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WO2016127399A1 - Utilisation d'acide chlorogénique dans la préparation d'un médicament pour le traitement de la sclérose latérale amyotrophique - Google Patents

Utilisation d'acide chlorogénique dans la préparation d'un médicament pour le traitement de la sclérose latérale amyotrophique Download PDF

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Publication number
WO2016127399A1
WO2016127399A1 PCT/CN2015/073026 CN2015073026W WO2016127399A1 WO 2016127399 A1 WO2016127399 A1 WO 2016127399A1 CN 2015073026 W CN2015073026 W CN 2015073026W WO 2016127399 A1 WO2016127399 A1 WO 2016127399A1
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WIPO (PCT)
Prior art keywords
chlorogenic acid
preparation
drug
mice
group
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Ceased
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PCT/CN2015/073026
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English (en)
Chinese (zh)
Inventor
张洁
张梦甜
黄望
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Sichuan Jiuzhang Biotechnology Co Ltd
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Sichuan Jiuzhang Biotechnology Co Ltd
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Priority to PCT/CN2015/073026 priority Critical patent/WO2016127399A1/fr
Publication of WO2016127399A1 publication Critical patent/WO2016127399A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate

Definitions

  • the present invention relates to the use of chlorogenic acid for the preparation of a medicament for the treatment of amyotrophic lateral sclerosis.
  • ALS Amyotrophic lateral sclerosis
  • MND motor neuron disease
  • Painter disease is a serious neurodegenerative disease with cerebral cortex, brainstem, and anterior horn of the spinal cord. Neuronal loss is characterized by muscle weakness, muscle atrophy, fasciculation, and pyramidal tract signs. The disease is a fatal motor neuron degenerative disease with hand muscle weakness and atrophy as the first symptom. The average survival time of the patient is about 4 years.
  • ALS amyotrophic lateral sclerosis
  • Riluzole is commonly used.
  • neurotrophic factors have good control, repair and treatment effects on the course of amyotrophic lateral sclerosis (ALS), and the amount of neurotrophic factors synthesized by the body itself is very limited. The effect of neurotrophic factors on the disease is even more drastic.
  • EPO erythropoietin
  • Chlorogenic acid CGA also known as caffeic acid, is a phenolic acid consisting of caffeic acid CA and quinic acid QA. Its chemical name is 3-o-caffeoyl quinine. Acid (3-o-caffeoylquinic acid CGA). Chlorogenic acid is a phenylpropanoid synthesized by plants in the process of aerobic respiration through the pentose phosphate pathway intermediate. Chlorogenic acid has been used in many fields such as food, health care products, cosmetics and pharmaceuticals.
  • cardiovascular protection Because it is widely found in a variety of common vegetables and fruits, it has a variety of biological activities, such as: cardiovascular protection, anti-oxidation, anti-ultraviolet and anti-radiation effects, anti-mutagenic and anti-cancer effects, antibacterial effects, anti- Viral action, lipid-lowering and hypoglycemic effects, immunomodulatory effects, etc. It has a wide range of applications in the fields of pharmaceutical, chemical and food.
  • the technical solution of the present invention is to provide the use of chlorogenic acid for the preparation of a medicament for treating amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • the present invention provides the use of chlorogenic acid for the preparation of a medicament for the treatment of amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • the drug is a drug that promotes the production of erythropoietin (EPO). .
  • the drug is a drug that promotes the production of brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB protein).
  • BDNF brain-derived neurotrophic factor
  • TrkB protein receptor tyrosine receptor kinase B
  • the drug is a drug that increases the number of spinal motor neurons and protects neuronal cells.
  • the medicament is prepared by adding chlorogenic acid as an active ingredient, adding a pharmaceutically acceptable adjuvant or an auxiliary component.
  • the preparation is an oral preparation and an injection preparation.
  • the preparation is used in a dose of 1-100 mg/kg.
  • chlorogenic acid has a therapeutic effect on amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • Chlorogenic acid can effectively improve the behavioral characteristics of mice with amyotrophic lateral sclerosis (ALS) and reduce the onset time.
  • Chlorogenic acid can effectively increase the erythropoietin content in the serum of mice with amyotrophic lateral sclerosis (ALS) model.
  • Chlorogenic acid can effectively promote brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) production in mice with amyotrophic lateral sclerosis (ALS) model, significantly increased The number of spinal motor neurons.
  • BDNF brain-derived neurotrophic factor
  • TrkB receptor tyrosine receptor kinase B
  • chlorogenic acid is beneficial for improving the symptoms of amyotrophic lateral sclerosis (ALS), beneficial to the biosynthesis of neurotrophic factors, and beneficial for repairing and protecting
  • Figure 2 Number of spinal motor neurons in each group of mice (staining results of spinal motor neuron cells in each group; (b) Cell count analysis results)
  • Example 1 Preparation of lyophilized powder injection using chlorogenic acid
  • the chlorogenic acid raw material used in the present embodiment is obtained by extracting and purifying from honeysuckle, and the purity is
  • the above prescription was completely dissolved in water for injection, filtered, and then finely filtered with a 0.22 ⁇ m sterile microfiltration membrane to adjust the pH. After the conventional operation of the sterile powder injection, 1000 ml of 2 ml powder injections were prepared. Contains 30mg of chlorogenic acid.
  • the chlorogenic acid used in the present example was extracted and purified from Eucommia ulmoides leaves, and the purity was 99.26%.
  • the chlorogenic acid used in the present example was extracted and purified from the burdock leaves, and the purity was 99.34%.
  • each oral solution is 100mL, Contains 200mg of chlorogenic acid.
  • the chlorogenic acid used in the present example was extracted and purified from Eucommia ulmoides leaves, and the purity was 98.47%.
  • a chlorogenic acid tablet is prepared by a wet granule tableting method.
  • (1) Prepare an aqueous solution of hypromellose according to the prescription; (2) mix the prescribed amount of chlorogenic acid, powdered sugar and lactose, add the hypromellose aqueous solution, stir well and make it soft. (3) the prepared soft material according to the conventional wet granulation operation procedure, sieving, drying and granulating to obtain granules of uniform size; (4) mixing the prepared granules with magnesium stearate uniformly After compression, a total of 1000 tablets were prepared, each containing 100 mg of chlorogenic acid.
