WO2018068565A1 - Application of albiflorin in production of products for improving function of melatonin system - Google Patents
Application of albiflorin in production of products for improving function of melatonin system Download PDFInfo
- Publication number
- WO2018068565A1 WO2018068565A1 PCT/CN2017/095985 CN2017095985W WO2018068565A1 WO 2018068565 A1 WO2018068565 A1 WO 2018068565A1 CN 2017095985 W CN2017095985 W CN 2017095985W WO 2018068565 A1 WO2018068565 A1 WO 2018068565A1
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- WO
- WIPO (PCT)
- Prior art keywords
- melatonin
- disease
- paeoniflorin
- improving
- function
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Images
Classifications
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- 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
- 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
- A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the invention belongs to the field of medicine, relates to the use of paeoniflorin (Albiflorin), and more particularly to the use of paeoniflorin in the preparation of a product for improving the function of the melatonin system, in particular, it is prepared for prevention and/or treatment.
- paeoniflorin Albiflorin
- Melatonin N-acetyl-5-methoxytryptamine
- Melatonin is a hormone mainly synthesized and secreted by the pineal gland, and is mainly synthesized by tryptophan and S-adenosylmethionine.
- Melatonin regulates mammalian circadian rhythms and reproductive functions, and is a lipophilic hormone that is widely distributed in the nervous system, blood, and surrounding tissues of mammals. Melatonin exerts its biological effects by interacting with specific melatonin receptors.
- the circadian rhythm is regulated by receptors present in the suprachiasmatic nucleus, and natural sleep is brought about by hypothermia or by regulating nerve and endocrine functions.
- the secretion of melatonin is inhibited by nighttime illumination, which is the cause of circadian rhythm disorders or accompanying sleep disorders.
- the secretion of melatonin decreases with ageing and is the main cause of sleep disorders in the elderly.
- melatonin has a wide range of effects on the body, including biological rhythm, hormone secretion, and neuro-endocrine- Immune system regulation, stress response, aging process, tumorigenesis, as well as free radical damage, elevated blood sugar, sedation, sleep, anti-inflammatory, analgesic and many other aspects.
- melatonin has anti-cancer functions, and many recent studies have reported that melatonin can inhibit the growth and proliferation of a variety of tumor cells including breast cancer, ovarian cancer, endometrial cancer, melanoma, prostate tumors, and intestinal tumors. .
- Melatonin is in mental disorders (bipolar, depression and anxiety disorders, schizophrenia, epilepsy and seizures), neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Treatment of muscle sclerosis) and neuroendocrine disorders (peptic ulcers, psoriasis) may be beneficial.
- PD Parkinson's disease
- melatonin has significant neuroprotective and anti-inflammatory functions and can be used as a neuroprotective drug after stroke.
- the neuroprotective effect of melatonin is believed to be achieved through its antioxidant and free radical scavenging functions.
- the object of the present invention is to provide a new use of bismuth lactone (Albiflorin) as a new product for improving the function of melatonin system, which can simultaneously promote endogenous melatonin in view of the deficiencies of the prior art.
- Secreting increasing the concentration of melatonin receptors in the body and/or increasing the activity of melatonin receptors in the organism, and thus can be used to prevent and/or treat sub-health states caused by melatonin system dysfunction and/or disease.
- the present invention also provides a method of improving the function of a melatonin system in a living body.
- Paeoniflorin a product that improves the function of the melatonin system, can be used to prepare drugs, foods, health supplements, food additives or nutritional supplements for the prevention and/or treatment of sub-health states, diseases caused by melatonin system dysfunction.
- the sub-health state caused by dysfunction of the melatonin system is selected from one or more of a biological rhythm disorder sleep disorder, an elderly sleep disorder, an affective disorder, a cognitive dysfunction, and an immune system dysfunction, and the disease is selected from insomnia.
- Albiflorin is a monoterpenoid compound with a molecular formula of C 23 H 28 O 11 and a molecular weight of 480.46.
- the molecular structure is as shown in the following formula. It is a natural active substance derived from the genus Ranunculaceae ( Paeonia lactiflora Pall) or the root of Paeonia veitchii Lynch, the root of P. suffrsticosa Andrz.
- the pharmaceutically acceptable salt of the compound of the formula (I) may be selected from the group consisting of citrate, hydrochloride, sulfate, malate, tartrate, citrate and phosphoric acid. One or more of the salts.
- the present invention discloses a paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract comprising paeoniflorin or a pharmaceutically acceptable salt thereof as an endogenous melatonin secretion promoter and/or melatonin
- the receptor agonist can improve the function of the human melatonin system by promoting endogenous melatonin secretion and increasing the concentration and activity of the melatonin receptor MT1; the human melatonin system function promoting agent paeoni lactone of the present invention Glycosides or pharmaceutically acceptable salts thereof, or extracts comprising paeoniflorin or a pharmaceutically acceptable salt thereof, can promote dopamine, which is closely related to biorhythm regulation and sleep, by increasing serotonin content in rat hippocampus, Secretion of melatonin and melatonin receptors, improve and treat sub-health states and diseases caused by melatonin system dysfunction, including biorhythm disorder sleep disorders, senile sleep disorders, cognitive
- the present invention discloses a paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract comprising paeoniflorin or a pharmaceutically acceptable salt thereof, by modulating N-acetyl serotonin-O-methyltransferase (ASMT) promotes endogenous melatonin secretion and affects the function of the melatonin system by increasing the activity and content of melatonin receptor (MT1).
- ASMT N-acetyl serotonin-O-methyltransferase
- the present invention provides a use of a paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract comprising a paeoniflorin or a pharmaceutically acceptable salt thereof, for the manufacture of a product for improving the function of a melatonin system ;
- the product for improving the function of the melatonin system is an endogenous melatonin secretion promoter and/or a melatonin receptor agonist, wherein the melatonin receptor agonist enhances melanin in vivo The concentration of the receptor and/or increase the activity of the melatonin receptor in the organism;
- the product that improves the function of the melatonin system is provided in the form of a drug, food, health supplement, food additive or nutritional supplement.
- the melatonin system function is to prevent and/or treat a sub-health state and/or disease caused by melatonin system dysfunction;
- the sub-health state is selected from one or more of, but not limited to, one of a biological rhythm disorder sleep disorder, an elderly sleep disorder, an affective disorder, a cognitive dysfunction, and an immune system dysfunction.
- the disease is selected from one or more of insomnia, depression, anxiety, Alzheimer's disease, and Parkinson's disease, but is not limited to these symptoms.
- the invention provides a method for improving the function of a melatonin system, the method comprising administering to a subject an effective amount of a paeoniflorin or a pharmaceutically acceptable salt thereof, or comprising a peony An extract of a lactone or a pharmaceutically acceptable salt thereof;
- said improving melatonin system functions to promote endogenous melatonin secretion and/or activate melatonin receptor, wherein said activation of melatonin receptor is to increase melatonin receptor concentration and / Or increase the activity of melatonin receptors.
- the melatonin system function is to prevent and/or treat a sub-health state and/or disease caused by melatonin system dysfunction;
- the sub-health state is selected from one or more of a biological rhythm disorder sleep disorder, an elderly sleep disorder, an affective disorder, a cognitive dysfunction, and an immune system dysfunction; but is not limited to these symptoms.
