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WO2016127832A1 - Utilisation de l'acide chlorogénique dans la préparation de médicaments destinés au traitement de l'épilepsie - Google Patents

Utilisation de l'acide chlorogénique dans la préparation de médicaments destinés au traitement de l'épilepsie Download PDF

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WO2016127832A1
WO2016127832A1 PCT/CN2016/072766 CN2016072766W WO2016127832A1 WO 2016127832 A1 WO2016127832 A1 WO 2016127832A1 CN 2016072766 W CN2016072766 W CN 2016072766W WO 2016127832 A1 WO2016127832 A1 WO 2016127832A1
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chlorogenic acid
group
rats
preparation
drug
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Chinese (zh)
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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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    • 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 invention belongs to the new medicinal use of chlorogenic acid, in particular to the use of chlorogenic acid in the preparation of a medicament for treating epilepsy.
  • Epilepsy is a common disease in the neurology family. It is a chronic recurrent transient brain dysfunction syndrome characterized by recurrent epileptic hair caused by abnormal discharge of brain neurons. The entire process of the occurrence, spread and termination of epilepsy is accompanied by many biochemical changes. At the time of seizures, the inhibitory neurotransmitter GABA in the brain tissue of patients will decrease significantly. This pathological feature is closely related to the degree and frequency of seizures. GABA is used as a target for regulation and control, and the control of epileptic symptoms is positive. The meaning.
  • ketone bodies can play a certain role in controlling the symptoms of seizures in epileptic seizures, and appropriately increase the source of ketones in patients with epilepsy, which can have obvious therapeutic effects on diseases (Kim do Y, Davis LM, Sullivan PG, et al. Ketone bodies are protective against oxidative stress in neocortical neurons. J Neurochem. 2007. 101(5): 1316-26.).
  • 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. Its extraction (usually extracted from plants), synthetic technology mature, chlorogenic acid has been used in food, health care products, cosmetics and pharmaceuticals and other fields. 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. In the fields of medicine, chemicals, food, etc. There are a wide range of applications.
  • the drug is a drug for up-regulating the HMGCS2 gene in the kidney.
  • the HMGCS2 gene is a gene encoding trihydroxytrimethyl-CoA synthetase 2, and the expression amount thereof is positively correlated with the corresponding enzyme activity. It is also positively correlated with the amount of ketone body produced in the body.
  • the drug is a drug that upregulates the expression of HMGCS2 protein.
  • the HMGCS2 protein is a downstream product controlled by the HMGCS2 gene, which can exert the biological activity of the protein, is a key substance in the synthesis of ketone bodies in the body, and its activity and amount are positively correlated with the amount of ketone body formation. .
  • the drug is a drug that modulates ketone body biosynthesis.
  • the ketone body is a general term for a class of compounds produced by the human body during starvation, providing sufficient energy supplement for the body.
  • ketone bodies for epileptic seizures especially refractory epilepsy
  • the control effect has therapeutic effects that are difficult to achieve with other drugs, and the mechanism is not clear.
  • many current clinical treatment options for epilepsy have shown that increasing the source of ketones in patients with epilepsy can effectively inhibit seizures.
  • the drug is a drug that enhances the GABA content of brain neurotransmitters.
  • the GABA is called ⁇ -aminobutyric acid, and is an important inhibitory neurotransmitter in the mammalian central nervous system, and its activity and content are closely related to the occurrence of epilepsy.
  • the level of GABA in brain tissue of patients with epilepsy is significantly lower than that of normal people, and the content of GABA is related to the degree and frequency of seizures in patients with epilepsy. It can improve the level of GABA in brain tissue of patients with epilepsy, and may have anti-epileptic effect. .
  • the medicament is a preparation prepared by adding chlorogenic acid as an active ingredient and adding one or more pharmaceutically acceptable pharmaceutical excipients.
  • chlorogenic acid can be used as the only active ingredient or as one of the active ingredients.
  • the preparation is an oral preparation or an injection preparation.