  • the chlorogenic acid used in the present example was obtained by extraction and purification from Eucommia ulmoides leaves, and the purity was 99.35%.
  • each capsule contains 50mg of chlorogenic acid.
  • the chlorogenic acid used in the present example was extracted and purified from Eucommia ulmoides leaves, and the purity was 98.92%.
  • Povidone K30 was taken and water for injection was added to prepare a solution. After the prescription amount of chlorogenic acid, mannitol and sucrose were uniformly mixed, the povidone K30 solution was added to prepare a soft material. According to the conventional preparation process of the granules, the granules are obtained after sieving, drying and granulating the soft materials. The granules were dispensed under aseptic conditions to prepare 400 bags of granules, each bag containing 500 mg of chlorogenic acid.
  • the chlorogenic acid raw material used in the present embodiment is obtained by extracting and purifying from the burdock leaves, and the purity is 99.82%.
  • Test Example 1 Pharmacological investigation of chlorogenic acid for the treatment of amyotrophic lateral sclerosis (ALS) and examination of various biochemical indicators.
  • ALS amyotrophic lateral sclerosis
  • EPO hemoglobin gene
  • BDNF brain-derived neurotrophic factor
  • TrkB protein BDNF receptor tyrosine receptor kinase B
  • NC group normal control group
  • the motor strength and coordination function of each group of mice were evaluated using the Rotarod test.
  • the Rotarod speed is set to 5, 15r/min.
  • the time that each mouse stayed on the rotating rod was automatically recorded. If the mouse stayed for 7 minutes, the test could be ended and scored 7 minutes.
  • the mice were evaluated for behavioral behavior every day, 3 times at each rotation speed, and the average time was taken for 28 days, and the average turning time of the mice was determined by taking one week as a small unit. The first day when the mouse could not stay on the 15r/min rod for 7 minutes was used as the onset of the onset.
  • Erythropoietin is a sialic acid-containing acidic glycoprotein that acts on endogenous hormones that promote the proliferation, differentiation, and eventual maturation of erythroid progenitor cells by bone marrow hematopoietic cells. EPO is a multifunctional protective factor with anti-inflammatory and immunomodulatory effects, which promotes the production of nerve growth factor and has neuroprotective effects.
  • mice During the 4 weeks of the experiment, each group of mice was bled by eyelid blood collection every weekend (experiment 7th, 14th, 21st, and 28th days), and the collected blood was placed on the blood. The tube was immersed in EDTA-2Na, centrifuged at 5000 r/min for 10 min, and the supernatant serum was taken. The EPO content in the serum was measured using an ELISA kit for mouse erythropoietin.
  • BDNF brain-derived neurotrophic factor
  • TrkB protein receptor tyrosine receptor kinase B
  • a neuropeptide is a type of polypeptide or protein molecule that promotes the survival, growth, and differentiation of nerve cells. It organizes the death of neurons after injury and promotes the repair of neurons. Is reflecting the brain and ridge An important indicator of myeloid repair.
  • BDNF is the most representative member of the neurotrophic factor family and is widely distributed in the nervous system, with the hippocampus being the most abundant. BDNF neuroprotection is achieved primarily by binding to Trk. BDNF helps the body maintain normal neuronal physiological functions, and plays an important role in reducing the apoptosis of damaged neurons and promoting neuronal repair.
  • the hippocampal tissue samples of each group of mice were centrifuged at 12,000 r/min for 10 min, and the supernatant was collected and stored in a refrigerator at -20 ° C for use.
  • the BDNF and TrkB of hippocampus were determined by double antibody boost ELISA. Protein level.
  • mice in each group were taken, and 10 slices were taken and stained with cresyl violet.
  • the anterior horn motor neurons were counted and the average value was taken as the number of motor neurons in each slice of each mouse. .
  • the experimental results of the test showed that compared with the control group, the average time of the rotation of the mice in the ALS model group was significantly decreased during the 4 weeks (28 days) of the experimental test.
  • the average turning time also decreased, but the rate of decline was relatively slow, and the daily activities of the mice were more healthy than those of the ALS group. More good.
  • Observations on motor function and behavior in mice revealed no significant differences between the Riluzole and LYS treatment groups. The overall trend of mouse turn time is shown in Figure 1.
  • chlorogenic acid can delay the loss of neuromotor function in mice to a certain extent, and the decreasing trend of the turning time is slower than that in other groups.
  • the number of days in mice in the chlorogenic acid treatment group is higher than that in the ALS control group. There is a certain degree of reduction.
  • mice Compared with the normal group of mice, the serum EPO content of the ALS model group increased slightly, but the increase was not significant. The EPO content of the two groups showed no statistical difference in the four weeks (p>0.05).
  • the serum EPO levels of the mice in the Riluzole and LYS treatment groups increased to some extent. Among them, the serum EPO content of the mice in the LYS treatment group increased significantly, and the weekly data values were significantly higher than those of the other three groups. Sexual differences (p ⁇ 0.05).
  • BDNF brain-derived neurotrophic factor
  • TrkB protein receptor tyrosine receptor kinase B
  • BDNF protein and TrkB protein showed that the expression levels of these two proteins increased slightly in mice of ALS group, suggesting that the body accelerates the production of neurotrophic factors in order to repair neurons.
  • the expression level of TrkB protein was significantly different from that of NC group (p ⁇ 0.05).
  • the expression of BDNF and TrkB protein in Riluzole and LYS treatment groups increased significantly.
  • the expression of BDNF and TrkB protein increased more than other groups, and the other three groups were smaller.
  • the data of the two protein expression levels of the mice were compared and showed significant differences (p ⁇ 0.05).
  • the results showed that chlorogenic acid can effectively promote the expression of BDNF and TrkB proteins.
  • Table 4 The specific experimental data is shown in Table 4:
  • Chlorogenic acid can effectively increase the erythropoietin content in the serum of mice with amyotrophic lateral sclerosis (ALS) model and effectively promote brain-derived neurotrophic factor (BDNF) and its receptor tyrosine
  • BDNF brain-derived neurotrophic factor
  • TrkB protein somatic kinase B