- the disease is selected from one or more of insomnia, depression, anxiety, Alzheimer's disease, and Parkinson's disease, but is not limited to these symptoms.
- the present invention provides a composition for improving the function of a melatonin system comprising a paeoniflorin or a pharmaceutically acceptable salt thereof, or a paeoni lactone or a pharmaceutically acceptable thereof Salt extract;
- said improving melatonin system functions to promote endogenous melatonin secretion and/or activate melatonin receptor, wherein said activation of melatonin receptor is to increase melatonin receptor concentration and / Or increase the activity of melatonin receptors.
- the composition for improving the function of the melatonin system is a medicine, a food, a health supplement, a food additive or a nutritional supplement.
- the melatonin system function is to prevent and/or treat a sub-health state and/or disease caused by melatonin system dysfunction;
- the sub-health state is selected from one or more of, but not limited to, one of a biological rhythm disorder sleep disorder, an elderly sleep disorder, an affective disorder, a cognitive dysfunction, and an immune system dysfunction.
- the disease is selected from one or more of insomnia, depression, anxiety, Alzheimer's disease, and Parkinson's disease, but is not limited to these symptoms.
- the present invention provides a paeoniflorin or a pharmaceutically acceptable salt thereof for improving the function of a melatonin system, or an extract comprising a paeoniflorin or a pharmaceutically acceptable salt thereof;
- said improving melatonin system functions to promote endogenous melatonin secretion and/or activate melatonin receptor, wherein said activation of melatonin receptor is to increase melatonin receptor concentration and / Or increase the activity of melatonin receptors.
- said improving the melatonin system function is to prevent and/or treat a sub-health state and/or disease caused by melatonin system dysfunction;
- the sub-health state is selected from the group consisting of a biological rhythm disorder sleep disorder, an elderly sleep disorder, One or more of affective disorder, cognitive dysfunction, and immune system dysfunction, but are not limited to these symptoms.
- the disease is selected from one or more of insomnia, depression, anxiety, Alzheimer's disease, and Parkinson's disease, but is not limited to these symptoms.
- the present invention promotes human melatonin-melatonin receptor by a multi-target multi-target by a paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof
- the present invention has the following advantages:
- the present invention promotes endogenous melatonin secretion and enhances melatonin system function by activating N-acetyl serotonin-O-methyltransferase (ASMT). Therefore, the present invention compensates for the defects and deficiencies in the regulation of the function of the endogenous melatonin system by the prior art using exogenous melatonin, and avoids the possible tolerance of long-term ingestion of exogenous melatonin. Defects such as dependence and efficacy instability.
- ASMT N-acetyl serotonin-O-methyltransferase
- the invention not only promotes the secretion of endogenous melatonin, but also increases the activity and content of melatonin receptor (MT1). Therefore, the present invention compensates for the inability of the exogenous melatonin to improve melatonin receptor secretion dysfunction by regulating the multi-target multi-target of the melatonin system and enhancing the function of the human melatonin system. Defects and deficiencies.
- the invention has the dual functions of anti-depression and improving sleep, and compensates for the side effects of SSRI affecting sleep, such as Baiyou solution of the first-line antidepressant drugs, and increases the patient's compliance and tolerance to drugs.
- the present invention increases the function of the melatonin system, increases slow wave sleep (SWS), improves the quality of deep sleep, improves sleep disorders, and does not produce benzodiazepines, barbituric sleeping pills, addiction, influence recognition Know the side effects such as function.
- SWS slow wave sleep
- Figure 1 shows that the paeoniflorin of the present invention improves depression by down-regulating kynuric acid and up-regulating the serotonin-melatonin metabolism pathway.
- Fig. 2 shows that the paeoniflorin of the present invention regulates biological rhythm, improves depression, and improves sleep by improving dopamine and melatonin.
- Figure 3 is a graph showing the effect of the paeoniflorin on the content of the rate-limiting enzyme N-acetyl serotonin-O-methyltransferase (ASMT) in the melatonin synthesis pathway in the hippocampus of chronically stressed rats.
- ASMT N-acetyl serotonin-O-methyltransferase
- Figure 4 is a graph showing the effect of paeoniflorin on the content of melatonin receptor (MT1) in the hippocampus of chronically stressed rats.
- Example 1 Effect of paeoniflorin on melatonin system function in CUMS rats
- Paeoniflorin can significantly increase the secretion of dopamine and melatonin in the hippocampus of chronic stress rats, which is closely related to biological rhythm and sleep, and thus play a role in improving sleep, see Figure 2.
- the final step in the synthesis of melatonin metabolism is the conversion of N-acetyl serotonin to melatonin by methylation.
- This step is performed by N-acetyl serotonin-O-methyltransferase (ASMT), so ASMT is the rate-limiting enzyme in the synthesis of melatonin in humans.
- ASMT N-acetyl serotonin-O-methyltransferase
- the content of ASMT in hippocampus of rats in chronic stress group (model group) was decreased (P ⁇ 0.01), and paeoniflorin could significantly increase the content of ASMT (P ⁇ 0.01), and restore and promote the synthesis of endogenous melatonin. See Table 1 below and Figure 3, wherein Figure 3 uses the Western blot method to determine the amount of N-acetyl serotonin-O-methyltransferase.
- paeoniflorin has a function of promoting endogenous melatonin and increasing secretion of melatonin receptor through a new generation of targeted metabolomics research; according to this function, paeoniflorin can be used And extracts and compositions containing paeoniflorin are developed into foods, health supplements, food additives or nutritional supplements capable of regulating and improving endogenous melatonin, prepared for antidepressant, anti-aging, improving sleep and improving Cognitive function, drugs that delay and prevent Alzheimer's disease.
- Example 3 Effect of paeoniflorin on learning and memory function in mice with scopolamine dementia
- the water maze test was performed to find the swimming time (ie, escape latency) and swimming distance of the mouse as the observation index after entering the water.
- the experimental results showed that compared with the model group, the escape latency of the paeoniflorin group was significantly shorter on the 4th and 5th day (P ⁇ 0.05), as shown in Table 5; compared with the model group, the paeoniflorin group 4, 5 The swimming distance of the day was shortened (P ⁇ 0.05), see Table 6.
- the results of this experiment indicate that paeoniflorin can significantly improve the learning and memory ability of mice with dementia induced by scopolamine.
- the test group animals were given three doses of paeoniflorin, and the control group was given a sleep phenomenon after the same volume of solvent. Sleep disappears as an indicator of righting reflex. When the mouse is placed in the back position, it can immediately correct the position. If it can't be corrected for more than 30 seconds, it means that the righting reflex disappears and goes to sleep. The recovery of righting reflex was the awakening of the animal, and the righting reflex disappeared until the recovery time was the animal's sleep time. The number of sleeping animals and the sleep time of the blank control group and the paeoniflorin group were recorded. The experimental results are shown in Table 7:
- the paeoniflorin has no direct sleep effect on experimental animals.
- Table 8 suggests that paeoniflorin, which is higher than the 14 mg/kg bw dose, can prolong the threshold time of pentobarbital sodium-induced sleep time in mice, and is significantly different from the sleep time of the control group (p ⁇ 0.05).
- the animals were given a blank control and different concentrations of paeoniflorin at the last 10 minutes before the peak effect.
- the animals in each group were intraperitoneally injected with the maximum subthreshold hypnotic dose of pentobarbital sodium (30 mg/kg BW), and the number of sleeping animals in 30 minutes was recorded. The righting reflection disappears for more than 1 minute).