  • the specific dosage form may be various pharmaceutical dosage forms such as powder, pill, oral solution, tablet, capsule, granule, lyophilized powder injection and the like.
  • the preparation contains 1-10 mg of chlorogenic acid per preparation unit.
  • the clinical use dose of the preparation is: 1-100 mg/kg.
  • the test of the present invention shows that chlorogenic acid has a therapeutic effect on the persistent episode of epilepsy and the onset of refractory temporal lobe epilepsy, and chlorogenic acid can significantly improve the behavioral characteristics of the epilepsy model group, and the number of seizures is significantly reduced.
  • chlorogenic acid can effectively enhance the expression of HMGCS2 gene and its corresponding HMGCS2 protein, which has an effect on the biosynthesis of ketone bodies.
  • the experimental data also show that chlorogenic acid can effectively regulate the blood ketone level of epileptic rats and enhance the rat brain.
  • the content of inhibitory neurotransmitter GABA in tissues are examples of inhibitory neurotransmitter GABA in tissues.
  • 1 chlorogenic acid can improve the frequency and severity of epileptic mouse model, and has obvious pharmacological effects.
  • chlorogenic acid can up-regulate the HMGCS2 gene, which is a gene encoding a downstream enzyme
  • the synthesis of the corresponding HMGCS2 protein is promoted, and the protein is a key substance in the synthesis of the ketone body, and its activity and content are positively correlated with the biosynthesis of the ketone body.
  • chlorogenic acid can increase the level of ketone body, which has a good effect on patients with Parkinson's disease. Chlorogenic acid can regulate the ketone body level of rat model.
  • Chlorogenic acid promotes the production of GABA in brain tissue of patients with epilepsy.
  • GABA is an inhibitory amino acid of neurons.
  • the pathogenesis of epilepsy is very complicated, and many factors are formed. Among them, the decrease of GABA level is one of the important pathological causes of its pathogenesis.
  • domestic and foreign research has confirmed and has been used clinically. It is to increase the ketone body intake in patients with epilepsy, so as to control the onset symptoms of epilepsy.
  • chlorogenic acid can increase the level of GABA in the brain tissue of epileptic mouse model, and chlorogenic acid can also up-regulate key enzymes of ketone body synthesis. The corresponding gene and protein levels promote the formation of ketone bodies, which in turn have a clear symptomatic effect on epilepsy.
  • chlorogenic acid is beneficial for the relief of epileptic seizures, which is beneficial to the control and regulation of GABA and blood ketone during seizures, and is beneficial to the epileptic seizure state and the onset of refractory temporal lobe epilepsy, not limited to these. attack.
  • Figure 1 is a graph showing changes in body weight of rats in each group of Example 1 of the present invention.
  • Figure 2 is a graph showing changes in the blood ketone content of each group of rats of Example 1 of the present invention.
  • Figure 3 is a graph showing the expression of HMGCS2 gene in the kidneys of the young rats of Example 2 of the present invention.
  • Figure 4 is a result of Western Blot electrophoresis of the expression of HMGCS2 protein in the kidneys of the young rats of Example 2 of the present invention
  • Fig. 5 is a graph showing the results of optical density analysis of the expression of HMGCS2 protein in the kidneys of the young rats of Example 2 of the present invention.
  • Example 1 In vivo pharmacodynamic study of chlorogenic acid in the treatment of persistent epileptic seizures induced by pilocarpine hydrochloride
  • Chlorogenic acid (Sichuan Jiuzhang Biotechnology Co., Ltd.), Topiramate (Tuotai, Xi'an Yangsen), Potassium Chloride (AR, China Pharmaceutical Group Shanghai Reagent Company), Pilocarpine Hydrochloride (SIGMA), Ethylenediaminetetraacetic Acid Disodium (SIGMA), a rat blood ketone ELISA test kit (Biyuntian).
