the following formula I, 4-hydroxybenzyl aldehyde represented in the following formula II and vanillin represented in the following formula III to a subject.
  • the present invention provides a method for inhibiting neuronal injury caused by ischemia and reperfusion comprising administering an effective amount of one or more compounds selected from a group consisting of 4-hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin to a subject.
  • the present invention provides a pharmaceutical composition for preventing and treating ischemic brain disease comprising one or more compounds selected from a group consisting of 4- hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin.
  • the present invention provides a pharmaceutical composition for inhibiting neuronal injury caused by ischemia and reperfusion comprising one or more compounds selected from a group consisting of 4-hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin.
  • the present invention provides a use of one or more compounds selected from a group consisting of 4- hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin for the preparation of an agent for preventing or treating ischemic brain disease.
  • the present invention provides a use of one or more compounds selected from a group consisting of 4- hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin for the preparation of an agent for inhibiting neuronal injury caused by ischemia and reperfusion.
  • the compounds according to the present invention are 4-hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin.
  • 4-hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin can be used by purchasing commercially or produced by chemical synthesis method which is known in the art.
  • Those compounds can also be isolated from natural sources, preferably from plants or more preferably from Gastrodia elata. .
  • Isolation and purification of the compounds according to the present invention from Gastrodia elata can be carried out by a method known in the art (Kiyoshi Hata et al., Yakugaku Zasshi., 83: 606-610, 1963; Kuk Hyun Shin et al., Arch. Pharm. Res., 17:
  • desired pure compound can be obtained by extracting an effective ingredient of Gastrodia elata using a solvent and then by isolating and purifying it using chromatography.
  • the numbers of surviving cells in the groups administered with the compounds of the present invention were much more than that of the control group, even though the numbers varied a little according to compounds, sex of animals and administration time (see FIG. 2a to FIG. 4b).
  • the numbers of surviving cells were more in females than males, more when administered before inducing ischemia than after inducing ischemia (except female group administered with vanillin).
  • NMDA receptor type 1 is concerned with the inflow of calcium into cells; 8-hydroxy-2'-deoxyguanosine is produced from guanosine by oxidation of radical and generated when DNA is damaged by oxidative stress; and GABAtransaminase accelerates transamination of GAB A.
  • the mechanism of 4- hydroxybenzyl aldehyde and vanillin of the present invention is to inhibit neuronal death by preventing the overexcitement of neurons by inhibiting GABA transaminase (the result is not shown), which are different from that of 4- hydroxybenzyl alcohol.
  • the present invention provides a method for preventing and treating ischemic brain disease comprising administering an effective amount of one or more compounds selected from a group consisting of 4-hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin to a subject. Also, the present invention provides a method for inhibiting neuronal injury caused by ischemia and reperfusion comprising administering an effective amount of one or more compounds selected from a group consisting of 4-hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin to a subject.
  • 4-hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin of the present invention may be admimstered into a subject after further comprising pharmaceutically acceptable carriers and being formulated as a dosage form according to the known methods.
  • pharmaceutically acceptable carrier refers to a substance that is physiologically acceptable and does not cause allergy responses such as gastrointestinal disorder, dizziness and the like, or responses similar thereto when admimstered into humans.
  • the pharmaceutically acceptable carriers may further include, for example, carriers for oral and parenteral administrations.
  • the carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like.
  • the carriers for parenteral administration may comprise water, suitable oils, saline, water-soluble glucose, glycols and the like.
  • the pharmaceutically acceptable carriers may further comprise stabilizers and preservatives.
  • a suitable stabilizer there are antioxidants such as ascorbic acid, sodium sulfite or sodium hydrogen sulfite.
  • suitable preservatives there are benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.
  • Remington's Pharmaceutical Sciences 19th ed., Mack Publishing Company, Easton, PA, 1995.
  • the 4-hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin of the present invention can be formulated into various parenteral or oral dosage forms, together with the pharmaceutically acceptable carriers as described above.
  • a typical dosage form for parenteral administration is that for injection and preferably, an isotonic aqueous solution or a suspension.