- the experiment should be carried out in a quiet environment of 24-25 °C.
- Table 9 The experimental results are shown in Table 9:
- Table 9 shows that the sleep incidence of the mice in each dose group caused by paeoniflorin to the subthreshold dose of pentobarbital was higher than that of the control group, and there was a significant difference compared with the control group (p ⁇ 0.01).
- paeoniflorin can shorten the sleep latency of experimental mice induced by barbital sodium.
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Abstract
An application of albiflorin or a pharmaceutically-acceptable salt thereof in production of products for improving the function of the human melatonin system. Albiflorin or a pharmaceutically-acceptable salt thereof, as an endogenous melatonin secretion promoter and a melatonin receptor agonist, can be used in production of medicine, foods, health supplements, food additives, or nutritional supplements that ameliorates and treats sub-health statuses and/or diseases caused by melatonin system dysfunction; the sub-health statuses are one or more of circadian rhythm sleep disorders, senile dyssomnia, affective disorders, cognitive disorders, and immune system disorders; the diseases are one or more of depression, anxiety, Alzheimer's disease, and Parkinson's disease.
Description
本发明属于医药领域，涉及芍药内酯苷(Albiflorin)的用途，更具体涉及芍药内酯苷在制备改善褪黑素系统功能的产品中的用途，特别是其在制备用于预防和/或治疗由褪黑素系统功能障碍引起的亚健康状态和/或疾病的药物、食品、保健品、食品添加剂或营养补充剂等中的用途。The invention belongs to the field of medicine, relates to the use of paeoniflorin (Albiflorin), and more particularly to the use of paeoniflorin in the preparation of a product for improving the function of the melatonin system, in particular, it is prepared for prevention and/or treatment. Use in medicines, foods, health products, food additives or nutritional supplements, etc., of sub-health states and/or diseases caused by melatonin system dysfunction.
褪黑素(N-乙酰-5-甲氧基色胺)是主要由松果腺合成和分泌的激素，主要通过色氨酸和S-腺苷甲硫氨酸合成。褪黑素能够调节哺乳动物昼夜节律和生殖功能，它属于在哺乳动物的神经系统、血液和周围组织中广泛分布的亲脂性激素。褪黑素通过与特定的褪黑素受体相互作用来发挥它的生物学效应。当褪黑素被分泌后，通过存在于视交叉上核的受体而调节昼夜节律，并且通过降体温作用或通过调节神经、内分泌功能而带来自然的睡眠。褪黑素的分泌受到夜间照明的抑制，成为昼夜节律紊乱或与其相伴的睡眠障碍的原因。此外，褪黑素的分泌随着老年化而减少，是老年睡眠障碍的主要原因。Melatonin (N-acetyl-5-methoxytryptamine) is a hormone mainly synthesized and secreted by the pineal gland, and is mainly synthesized by tryptophan and S-adenosylmethionine. Melatonin regulates mammalian circadian rhythms and reproductive functions, and is a lipophilic hormone that is widely distributed in the nervous system, blood, and surrounding tissues of mammals. Melatonin exerts its biological effects by interacting with specific melatonin receptors. When melatonin is secreted, the circadian rhythm is regulated by receptors present in the suprachiasmatic nucleus, and natural sleep is brought about by hypothermia or by regulating nerve and endocrine functions. The secretion of melatonin is inhibited by nighttime illumination, which is the cause of circadian rhythm disorders or accompanying sleep disorders. In addition, the secretion of melatonin decreases with ageing and is the main cause of sleep disorders in the elderly.
近十几年来，人们对褪黑素的分泌、调节、作用方式及机制进行了大量的基础研究，发现褪黑素对机体的作用极其广泛，涉及领域包括生物节律、激素分泌、神经-内分泌-免疫系统调节、应激反应、衰老过程、肿瘤发生，以及自由基损伤、升高血糖、镇静、睡眠、抗炎、镇痛等多个方面。In the past ten years, people have carried out a lot of basic research on the secretion, regulation, action mode and mechanism of melatonin. It is found that melatonin has a wide range of effects on the body, including biological rhythm, hormone secretion, and neuro-endocrine- Immune system regulation, stress response, aging process, tumorigenesis, as well as free radical damage, elevated blood sugar, sedation, sleep, anti-inflammatory, analgesic and many other aspects.
褪黑素具有抗癌功能，许多近期研究报道了褪黑素能够抑制多种肿瘤细胞(包括乳腺癌、卵巢癌、子宫内膜癌、黑素瘤、前列腺肿瘤和肠肿瘤等)的生长和增殖。Melatonin has anti-cancer functions, and many recent studies have reported that melatonin can inhibit the growth and proliferation of a variety of tumor cells including breast cancer, ovarian cancer, endometrial cancer, melanoma, prostate tumors, and intestinal tumors. .
褪黑素在精神失调(双极的、抑郁和忧虑失调、精神分裂症、癫痫和癫痫发作)、神经变性疾病(Parkinson’s病、阿尔茨海默氏病、Huntington’s病、肌萎缩性侧索硬化、肌肉硬化)和神经内分泌失调(消化性溃疡、银屑病)的治疗方面可能是有益的。新近的研究提供了实验证据，支持褪黑素可能是最有希望成为治疗帕金森症(PD)的药物。Melatonin is in mental disorders (bipolar, depression and anxiety disorders, schizophrenia, epilepsy and seizures), neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Treatment of muscle sclerosis) and neuroendocrine disorders (peptic ulcers, psoriasis) may be beneficial. Recent research provides experimental evidence that support melatonin may be the most promising drug for the treatment of Parkinson's disease (PD).
病灶脑缺血动物模型实验证明，褪黑素具有显著的神经保护和抗炎功能，可以作为中风后进行神经保护的药物。褪黑素的神经保护作用，被认为是通过它的抗氧化和清除自由基的功能来实现的。Animal models of focal cerebral ischemia have demonstrated that melatonin has significant neuroprotective and anti-inflammatory functions and can be used as a neuroprotective drug after stroke. The neuroprotective effect of melatonin is believed to be achieved through its antioxidant and free radical scavenging functions.
用化学方法在体外合成褪黑素已经实现，部分中草药和食品中也含有褪黑素，使用这些外源性褪黑素补充体内褪黑素分泌的不足和匮乏，可以调整
和恢复人体褪黑素系统的功能，可以调节人体的昼夜节律，可以改善和增强慢波深度睡眠(SWS)，可以调整机体的功能状态，保护神经系统，提高生活质量，延缓衰老和提高认知功能。现实中，体外合成的褪黑素已经作为改善睡眠的保健食品上市销售。The chemical synthesis of melatonin in vitro has been achieved, and some Chinese herbal medicines and foods also contain melatonin. The use of these exogenous melatonin to supplement the deficiency and deficiency of melatonin secretion in the body can be adjusted.
And restore the function of the human melatonin system, can adjust the body's circadian rhythm, can improve and enhance slow wave deep sleep (SWS), can adjust the body's functional state, protect the nervous system, improve the quality of life, delay aging and improve cognition Features. In reality, in vitro synthesized melatonin has been marketed as a health food for improving sleep.