  • the SD rats used in the experiment were intraperitoneally injected with potassium chloride at a dose of 3 meq/kg. After 18 hours, freshly prepared pilocarpine hydrochloride was intraperitoneally injected at a dose of 30 mg/kg. All rats injected with pilocarpine developed a tonic-clonic seizure status (SE) within 30 min, and 30 min later, the model rats were intraperitoneally injected with scopolamine at a dose of 1 mg/kg to antagonize Its peripheral cholinergic response.
  • SE tonic-clonic seizure status
  • Rats in each group were fed according to the standard feeding method. The experiment was carried out for 4 weeks. During the 4 weeks, the body weight of each group was measured and recorded daily, and one week was used as a unit to calculate the rats of each group. The average weight.
  • the silent period of each group of epileptic rats (interval from SE to the first spontaneous recurrent episode) and the average number of weekly spontaneous recurrent episodes (SRS) (28 h observed weekly, 4 h per day).
  • the duration of the experiment was 4 weeks.
  • the day of the experimental modeling was set to day 0, and blood was taken from each group on the 0th, 7th, 14th, 21st and 28th day of the experiment, and the blood was placed in the disodium edetate.
  • the washed test tubes are numbered separately and stored in a -70 ° C refrigerator for later use. After collecting 5 blood samples, all samples were slowly thawed, centrifuged at 2000 g/min for 15 min, and the supernatant was taken.
  • the blood ketone body content of the rat was determined using a rat ketone body detection ELISA kit.
  • the silent period (since SE to SRS interval) and the average number of weekly SRS (28 hours observed per week) in each group of epilepsy rats were shown.
  • the number of SRS in the SE model control group was significantly higher than that in the other treatment groups.
  • the number of SRS episodes in the TMP-treated epileptic rats was significantly lower than that in the SE model control group (*p ⁇ 0.05).
  • the number of SRS in the chlorogenic acid treatment group was also lower than that in the SE control group. Among them, the SRS frequency of the middle and high dose chlorogenic acid treatment group decreased to a large extent, and there was no statistical difference between the value and the TMP treatment group. p>0.05).
  • the silent period of each group of epileptic rats and the average number of SRS per week (28h) are shown in Table 2:
  • the blood ketone content of each group of rats was detected by using a rat blood ketone ELISA test kit.
  • the experimental results are shown in Table 3.
  • the blood ketone content of the rats in the high, medium and low dose chlorogenic acid treatment group increased, and the blood ketone content of the rats in the high dose chlorogenic acid treatment group.
  • the trend of blood ketone content in each group of rats is shown in Figure 2.
  • a model of continuous epilepsy in rats was established by intraperitoneal injection of pilocarpine hydrochloride, and a broad-spectrum antiepileptic drug topiramate was used as a positive therapeutic drug to compare the pharmacodynamics of chlorogenic acid as an antiepileptic drug.
  • the results of the experiment showed that high, medium and low doses of chlorogenic acid could reduce the number of SRS in epileptic rats. Among them, medium and high dose group of chlorogenic acid There was no significant difference in the number of SRS between the treatment group and the topiramate treatment group (p>0.05). In the chlorogenic acid treatment group, the weight gain trend was enhanced.
  • chlorogenic acid has a certain therapeutic effect on the episode of epilepsy, can significantly improve the symptoms of the disease, does not affect the growth of model rats, and shows good efficacy.
  • Example 2 Effect of chlorogenic acid on various biochemical indicators of kainic acid-induced refractory temporal lobe epilepsy
  • Chlorogenic acid (freeze-dried powder injection, Sichuan Jiuzhang Biotechnology Co., Ltd.), topiramate (tope, Xi'an Janssen), kaimic acid (SIGMA), gamma-aminobutyric acid (GABA) standard, ethylenediaminetetraacetic acid Disodium (SIGMA), UV spectrophotometer (Shimadzu), fluorescence real-time quantitative PCR instrument (ABI), electrophoresis tank (Beijing Junyi Oriental Electrophoresis Equipment Co., Ltd.), total RNA extraction kit (Tiangen Biochemical Technology Co., Ltd., TIANScript cDNA First Chain Synthesis Kit (Tiangen Biochemical Technology Co., Ltd.).