  • the dosage form for injection can be prepared using a suitable dispersion agent, wetting agent and suspension agent according to the known methods in the pertinent art. For example, each ingredient is dissolved in saline or buffer and then can be prepared into a dosage form for injection.
  • a dosage form for oral administration for example, there are powders, granules, tablets, pills, capsules, etc., which may comprise diluents (such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine) and/or lubricants (such as silica, talc, stearic acid and magnesium or calcium salt thereof and/or polyethylene glycol) as well as the active ingredient.
  • diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine
  • lubricants such as silica, talc, stearic acid and magnesium or calcium salt thereof and/or polyethylene glycol
  • the tablets may further comprise binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine and if necessary, they may further comprise disintegrants or effervescent mixtures such as starch, agar, alginic acid or sodium salt thereof, and/or absorbents, colorants, flavors and sweeteners.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine
  • disintegrants or effervescent mixtures such as starch, agar, alginic acid or sodium salt thereof, and/or absorbents, colorants, flavors and sweeteners.
  • Such dosage forms can be prepared by conventional mixing, granulation or coating methods.
  • the pharmaceutical composition formulated according to the above method can be administered into a patient via several routes including oral, intraperitoneal, percutaneous, subcutaneous, venous
  • the "effective amount” as used herein refers to an amount of the compound capable of having preventive or therapeutic effects on ischemic brain disease when administered into a subject. Its ordinary dose per day is preferably 1 to 100 rag/kg, more preferably 40 to 60 mg/kg.
  • the compounds of the invention may be admimstered once or more times a day within the preferred dose.
  • the dose of the compounds of the present invention may be suitably selected according to administration route, subject, age, sex, body weight, individual variation and condition of disease.
  • the "subject” as used herein refers to mammals including humans and preferably humans diagnosed as ischemic brain disease.
  • the "ischemic brain disease” as used herein may include all diseases induced by ischemia and reperfusion injury comprising, but not limited to, stroke, cerebral infarction, cerebral hemorrhage, epilepsy, Parkinson's disease and the like.
  • the present invention provides a pharmaceutical composition for preventing and treating ischemic brain disease comprising one or more compounds selected from a group consisting of 4-hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin.
  • the present invention provides a pharmaceutical composition for inhibiting neuronal injury caused by ischemia and reperfusion comprising one or more compounds selected from a group consisting of 4-hydroxybenzyl alcohol, 4- hydroxybenzyl aldehyde and vanillin.
  • the pharmaceutical composition of the present invention may further comprise pharmaceutically acceptable carriers. Examples of the pharmaceutically acceptable carriers are as described above.
  • the pharmaceutical composition according to the present invention can be formulated as a dosage form according to the methods known in the art so that after being administered into a subject, it can release the active ingredient in a prompt, continuous or prolonged way.
  • the present invention provides a use of one or more compounds selected from a group consisting of 4-hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin for the preparation of an agent for preventing or treating ischemic brain disease. Also, the present invention provides a use of one or more compounds selected from a group consisting of 4-hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin for the preparation of an agent for inhibiting ischemia and reperfusion.
  • the agent comprising the compounds of the invention may further comprise pharmaceutically acceptable carriers and be formulated as a suitable form according to the known methods. Examples of the "ischemic brain disease" are as described above.
  • FIG. 1 shows the microphotographs of hippocampus tissue and CA1 area of sham-operated group and control group, which were stained with cresyl violet (A: hippocampus tissue of sham-operated group, B: hippocampus tissue of control group, C: hippocampus CA1 area of sham-operated group, D: hippocampus CA1 area of control group).
  • FIG. 2a and 2b show the microphotographs of hippocampus tissue and
  • CA1 area of 4-hydroxybenzyl alcohol administering group which were stained with cresyl violet (A: administering group at 30 min before inducing ischemia(male), B: administering group at 30 min after inducing ischemia(male), C: administering group at 30 min before inducing ischemia(female), D: administering group at 30 min after inducing ischemia(female)).