但是，由于外源性褪黑素在体内的半衰期较短，机体单纯依靠补充外源性褪黑素的生物作用有限，而且长期大量摄入褪黑素会进一步降低机体内源性褪黑素的分泌。另外，褪黑素系统功能是褪黑素通过褪黑素受体相互作用完成的，对于褪黑素受体功能下调和分泌匮乏引起的系统功能受损，仅是补充外源性褪黑素并不能达到预期功效。因此，寻求既能促进内源性褪黑素分泌、又能改善褪黑素受体功能的药物、营养剂/保健食品，已经成为全球医药界研究的热点课题。However, due to the short half-life of exogenous melatonin in the body, the body's biological effects of supplementing exogenous melatonin alone are limited, and long-term high intake of melatonin will further reduce the body-derived melatonin. secretion. In addition, the melatonin system functions by melatonin through melatonin receptor interaction, impaired systemic function caused by melatonin receptor down-regulation and secretion deficiency, only supplementing exogenous melatonin Can not achieve the expected effect. Therefore, the search for drugs and nutrients/health foods that can promote endogenous melatonin secretion and improve melatonin receptor function has become a hot topic in the global medical research.
发明内容Summary of the invention
本发明的目的在于针对现有技术的不足，提供一种芍药内酯苷(Albiflorin)的新用途，其作为一种新的改善褪黑素系统功能的产品，能同时促进内源性褪黑素分泌、提高生物体内褪黑素受体的浓度和/或增加生物体内褪黑素受体的活性，因此可以用于预防和/或治疗由褪黑素系统功能障碍引起的亚健康状态和/或疾病。The object of the present invention is to provide a new use of bismuth lactone (Albiflorin) as a new product for improving the function of melatonin system, which can simultaneously promote endogenous melatonin in view of the deficiencies of the prior art. Secreting, increasing the concentration of melatonin receptors in the body and/or increasing the activity of melatonin receptors in the organism, and thus can be used to prevent and/or treat sub-health states caused by melatonin system dysfunction and/or disease.
本发明还提供了一种改善生物体内的褪黑素系统功能的方法。The present invention also provides a method of improving the function of a melatonin system in a living body.
芍药内酯苷作为改善褪黑素系统功能的产品，可以用于制备预防和/或治疗由褪黑素系统功能障碍引起的亚健康状态、疾病的药物、食品、保健品、食品添加剂或营养补充剂。这些因褪黑素系统功能障碍引起的亚健康状态选自生物节律紊乱性睡眠障碍、老年睡眠障碍、情感障碍、认知功能障碍和免疫系统功能障碍中的一种或多种，疾病选自失眠、抑郁症、焦虑症、阿尔茨海默症和帕金森症中的一种或多种。Paeoniflorin, a product that improves the function of the melatonin system, can be used to prepare drugs, foods, health supplements, food additives or nutritional supplements for the prevention and/or treatment of sub-health states, diseases caused by melatonin system dysfunction. Agent. The sub-health state caused by dysfunction of the melatonin system is selected from one or more of a biological rhythm disorder sleep disorder, an elderly sleep disorder, an affective disorder, a cognitive dysfunction, and an immune system dysfunction, and the disease is selected from insomnia. One or more of depression, anxiety, Alzheimer's, and Parkinson's disease.
芍药内酯苷(Albiflorin)为单萜类化合物，其分子式为C23H28O11，分子量为480.46，分子结构如下式所示，是一种天然活性物质，来源于毛莨科植物白芍(Paeonia lactiflora Pall)或川赤芍(Paeonia veitchii Lynch)的根、牡丹(P.suffrsticosa Andrz)的根。Albiflorin is a monoterpenoid compound with a molecular formula of C 23 H 28 O 11 and a molecular weight of 480.46. The molecular structure is as shown in the following formula. It is a natural active substance derived from the genus Ranunculaceae ( Paeonia lactiflora Pall) or the root of Paeonia veitchii Lynch, the root of P. suffrsticosa Andrz.
根据本发明提供的用途，其中，式(I)所示化合物的药学上可接受的盐可以选自枸橼酸盐、盐酸盐、硫酸盐、苹果酸盐、酒石酸盐、柠檬酸盐和磷酸盐中的一种或多种。According to the use provided by the present invention, the pharmaceutically acceptable salt of the compound of the formula (I) may be selected from the group consisting of citrate, hydrochloride, sulfate, malate, tartrate, citrate and phosphoric acid. One or more of the salts.
本发明披露了芍药内酯苷或其药学上可接受的盐，或者包含芍药内酯苷或其药学上可接受的盐的提取物作为内源性褪黑素分泌促进剂和/或褪黑素受体激动剂，可以通过促进内源性褪黑素分泌和增加褪黑素受体MT1的浓度及活性改善人体褪黑素系统的功能；本发明的人体褪黑素系统功能促进剂芍药内酯苷或其药学上可接受的盐，或者包含芍药内酯苷或其药学上可接受的盐的提取物可以通过增加大鼠海马中血清素含量，促进与生物节律调节和睡眠密切相关的多巴胺、褪黑素和褪黑素受体的分泌，改善和治疗由褪黑素系统功能障碍引起的人体亚健康状态和疾病，其中包括生物节律紊乱性睡眠障碍、老年睡眠障碍、认知功能障碍、免疫系统功能障碍、抑郁症、阿尔茨海默症和帕金森症等疾病，但不限于这些身体不适症状和疾病。The present invention discloses a paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract comprising paeoniflorin or a pharmaceutically acceptable salt thereof as an endogenous melatonin secretion promoter and/or melatonin The receptor agonist can improve the function of the human melatonin system by promoting endogenous melatonin secretion and increasing the concentration and activity of the melatonin receptor MT1; the human melatonin system function promoting agent paeoni lactone of the present invention Glycosides or pharmaceutically acceptable salts thereof, or extracts comprising paeoniflorin or a pharmaceutically acceptable salt thereof, can promote dopamine, which is closely related to biorhythm regulation and sleep, by increasing serotonin content in rat hippocampus, Secretion of melatonin and melatonin receptors, improve and treat sub-health states and diseases caused by melatonin system dysfunction, including biorhythm disorder sleep disorders, senile sleep disorders, cognitive dysfunction, immunity Systemic dysfunction, depression, Alzheimer's and Parkinson's disease, but not limited to these symptoms and diseases.
本发明披露了芍药内酯苷或其药学上可接受的盐，或者包含芍药内酯苷或其药学上可接受的盐的提取物，是通过调节N-乙酰血清素-O-甲基转移酶(ASMT)促进内源性褪黑素分泌，通过增加褪黑素受体(MT1)的活性和含量影响褪黑素系统的功能。The present invention discloses a paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract comprising paeoniflorin or a pharmaceutically acceptable salt thereof, by modulating N-acetyl serotonin-O-methyltransferase (ASMT) promotes endogenous melatonin secretion and affects the function of the melatonin system by increasing the activity and content of melatonin receptor (MT1).
一方面，本发明提供了芍药内酯苷或其药学上可接受的盐，或者包含芍药内酯苷或其药学上可接受的盐的提取物在制备改善褪黑素系统功能的产品中的用途；In one aspect, the present invention provides a use of a paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract comprising a paeoniflorin or a pharmaceutically acceptable salt thereof, for the manufacture of a product for improving the function of a melatonin system ;
优选地，所述改善褪黑素系统功能的产品为内源性褪黑素分泌促进剂和/或褪黑素受体激动剂，其中所述褪黑素受体激动剂提高生物体内褪黑素受体的浓度和/或增加生物体内褪黑素受体的活性；Preferably, the product for improving the function of the melatonin system is an endogenous melatonin secretion promoter and/or a melatonin receptor agonist, wherein the melatonin receptor agonist enhances melanin in vivo The concentration of the receptor and/or increase the activity of the melatonin receptor in the organism;
优选地，所述改善褪黑素系统功能的产品以选自药物、食品、保健品、食品添加剂或营养补充剂的形式提供。Preferably, the product that improves the function of the melatonin system is provided in the form of a drug, food, health supplement, food additive or nutritional supplement.