  • the Wistar rats used in the experiment were intraperitoneally injected with kainate acid at a dose of 1 mg/kg.
  • the grading criteria for seizures in experimental young rats were as follows: grade I, facial sputum, including blinking, moving, rhythmic chewing, etc. II Grade, grade I plus rhythm nod; grade III, grade II plus forelimb clump; grade IV, grade III plus hind limbs standing; grade V, grade IV plus falls; grade VI, rushing screaming; VII, tonic attack). Seven young rats died in the modeling were removed, and the remaining young rats were randomly divided into three groups of 11 each.
  • Topiramate (TPM) was used as a positive treatment group, and model rats injected with physiological saline were used as a model control group.
  • NC normal control group
  • the day of modeling was taken as the 0th day. From the first day, the behavior of the young rats was observed for 4 hours every day for 28 hours, and the convulsions of each group were recorded in detail. The total number of times and the specific performance at the time of the attack.
  • GABA ⁇ -aminobutyric acid
  • the filter paper is colored, dried, and the color point is cut, and immersed in 85% ethanol for 40 min, and the absorption value is detected by an ultraviolet spectrophotometer at a wavelength of 505 nm, and the GABA content is calculated according to the concentration of the standard sample.
  • the young rats were sacrificed and the kidneys were dissected and grouped.
  • the kidneys of each group were cut and homogenized and divided into three parts: A, B and C.
  • the samples from groups B and C were frozen. Store in a -70 ° C refrigerator.
  • a tissue homogenate was taken, and 350 ⁇ l of lysate RL pre-added with ⁇ -mercaptoethanol was added thereto, and allowed to stand for 5 minutes.
  • the first strand cDNA is synthesized by using the cDNA first strand synthesis kit and the mRNA solution extracted by the above steps.
  • the specific reverse transcription process was carried out according to the instructions, and the obtained first strand of cDNA was stored at -20 ° C for storage and set aside.
  • the combination of SYBER GREEN fluorescent dye and double-stranded DNA produces strong fluorescence. By detecting and recording the final fluorescence intensity, the total amount of DNA produced can be obtained.
  • the fluorescent dye, the cDNA product synthesized in (1) step (2), the HMGCS2 primer (upstream primer: GTATGGGCTTCTGTTCG, the downstream primer: GGCGTTGGTGGTATCTA) were uniformly mixed and then subjected to RT-PCR. The system was replaced with RNase-free water.
  • the cDNA products group was an NTC control. Each sample was set to a relative value of the ⁇ -actin primer set for relative quantification.
  • the protein sample is made into the same concentration, added to the sample buffer, and boiled for 5 minutes;
  • GABA ⁇ -aminobutyric acid
  • ⁇ -actin was used as the internal reference gene, and the expression of HMGCS2 gene relative to ⁇ -actin was used as the final statistical value.
  • the results obtained showed that HMGCS2 in the kidney tissue of the young model rats of the model control group (EP group).
  • the gene expression level was significantly lower than that of the normal group, and the down-regulation of HMGCS2 gene expression in the model of epilepsy was part of its pathological features.
  • the expression level of HMGCS2 gene was significantly up-regulated, and there was a significant difference between the model group and the model group (p ⁇ 0.05).
  • the young rats of the positive control drug TMP treatment group The level of HMGCS2 gene in kidney tissue also increased to some extent, compared with the EP group, there was a significant difference (P ⁇ 0.05), but there was a significant difference between the normal control group and the normal control group (p ⁇ 0.05).
  • Figure 3 shows.
  • the HMGCS2 protein in the kidneys of each group was detected by Western Blot.
  • the results are shown in Figure 4 (Western Blot results): HMGCS2 protein expression in the model control group (EP group) and the normal group control group Compared to it, it is obviously weaker.
  • the expression of HMGCS2 protein in the kidney of the chlorogenic acid treatment group was enhanced to some extent compared with the EP group.