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  • Health & Medical Sciences (AREA)
  • Emergency Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne l'utilisation d'acide chlorogénique dans la préparation d'un médicament pour le traitement de la sclérose latérale amyotrophique. L'acide chlorogénique est bénéfique pour soulager les symptômes de la sclérose latérale amyotrophique (ALS), bénéfique pour synthétiser biologiquement des facteurs neurotrophiques et bénéfique pour réparer et protéger les neurones.
PCT/CN2015/073026 2015-02-13 2015-02-13 Utilisation d'acide chlorogénique dans la préparation d'un médicament pour le traitement de la sclérose latérale amyotrophique Ceased WO2016127399A1 (fr)

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PCT/CN2015/073026 WO2016127399A1 (fr) 2015-02-13 2015-02-13 Utilisation d'acide chlorogénique dans la préparation d'un médicament pour le traitement de la sclérose latérale amyotrophique

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PCT/CN2015/073026 WO2016127399A1 (fr) 2015-02-13 2015-02-13 Utilisation d'acide chlorogénique dans la préparation d'un médicament pour le traitement de la sclérose latérale amyotrophique

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110740648A (zh) * 2016-12-30 2020-01-31 延世大学校产学协力团 含有3，5-二咖啡酰奎宁酸或菊花提取物的用于预防及治疗肌肉疾病或改善肌功能的组合物
US11376267B2 (en) * 2018-07-24 2022-07-05 Sichuan Jiuzhang Biological Science And Technology Co., Ltd. Drug combination for treatment of amyotrophic lateral sclerosis, preparation method and use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ERIN, H. ET AL.: "Cognitive and Neuroprotective Effects of Chlorogenic Acid", NUTRITIONAL NEUROSCIENCE, vol. 0, no. 0, 31 December 2014 (2014-12-31), pages 3 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110740648A (zh) * 2016-12-30 2020-01-31 延世大学校产学协力团 含有3，5-二咖啡酰奎宁酸或菊花提取物的用于预防及治疗肌肉疾病或改善肌功能的组合物
US11376267B2 (en) * 2018-07-24 2022-07-05 Sichuan Jiuzhang Biological Science And Technology Co., Ltd. Drug combination for treatment of amyotrophic lateral sclerosis, preparation method and use thereof

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