其中所述改善褪黑素系统功能为预防和/或治疗由褪黑素系统功能障碍引起的亚健康状态和/或疾病；Wherein the melatonin system function is to prevent and/or treat a sub-health state and/or disease caused by melatonin system dysfunction;
优选地，所述亚健康状态选自生物节律紊乱性睡眠障碍、老年睡眠障碍、情感障碍、认知功能障碍和免疫系统功能障碍中的一种或多种，但不限于这些症状。Preferably, the sub-health state is selected from one or more of, but not limited to, one of a biological rhythm disorder sleep disorder, an elderly sleep disorder, an affective disorder, a cognitive dysfunction, and an immune system dysfunction.
优选地，所述疾病选自失眠、抑郁症、焦虑症、阿尔茨海默症和帕金森症中的一种或多种，但不限于这些症状。Preferably, the disease is selected from one or more of insomnia, depression, anxiety, Alzheimer's disease, and Parkinson's disease, but is not limited to these symptoms.
另一方面，本发明提供了一种用于改善褪黑素系统功能的方法，所述方法包括给予对象有效量的芍药内酯苷或其药学上可接受的盐、或者包含芍药
内酯苷或其药学上可接受的盐的提取物；In another aspect, the invention provides a method for improving the function of a melatonin system, the method comprising administering to a subject an effective amount of a paeoniflorin or a pharmaceutically acceptable salt thereof, or comprising a peony
An extract of a lactone or a pharmaceutically acceptable salt thereof;
优选地，所述改善褪黑素系统功能为促进内源性褪黑素分泌和/或激活褪黑素受体，其中所述激活褪黑素受体为提高褪黑素受体的浓度和/或增加褪黑素受体的活性。Preferably, said improving melatonin system functions to promote endogenous melatonin secretion and/or activate melatonin receptor, wherein said activation of melatonin receptor is to increase melatonin receptor concentration and / Or increase the activity of melatonin receptors.
优选地，所述改善褪黑素系统功能为预防和/或治疗由褪黑素系统功能障碍引起的亚健康状态和/或疾病；Preferably, the melatonin system function is to prevent and/or treat a sub-health state and/or disease caused by melatonin system dysfunction;
优选地，所述亚健康状态选自生物节律紊乱性睡眠障碍、老年睡眠障碍、情感障碍、认知功能障碍和免疫系统功能障碍中的一种或多种；但不限于这些症状。Preferably, the sub-health state is selected from one or more of a biological rhythm disorder sleep disorder, an elderly sleep disorder, an affective disorder, a cognitive dysfunction, and an immune system dysfunction; but is not limited to these symptoms.
优选地，所述疾病选自失眠、抑郁症、焦虑症、阿尔茨海默症和帕金森症中的一种或多种，但不限于这些症状。Preferably, the disease is selected from one or more of insomnia, depression, anxiety, Alzheimer's disease, and Parkinson's disease, but is not limited to these symptoms.
再一方面，本发明提供了一种用于改善褪黑素系统功能的组合物，其包含芍药内酯苷或其药学上可接受的盐、或者包含芍药内酯苷或其药学上可接受的盐的提取物；In a further aspect, the present invention provides a composition for improving the function of a melatonin system comprising a paeoniflorin or a pharmaceutically acceptable salt thereof, or a paeoni lactone or a pharmaceutically acceptable thereof Salt extract;
优选地，所述改善褪黑素系统功能为促进内源性褪黑素分泌和/或激活褪黑素受体，其中所述激活褪黑素受体为提高褪黑素受体的浓度和/或增加褪黑素受体的活性。Preferably, said improving melatonin system functions to promote endogenous melatonin secretion and/or activate melatonin receptor, wherein said activation of melatonin receptor is to increase melatonin receptor concentration and / Or increase the activity of melatonin receptors.
优选地，所述用于改善褪黑素系统功能的组合物为药物、食品、保健品、食品添加剂或营养补充剂。Preferably, the composition for improving the function of the melatonin system is a medicine, a food, a health supplement, a food additive or a nutritional supplement.
优选地，所述改善褪黑素系统功能为预防和/或治疗由褪黑素系统功能障碍引起的亚健康状态和/或疾病；Preferably, the melatonin system function is to prevent and/or treat a sub-health state and/or disease caused by melatonin system dysfunction;
优选地，所述亚健康状态选自生物节律紊乱性睡眠障碍、老年睡眠障碍、情感障碍、认知功能障碍和免疫系统功能障碍中的一种或多种，但不限于这些症状。Preferably, the sub-health state is selected from one or more of, but not limited to, one of a biological rhythm disorder sleep disorder, an elderly sleep disorder, an affective disorder, a cognitive dysfunction, and an immune system dysfunction.
优选地，所述疾病选自失眠、抑郁症、焦虑症、阿尔茨海默症和帕金森症中的一种或多种，但不限于这些症状。Preferably, the disease is selected from one or more of insomnia, depression, anxiety, Alzheimer's disease, and Parkinson's disease, but is not limited to these symptoms.
在另一方面，本发明还提供了用于改善褪黑素系统功能的芍药内酯苷或其药学上可接受的盐、或者包含芍药内酯苷或其药学上可接受的盐的提取物；In another aspect, the present invention provides a paeoniflorin or a pharmaceutically acceptable salt thereof for improving the function of a melatonin system, or an extract comprising a paeoniflorin or a pharmaceutically acceptable salt thereof;
优选地，所述改善褪黑素系统功能为促进内源性褪黑素分泌和/或激活褪黑素受体，其中所述激活褪黑素受体为提高褪黑素受体的浓度和/或增加褪黑素受体的活性。Preferably, said improving melatonin system functions to promote endogenous melatonin secretion and/or activate melatonin receptor, wherein said activation of melatonin receptor is to increase melatonin receptor concentration and / Or increase the activity of melatonin receptors.
优选地，其中所述改善褪黑素系统功能为预防和/或治疗由褪黑素系统功能障碍引起的亚健康状态和/或疾病；Preferably wherein said improving the melatonin system function is to prevent and/or treat a sub-health state and/or disease caused by melatonin system dysfunction;
优选地，所述亚健康状态选自生物节律紊乱性睡眠障碍、老年睡眠障碍、
情感障碍、认知功能障碍和免疫系统功能障碍中的一种或多种，但不限于这些症状。Preferably, the sub-health state is selected from the group consisting of a biological rhythm disorder sleep disorder, an elderly sleep disorder,
One or more of affective disorder, cognitive dysfunction, and immune system dysfunction, but are not limited to these symptoms.
优选地，所述疾病选自失眠、抑郁症、焦虑症、阿尔茨海默症和帕金森症中的一种或多种，但不限于这些症状。Preferably, the disease is selected from one or more of insomnia, depression, anxiety, Alzheimer's disease, and Parkinson's disease, but is not limited to these symptoms.