  • A administering group at 30 min before inducing ischemia(male)
  • B administering group at 30 min after inducing ischemia(male)
  • C administering group at 30 min before inducing ischemia(female)
  • D administering group at 30 min after inducing ischemia(female)
  • FIG. 3a and 3b show the microphotographs of hippocampus tissue and CAl area of 4-hydroxybenzyl aldehyde administering group, which were stained with cresyl violet (A: administering group at 30 min before inducing ischemia(male), B: administering group at 30 min after inducing ischemia(male), C: administering group at 30 min before inducing ischemia(female), D: administering group at 30 min after inducing ischemia(female)).
  • FIG. 4a and 4b show the microphotographs of hippocampus tissue and
  • FIG. 5 shows the average number of surviving hippocampus cells after inducing ischemia counted in hippocampus tissues of each group, taking sham- operated group as a standard.
  • FIG. 6 shows the microphotographs of hippocampus CAl area by using immunohistostaining upon NMDA receptor type 1, when administered with 4- hydroxybenzyl alcohol at 30 min before inducing ischemia (A: before inducing brain ischemia, B: 30 min after inducing brain ischemia, C: 3 hours after inducing brain ischemia, D: 6 hours after inducing ischemia, E: 12 hours after inducing ischemia, F: 24 hours after inducing ischemia).
  • A before inducing brain ischemia
  • B 30 min after inducing brain ischemia
  • C 3 hours after inducing brain ischemia
  • D 6 hours after inducing ischemia
  • E 12 hours after inducing ischemia
  • F 24 hours after inducing ischemia
  • FIG. 7 shows the microphotographs of hippocampus CAl area by using immunohistostaining upon 8-hydroxy-2'-deoxyguanosine, when administered with 4-hydroxybenzyl alcohol at 30 min before inducing ischemia (A: before inducing brain ischemia, B: 30 min after inducing brain ischemia, C: 3 hours after inducing brain ischemia, D: 6 hours after inducing ischemia, E: 12 hours after inducing ischemia, F: 24 hours after inducing ischemia).
  • A before inducing brain ischemia
  • B 30 min after inducing brain ischemia
  • C 3 hours after inducing brain ischemia
  • D 6 hours after inducing ischemia
  • E 12 hours after inducing ischemia
  • F 24 hours after inducing ischemia
  • FIG. 8 shows the microphotographs of hippocampus CAl area by using immunohistostaining upon GABA transaminase, when administered with 4- hydroxybenzyl alcohol at 30 min before inducing ischemia (A: before inducing brain ischemia, B: 30 min after inducing brain ischemia, C: 3 hours after inducing brain ischemia, D: 6 hours after inducing ischemia, E: 12 hours after inducing ischemia, F: 24 hours after inducing ischemia).
  • the test animals were utilized as test animals.
  • the test animals had been raised for 14 days at constant temperature(23 ⁇ 2 ° C) and relative humidity(50 ⁇ 10%) with a fixed 12 h light/dark cycle(exposed to the light from 7 am to 7 pm) and free access to water and food.
  • the Mongolian gerbils were anesthetized generally by using a mixture of 2.5 volume% isoflurane (Baxtor, USA) in 67 volume% nitrous oxide and 33 volume% oxygen. The animals had their hair around neck cut and the region was sterilized.
  • the neck area was cut to expose both common carotid arteries, and ischemia was induced by occluding the arteries for 5 minutes using non-traumatic aneurysm clip (Staelting, USA).
  • aneurysm clip Staelting, USA.
  • Body temperature of the animals was monitored using a thermometer inserted in rectum and maintained at 37 ⁇ 0.3 °C using an automatic heat pad.
  • the aneurysm clip was removed after inducing ischemia, resulting in reperfusion. The reperfusion was confirmed by direct observation with a microscope.