  • the expression of HMGCS2 protein in the kidney of the TMP-treated group also increased to some extent.
  • the results of optical density analysis of the protein bands are shown in Figure 5 (optical density analysis of protein content in the kidneys of young rats): the expression of HMGCS2 protein in the model group was significantly lower than that in the other groups, with the remaining groups. There was a significant difference between the normal control group, the TMP treatment group, and the chlorogenic acid treatment group, and there was no statistical difference in HMGCS2 protein expression.
  • chlorogenic acid can significantly improve the behavioral characteristics of the epilepsy model group, and significantly reduce the number of seizures.
  • chlorogenic acid can effectively enhance the expression of HMGCS2 gene and its corresponding HMGCS2 protein.
  • the key catalytic enzymes for ketone body synthesis are consistent with the experimental results of chlorogenic acid in Example 1 which can increase the blood ketone content of epileptic mice.
  • chlorogenic acid can enhance the content of inhibitory neurotransmitter GABA in rat brain tissue.
  • chlorogenic acid can alleviate epileptic seizures, improve signs and biochemical indicators of epilepsy, and have therapeutic effects on refractory temporal lobe epilepsy, and not limited to the treatment of refractory temporal lobe epilepsy.
  • the chlorogenic acid raw material used in the present embodiment was obtained by extracting and purifying from the leaves of Eucommia ulmoides, and the purity was 98.82%.
  • the chlorogenic acid used in the present example was obtained by extracting and purifying from honeysuckle, and the purity was 98.25%.
  • the chlorogenic acid used in the present example was extracted and purified from the burdock leaves, and the purity was 99.04%.
  • the chlorogenic acid used in the present example was obtained by extracting and purifying from honeysuckle, and the purity was 98.37%.
  • a chlorogenic acid tablet is prepared by a wet granule tableting method.
  • (1) Prepare water-soluble povidone K30 according to the prescription (2) After the prescription amount of chlorogenic acid, starch and dextrin are uniformly mixed, the povidone K30 aqueous solution is added, and the mixture is uniformly stirred to form a soft material; (3) the prepared soft material is conventionally wet. The granulation operation procedure, sieving, drying and granulating to obtain granules of uniform size; (4) mixing the prepared granules with magnesium stearate and then compressing the tablets to form 1000 tablets, each containing Chlorogenic acid 100mg.
  • the chlorogenic acid used in the present example was extracted and purified from the burdock leaves, and the purity was 98.37%.
  • each capsule contains 50mg 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 98.63%.
  • Povidone K30 was taken and water for injection was added to prepare a solution. After the prescription amount of chlorogenic acid, mannitol and lactose 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 1000 bags of granules, and each bag of granules contained 600 mg of chlorogenic acid.
  • the chlorogenic acid raw material used in the present embodiment was extracted and purified from Eucommia ulmoides leaves, and the purity was 99.52%.
  • 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 60mg of chlorogenic acid.

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Abstract

La présente invention concerne une utilisation de l'acide chlorogénique dans la préparation de médicaments destinés au traitement de l'épilepsie. L'acide chlorogénique contribue à soulager une crise d'épilepsie.
PCT/CN2016/072766 2015-02-13 2016-01-29 Utilisation de l'acide chlorogénique dans la préparation de médicaments destinés au traitement de l'épilepsie Ceased WO2016127832A1 (fr)

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CN109182488A (zh) * 2018-08-14 2019-01-11 深圳大学 Hmgcs2作为慢性肾脏疾病肾脏纤维化治疗的新靶点

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BRANCO, C.D. S. ET AL.: "Anticonvulsant Neuroprotective and Behavioral Effects of Organic and Conventional Yerba Mate (Ilex Paraguariensis St. Hill.) on Pentylenetetrazol-Induced Seizures in Wistar Rats", BRAIN RESEARCH BULLETIN, vol. 92, 24 December 2012 (2012-12-24) *

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