本发明通过芍药内酯苷或其药学上可接受的盐，或者含芍药内酯苷或其药学上可接受的盐的提取物，全流程多靶点促进人体褪黑素-褪黑素受体的功能，用于防治因褪黑素系统功能障碍引起的亚健康状态和疾病。与现有人工合成的褪黑素，或是与现有的抗抑郁、改善睡眠的药物相比，本发明具有以下优点：The present invention promotes human melatonin-melatonin receptor by a multi-target multi-target by a paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof The function of preventing sub-health conditions and diseases caused by dysfunction of the melatonin system. Compared with the existing synthetic melatonin or the existing antidepressant and sleep improving drugs, the present invention has the following advantages:
1、本发明系通过激活N-乙酰血清素-O-甲基转移酶(ASMT)促进内源性褪黑素分泌、提高褪黑素系统功能。因此，本发明弥补了使用外源性褪黑素的现有技术调节内源性褪黑素系统功能的缺陷和不足，避免了长期大量摄入外源性褪黑素可能出现的耐受性、依赖性和功效不稳定性等缺陷。1. The present invention promotes endogenous melatonin secretion and enhances melatonin system function by activating N-acetyl serotonin-O-methyltransferase (ASMT). Therefore, the present invention compensates for the defects and deficiencies in the regulation of the function of the endogenous melatonin system by the prior art using exogenous melatonin, and avoids the possible tolerance of long-term ingestion of exogenous melatonin. Defects such as dependence and efficacy instability.
2、本发明既促进内源性褪黑素分泌，又可提高褪黑素受体(MT1)的活性和含量。因此，本发明系通过对褪黑素系统全通路多靶点的调节和提升人体褪黑素系统的功能，弥补了现有技术外源性褪黑素不能改善褪黑素受体分泌功能障碍的缺陷和不足。2. The invention not only promotes the secretion of endogenous melatonin, but also increases the activity and content of melatonin receptor (MT1). Therefore, the present invention compensates for the inability of the exogenous melatonin to improve melatonin receptor secretion dysfunction by regulating the multi-target multi-target of the melatonin system and enhancing the function of the human melatonin system. Defects and deficiencies.
3、本发明兼有抗抑郁和改善睡眠的双重功能，弥补了现有的一线抗抑郁药物百优解等SSRI影响睡眠的副作用，增加了患者对药物的依从性和耐受度。3. The invention has the dual functions of anti-depression and improving sleep, and compensates for the side effects of SSRI affecting sleep, such as Baiyou solution of the first-line antidepressant drugs, and increases the patient's compliance and tolerance to drugs.
4、本发明通过调节褪黑素系统功能，增加慢波睡眠(SWS)，提高深度睡眠质量，改善睡眠障碍，且不会产生苯二氮卓类、巴比妥类安眠药成瘾性、影响认知功能等副作用。4. The present invention increases the function of the melatonin system, increases slow wave sleep (SWS), improves the quality of deep sleep, improves sleep disorders, and does not produce benzodiazepines, barbituric sleeping pills, addiction, influence recognition Know the side effects such as function.
附图的简要说明BRIEF DESCRIPTION OF THE DRAWINGS
图1为本发明的芍药内酯苷通过下调犬尿酸、上调血清素-褪黑素代谢途径改善抑郁症。Figure 1 shows that the paeoniflorin of the present invention improves depression by down-regulating kynuric acid and up-regulating the serotonin-melatonin metabolism pathway.
图2为本发明的芍药内酯苷通过改善多巴胺、褪黑素调节生物节律，抗抑郁、改善睡眠。Fig. 2 shows that the paeoniflorin of the present invention regulates biological rhythm, improves depression, and improves sleep by improving dopamine and melatonin.
图3为本发明的芍药内酯苷对慢性应激大鼠海马区体内褪黑素合成途径中限速酶N-乙酰血清素-O-甲基转移酶(ASMT)含量的影响。Figure 3 is a graph showing the effect of the paeoniflorin on the content of the rate-limiting enzyme N-acetyl serotonin-O-methyltransferase (ASMT) in the melatonin synthesis pathway in the hippocampus of chronically stressed rats.
图4为本发明的芍药内酯苷对慢性应激大鼠海马区褪黑素受体(MT1)含量的影响。Figure 4 is a graph showing the effect of paeoniflorin on the content of melatonin receptor (MT1) in the hippocampus of chronically stressed rats.
实施发明的最佳方式The best way to implement the invention
下面结合具体实施案例，进一步阐释本发明。下述实施案例仅限于说明本发明在治疗抑郁症和提高认知功能方面的具体应用，不是用于限制本发明的应用范围。The present invention will be further explained below in conjunction with specific embodiments. The following examples are intended to illustrate the specific application of the present invention in the treatment of depression and in the enhancement of cognitive function, and are not intended to limit the scope of application of the present invention.
实施案例1：芍药内酯苷对CUMS大鼠褪黑素系统功能的影响Example 1: Effect of paeoniflorin on melatonin system function in CUMS rats
我们在利用新一代靶向代谢组学技术对芍药内酯苷抗应激、抗抑郁、改善睡眠和认知功能的作用机制研究中发现，慢性不可预见性温和应激模型(chronic unpredictable mild stress,CUMS)大鼠海马血清素、褪黑素、褪黑素受体、多巴胺分泌受到抑制，芍药内酯苷给药(7mg/kg)7天后：We have used a new generation of targeted metabolomics techniques to study the mechanism of anti-stress, anti-depression, sleep and cognitive function of paeoniflorin. Chronic unpredictable mild stress (chronic unpredictable mild stress, CUMS) Rat hippocampal serotonin, melatonin, melatonin receptor, and dopamine secretion were inhibited, and paeoniflorin was administered (7 mg/kg) for 7 days:
1.1慢性应激大鼠海马中犬尿酸和喹啉酸的含量显著降低，表明犬尿酸代谢途径下调，而海马中的血清素、褪黑素的含量显著增加，表明血清素、褪黑素代谢途径上调，见附图1。1.1 The content of uric acid and quinolinic acid in hippocampus of rats with chronic stress was significantly decreased, indicating that the uric acid metabolism pathway was down-regulated, while the content of serotonin and melatonin in hippocampus was significantly increased, indicating that serotonin and melatonin metabolism pathway Up, see Figure 1.
1.2芍药内酯苷能够显著增加慢性应激大鼠海马中与生物节律和睡眠密切相关的多巴胺、褪黑素分泌，进而起到改善睡眠的作用，见附图2。1.2 Paeoniflorin can significantly increase the secretion of dopamine and melatonin in the hippocampus of chronic stress rats, which is closely related to biological rhythm and sleep, and thus play a role in improving sleep, see Figure 2.
1.3褪黑素代谢合成的最后步骤是由N-乙酰血清素通过甲基化反应转化为褪黑素，这一步是由N-乙酰血清素-O-甲基转移酶(ASMT)完成的，因此，ASMT是人体内源性褪黑素合成的限速酶。慢性应激组(模型组)大鼠海马组织中ASMT的含量降低(P<0.01)，芍药内酯苷能够显著增加ASMT的含量(P<0.01)，恢复和促进内源性褪黑素的合成，见下表1和附图3，其中附图3采用蛋白质印记方法测定N-乙酰血清素-O-甲基转移酶的含量。1.3 The final step in the synthesis of melatonin metabolism is the conversion of N-acetyl serotonin to melatonin by methylation. This step is performed by N-acetyl serotonin-O-methyltransferase (ASMT), so ASMT is the rate-limiting enzyme in the synthesis of melatonin in humans. The content of ASMT in hippocampus of rats in chronic stress group (model group) was decreased (P<0.01), and paeoniflorin could significantly increase the content of ASMT (P<0.01), and restore and promote the synthesis of endogenous melatonin. See Table 1 below and Figure 3, wherein Figure 3 uses the Western blot method to determine the amount of N-acetyl serotonin-O-methyltransferase.