  • vanillin (Sigma Chemical) were suspended in 1 ml of 10% Tween 80 solution dissolved in 0.9% saline respectively, and injected via the intraperitoneal space to female and male Mongolian gerbil with 40 mg/weight kg dosage at 30 min before and after inducing ischemia, resulting in the preparation of 4-hydroxybenzyl alcohol administering group, 4-hydroxybenzyl aldehyde administering group and vanillin administering group respectively.
  • the control group was also prepared by injecting 10% Tween 80 solution dissolved in 0.9% saline with 40 mg/weight kg dosage at 30 min before and after inducing ischemia.
  • the sham-operated group was prepared by the sham operation having the same procedure except that ischemia was not induced by omitting occluding common carotid arteries. Animal groups differently treated as explained above were presented in the below Table 1.
  • the intracranial cavity was opened with a bone- cutter to take out the brain, and then post-fixation was performed for 4-6 hours in the same fixing solution. Then the brain was put in 30% sucrose solution dissolved in 0.1 M phosphate buffer until sinking completely to the bottom. The brain was sectioned by a sliding microtome (Reichert-Jung, Germany) by 30 ⁇ in thickness. The brain sections were put in 6 well plate containing storing solution and stored at 4°C. The tissues showing distinct hippocampal formation were selected from all the tissue sections, the storing solution was removed therefrom, and the tissues were dried on the slide covered with gelatin.
  • a sliding microtome Reichert-Jung, Germany
  • FIG. 1 Microphotographs of hippocampus tissue and CAl area of each group, stained with cresyl violet, were shown in FIG. 1 to FIG. 4. As shown in FIG. 1, cell damage was hardly observed in sham-operated group in which ischemia was not induced (FIG. 1A and IC), whereas serious cell damage was observed in control group (FIG. IB and ID).
  • FIG. 5 shows the average number of surviving hippocampus cells after inducing ischemia counted in hippocampus tissues of each group, taking sham- operated group as a standard (100%).
  • the numbers of surviving cells of the groups administered with the compounds of the invention were more in females than males, more when admimstered before inducing ischemia than after inducing ischemia (except the female group administered with vanillin).
  • the animals were sacrificed before inducing ischemia, and at 30 min, 3 h, 6 h, 12 h and 24 h after inducing ischemia, respectively.
  • Perfusive fixation was performed using the same method as explained above.
  • the tissues were sectioned by 30 ⁇ in thickness, which were put in 6 well plate containing a storing solution.
  • the tissues showing distinct hippocampus were selected from each tissue section, and then rinsed with 0.1 M PBS (phosphate buffered saline, pH 7.4) three times for 10 minutes to remove the remaining storing solution. Immunostaining was carried out using the ABC method presented below.
  • the rinsed tissue sections were treated with 0.3% H 2 O 2 in 0.01 M PBS for 30 min to eliminate intrinsic peroxidase in the tissues, and then treated and reacted with 5% normal goat serum to prevent nonspecific reaction for 30 min.
  • anti-NMDA receptor type 1 Chemicon International, USA
  • mouse anti-8-hydroxy-2'-deoxyguanosine Peninsula, USA
  • mouse anti-GABA transaminase provided by Prof. CHOI Su- Young, Hallym University, Korea
  • biotinylated-goat anti-mouse IgG (Vector, USA) was diluted with 0.1 M PBS solution containing 2% normal goat serum and 0.1% Triton X-100 at the ratio of 1:200, which was also reacted with the tissues at room temperature for 2 hours. Then, the tissues were reacted with vector kit solution (Vector, USA) at room temperature for 1 hour. After each reaction in every step, the tissues were rinsed with PBS solution four times. Colorization of the tissues was carried out in Tris buffer solution (pH 7.4) containing 0.03% H 2 O 2 and 0.05% DAB (3,3'-diaminobenzidine tetrachloride: Sigma, USA) for 2 minutes.