表1芍药内酯苷对大鼠海马组织ASMT的影响(Mean±SE)Table 1 Effect of paeoniflorin on ASMT in rat hippocampus (Mean±SE)
##与模型组比较P<0.01##Compared with model group P<0.01
1.4慢性应激组(模型组)大鼠海马组织中褪黑素受体(MT1)降低(P<0.01)，芍药内酯苷能够显著增加褪黑素受体(MT1)的含量(P<0.01)，恢复和增强褪黑素系统的功能，见表2和附图4，其中附图4采用蛋白质印记方法测定褪黑素受体的含量。
1.4 In the chronic stress group (model group), the melatonin receptor (MT1) was decreased in the hippocampus of rats (P<0.01), and the paeoniflorin could significantly increase the melatonin receptor (MT1) content (P<0.01). The function of the melatonin system was restored and enhanced, see Table 2 and Figure 4, wherein Figure 4 uses the Western blot method to determine the melatonin receptor content.
表2芍药内酯苷对大鼠褪黑素受体1(MT1)的影响(Mean±SE)Table 2 Effect of paeoniflorin on melatonin receptor 1 (MT1) in rats (Mean±SE)
##与模型组比较升高P<0.01；**与模型组比较降低P<0.01 ## Compared with the model group, P<0.01; ** decreased compared with the model group, P<0.01
综上所述，本发明通过新一代靶向代谢组学研究发现芍药内酯苷具有促进内源性褪黑素和增加褪黑素受体分泌的功能；依据该功能，可以将芍药内酯苷及含有芍药内酯苷的提取物、组合物开发成能够调节和改善内源性褪黑素的食品、保健品、食品添加剂或营养补充剂，制备用于抗抑郁、抗衰老、改善睡眠和提高认知功能、延缓和防治阿尔茨海默病的药物。In summary, the present invention finds that paeoniflorin has a function of promoting endogenous melatonin and increasing secretion of melatonin receptor through a new generation of targeted metabolomics research; according to this function, paeoniflorin can be used And extracts and compositions containing paeoniflorin are developed into foods, health supplements, food additives or nutritional supplements capable of regulating and improving endogenous melatonin, prepared for antidepressant, anti-aging, improving sleep and improving Cognitive function, drugs that delay and prevent Alzheimer's disease.
实施案例2：芍药内酯苷对CUMS大鼠学习记忆功能的影响Example 2: Effect of paeoniflorin on learning and memory function in CUMS rats
2.1芍药内酯苷对慢性应激大鼠开场活动的影响2.1 Effects of paeoniflorin on the opening activities of chronic stress rats
大鼠慢性应激21天成功造模后，灌胃给药芍药内酯苷(7mg/kg)7天进行开场活动实验，结果表明：模型组大鼠经过慢应激后穿越横格数和直立次数均明显减少，与空白对照组比较具有显著性差异(P<0.01)，见表3。给药7天后，氟西汀组、芍药内酯苷组与模型组比较具有显著性差异(P<0.05或P<0.01)，提示芍药内酯苷对受试大鼠学习记忆功能损伤有明显的改善作用。After 21 days of successful chronic stress in rats, the start-up activity was carried out by intragastric administration of paeoniflorin (7 mg/kg) for 7 days. The results showed that the rats in the model group crossed the horizontal grid and erect after slow stress. The number of times was significantly reduced, and there was a significant difference compared with the blank control group (P<0.01), as shown in Table 3. After 7 days of administration, there was a significant difference between the fluoxetine group and the paeoniflorin group (P<0.05 or P<0.01), suggesting that paeoniflorin has obvious learning and memory impairment in the test rats. Improve the role.
表3大鼠开场行为比较(mean±s，n＝8)Table 3 Comparison of opening behaviors of rats (mean±s, n=8)
##与对照组比较P<0.01；**与模型组比较P<0.01##Compared with the control group P<0.01; **Compared with the model group P<0.01
2.2芍药内酯苷对慢性应激大鼠跳台被动回避实验的影响2.2 Effect of paeoniflorin on passive avoidance experiment in chronic stress rats
大鼠慢性应激21天成功造模后，口服给药芍药内酯苷(7mg/kg)7天进行跳台被动回避实验，结果表明：与空白组相比，模型组大鼠训练期错误次数和测试期错误次数均显著增加，其中训练期错误次数增加更显著
(P<0.01)；与模型组相比，芍药内酯苷及氟西汀组大鼠训练期错误次数和测试期错误次数显著降低(P<0.01)，见表4。跳台实验是一种被动回避实验，能反映出受试动物的学习记忆能力。本实验结果，提示芍药内酯苷对受试动物学习记忆功能损伤有明显的改善作用。After 21 days of successful chronic stress in rats, oral administration of paeoniflorin (7 mg/kg) for 7 days was used for passive avoidance experiments. The results showed that the number of training sessions in the model group was lower than that in the blank group. The number of errors in the test period has increased significantly, and the number of errors in the training period has increased significantly.
(P<0.01); compared with the model group, the number of errors in the training period and the number of errors in the test period were significantly lower in the paeoniflorin and fluoxetine groups (P<0.01), as shown in Table 4. The platform test is a passive avoidance experiment that reflects the learning and memory ability of the test animals. The results of this experiment suggest that paeoniflorin can significantly improve the learning and memory impairment of the test animals.
表4大鼠跳台被动回避实验(mean±s，n＝12)Table 4 Passive avoidance experiment of rat jumping platform (mean±s, n=12)
**与模型组比较P<0.01，*与模型组比较P<0.05**Compared with model group P<0.01,* compared with model group P<0.05
实施案例3：芍药内酯苷对东莨菪碱痴呆小鼠学习记忆功能影响Example 3: Effect of paeoniflorin on learning and memory function in mice with scopolamine dementia
小鼠腹腔注射氢溴酸东莨菪碱制备学习记忆障碍痴呆模型后，进行水迷宫测试，以小鼠入水后到找到平台的游泳时间(即逃避潜伏期)和游泳路程作为观测指标。实验结果表明：与模型组相比，芍药内酯苷组第4、5天的逃避潜伏期明显缩短(P<0.05)，见表5；与模型组相比，芍药内酯苷组第4、5天的游泳路程缩短(P<0.05)，见表6。本实验结果说明，芍药内酯苷对东莨菪碱所致痴呆模型小鼠的学习记忆能力有明显的改善作用。After the mice were injected intraperitoneally with scopolamine hydrobromide to prepare a model of learning and memory impairment, the water maze test was performed to find the swimming time (ie, escape latency) and swimming distance of the mouse as the observation index after entering the water. The experimental results showed that compared with the model group, the escape latency of the paeoniflorin group was significantly shorter on the 4th and 5th day (P<0.05), as shown in Table 5; compared with the model group, the paeoniflorin group 4, 5 The swimming distance of the day was shortened (P<0.05), see Table 6. The results of this experiment indicate that paeoniflorin can significantly improve the learning and memory ability of mice with dementia induced by scopolamine.