  • Tris buffer solution pH 7.4
  • DAB 3,3'-diaminobenzidine tetrachloride: Sigma, USA
  • NMDA receptor type 1 known to be concerned with the inflow of calcium into cells was hardly changed after inducing ischemia (FIG. 6). From the above results, it was confirmed that the administration of 4-hydroxybenzyl alcohol does not affect the expression of NMDA receptor type 1, suggesting that 4-hydroxybenzyl alcohol does not affect the inflow of calcium in the early stage of ischemia. Meanwhile, as shown in FIG. 7, 8-hydroxy-2'-deoxyguanosine, an oxide generated by DNA damage caused by oxidative stress, increased by degrees until 12 hr after inducing brain ischemia, and the immune response at 12 hr after inducing brain ischemia increased by 150%, comparing to that before inducing ischemia.
  • 4-hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde and vanillin of the present invention have an effect on inhibiting neuronal injury which is caused by brain ischemia and reperfusion. Accordingly, such compounds can be effectively used for preventing and treating ischemic brain disease.

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Abstract

La présente invention a trait à une nouvelle utilisation thérapeutique d'alcool 4-hydroxybenzylique, d'aldéhyde 4-hydroxybenzylique et de vanilline. Plus particulièrement la présente invention a trait à un procédé pour le traitement de la maladie cérébrale ischémique comprenant l'administration d'alcool 4-hydroxybenzylique, d'aldéhyde 4-hydroxybenzylique et de vanilline à un sujet, et à un procédé pour l'inhibition de la lésion neurale provoquée par l'ischémie et la reperfusion comprenant l'administration d'alcool 4-hydroxybenzylique, d'aldéhyde 4-hydroxybenzylique et de vanilline à un sujet.
PCT/KR2003/002578 2003-09-30 2003-11-26 Nouvelle utilisation therapeutique d'alcool 4-hydroxybenzylique, d'aldehyde de 4-hydroxybenzylique et de vanilline WO2005030189A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010015965A2 (fr) * 2008-08-04 2010-02-11 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Procédés et compositions de traitement d'un dommage neuronal et de modulation de canaux potentiels de récepteurs transitoires
EP2886656A1 (fr) 2013-12-18 2015-06-24 Commissariat A L'energie Atomique Et Aux Energies Alternatives Nouvelle enzyme et procédé de préparation de l'alcool benzylique 4-hydroxyle et leurs dérivés

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ABEL S.M. ET AL.: "Elevated gamma-aminobutyric acid levels attenuate the metabolic response to bilateral ischemia", JOURNAL OF NEUROCHEMISTRY, vol. 58, no. 2, 1992, pages 740 - 744 *
JEOUNG-HEE HA ET AL.: "4-hydroxybenzaldehyde from Gastrodia elata B1 is active in the antioxidation and GABAergic neuromodulation of the rat brain", JOURNAL OF ETHNOPHARMACOLOGY, 2000, pages 329 - 333 *
JEOUNG-HEE HA ET AL.: "In vivo effects of hydroxybenzaldehydes from Gastrodia elata and their analogues on GABAergic neurotransmission, and a structure-activity correlation", PLANTA MED., 2001, pages 877 - 880 *
TAE-CHEON KANG ET AL.: "Elevation of the gamma-aminobutyric acid transaminase expression in the gerbil CA1 area after ischemia-reperfusion damage", NEUROSCIENCE LETTERS, 2000, pages 33 - 36 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010015965A2 (fr) * 2008-08-04 2010-02-11 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Procédés et compositions de traitement d'un dommage neuronal et de modulation de canaux potentiels de récepteurs transitoires
WO2010015965A3 (fr) * 2008-08-04 2010-04-01 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Procédés et compositions de traitement d'un dommage neuronal et de modulation de canaux potentiels de récepteurs transitoires
EP2886656A1 (fr) 2013-12-18 2015-06-24 Commissariat A L'energie Atomique Et Aux Energies Alternatives Nouvelle enzyme et procédé de préparation de l'alcool benzylique 4-hydroxyle et leurs dérivés
WO2015091755A2 (fr) 2013-12-18 2015-06-25 Commissariat A L'energie Atomique Et Aux Energies Alternatives Nouvelles enzymes et procédé de préparation d'alcool 4-hydroxylique benzylique et dérivés correspondants

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