表5芍药内酯苷对东莨菪碱致痴呆模型小鼠逃避潜伏期的影响(x±s)Table 5 Effect of paeoniflorin on escape latency of scopolamine-induced dementia model mice (x±s)
注：与空白组比较，*P<0.05，**P<0.01；与模型组比较，#P<0.05，##P<0.01。
Note: Compared with the blank group, *P<0.05, **P<0.01; compared with the model group, #P<0.05, ##P<0.01.
表6芍药内酯苷对东莨菪碱致痴呆模型小鼠游泳路程的影响(x±s)Table 6 Effect of paeoniflorin on swimming distance of scopolamine-induced dementia model mice (x±s)
注：与空白比较，*P<0.05，**P<0.01；与模型组比较，#P<0.05，##P<0.01。Note: Compared with the blank, *P<0.05, **P<0.01; compared with the model group, #P<0.05, ##P<0.01.
实施案例4：芍药内酯苷对小鼠睡眠的影响Example 4: Effect of paeoniflorin on sleep in mice
4.1直接睡眠实验4.1 Direct sleep experiment
观察受试组动物给于3个剂量的芍药内酯苷，对照组给予同体积溶剂后,是否出现睡眠现象。睡眠以翻正反射消失为指标。当小鼠置于背卧位时，能立即翻正身位。如超过30秒不能翻正者，即认为翻正反射消失，进入睡眠。翻正反射恢复即为动物觉醒，翻正反射消失至恢复这段时间为动物睡眠时间，记录空白对照组与芍药内酯苷组入睡动物数及睡眠时间。实验结果见表7：The test group animals were given three doses of paeoniflorin, and the control group was given a sleep phenomenon after the same volume of solvent. Sleep disappears as an indicator of righting reflex. When the mouse is placed in the back position, it can immediately correct the position. If it can't be corrected for more than 30 seconds, it means that the righting reflex disappears and goes to sleep. The recovery of righting reflex was the awakening of the animal, and the righting reflex disappeared until the recovery time was the animal's sleep time. The number of sleeping animals and the sleep time of the blank control group and the paeoniflorin group were recorded. The experimental results are shown in Table 7:
表7.芍药内酯苷对小鼠直接睡眠作用的影响Table 7. Effect of paeoniflorin on direct sleep in mice
由表7可见，芍药内酯苷对实验动物无直接睡眠作用。As can be seen from Table 7, the paeoniflorin has no direct sleep effect on experimental animals.
4.2延长戊巴比妥钠睡眠时间实验4.2 Extension of pentobarbital sodium sleep time experiment
做正式实验前先进行预实验，确定使动物100％入睡，但又不使睡眠时间过长的戊巴比妥钠剂量(30-60mg/kg)，用此剂量正式实验。Before the formal experiment, a preliminary experiment was carried out to determine the dose of sodium pentobarbital (30-60 mg/kg) which made the animal 100% sleep, but did not make the sleep time too long, and the dose was officially tested.
动物末次给予溶剂对照及不同浓度芍药内酯苷后，出现峰作用前10分钟，给各组动物腹腔注射戊巴比妥钠(48mg/kgBW)，注射量为0.1mL/10g，以翻正反射消失为指标，观察芍药内酯苷能否延长戊巴比妥钠睡眠时间。实验结果见表8：
Animals were given the control of the solvent and different concentrations of paeoniflorin at the last 10 minutes before the peak effect. The rats in each group were intraperitoneally injected with sodium pentobarbital (48 mg/kg BW) at a dose of 0.1 mL/10 g to correct the reflex Disappeared as an indicator to see if the paeoniflorin can prolong the sleep time of sodium pentobarbital. The experimental results are shown in Table 8:
表8.芍药内酯苷对戊巴比妥钠诱导小鼠睡眠时间的影响Table 8. Effect of paeoniflorin on sleep time in mice induced by sodium pentobarbital
**示与对照组比较p<0.01；*示与对照组比较p<0.05** showed p<0.01 compared with the control group; * showed comparison with the control group p<0.05
表8提示高于14mg/kgbw剂量的芍药内酯苷，能延长阈剂量的戊巴比妥钠诱导的小鼠睡眠时间，与对照组实验小鼠睡眠时间有显著性差异(p<0.05)。Table 8 suggests that paeoniflorin, which is higher than the 14 mg/kg bw dose, can prolong the threshold time of pentobarbital sodium-induced sleep time in mice, and is significantly different from the sleep time of the control group (p<0.05).
4.3戊巴比妥钠阈下剂量催眠实验4.3 pentobarbital sodium subthreshold dose hypnosis experiment
动物末次给予空白对照及不同浓度芍药内酯苷后，出现峰作用前10分钟，各组动物腹腔注射戊巴比妥钠最大阈下催眠剂量(30mg/kgBW)，记录30分钟内入睡动物数(翻正反射消失达1分钟以上者)。实验宜在24-25℃安静环境下进行。实验结果见表9：The animals were given a blank control and different concentrations of paeoniflorin at the last 10 minutes before the peak effect. The animals in each group were intraperitoneally injected with the maximum subthreshold hypnotic dose of pentobarbital sodium (30 mg/kg BW), and the number of sleeping animals in 30 minutes was recorded. The righting reflection disappears for more than 1 minute). The experiment should be carried out in a quiet environment of 24-25 °C. The experimental results are shown in Table 9:
表9.芍药内酯苷对阈下剂量戊巴比妥钠诱导小鼠睡眠的影响Table 9. Effect of paeoniflorin on sleep induced by subliminal dose of pentobarbital sodium in mice
表9可见芍药内酯苷对阈下剂量戊巴比妥钠引起的各剂量组实验小鼠睡眠发生率较对照组高，与对照组比较有显著性差异(p<0.01)。Table 9 shows that the sleep incidence of the mice in each dose group caused by paeoniflorin to the subthreshold dose of pentobarbital was higher than that of the control group, and there was a significant difference compared with the control group (p<0.01).
4.4巴比妥钠睡眠潜伏期实验4.4 Barbiturate sodium sleep latency test
做正式实验前先进行预实验，确定使动物100％入睡，但又不使睡眠时间过长的巴比妥钠的剂量，用此剂量正式实验。Before the formal experiment, a preliminary experiment was carried out to determine the dose of barbital sodium which made the animal 100% sleep, but did not make the sleep time too long, and the dose was officially tested.
动物末次给于溶剂对照及不同浓度芍药内酯苷10-20分钟后，给各组动物腹腔注射巴比妥钠(400mg/kg)注射量为0.2mL/20g，以翻正反射消失为指标，观察芍药内酯苷对巴比妥钠睡眠潜伏期的影响。实验结果见表10：
After the animals were given the solvent control and different concentrations of paeoniflorin for 10-20 minutes, the intraperitoneal injection of barbital sodium (400 mg/kg) was 0.2 mL/20 g, and the disappearance of the righting reflex was used as an indicator. To observe the effect of paeoniflorin on the sleep latency of barbital sodium. The experimental results are shown in Table 10:
表10芍药内酯苷对巴比妥钠诱导小鼠睡眠潜伏期的影响Table 10 Effect of paeoniflorin on sleep latency in mice induced by barbital sodium
**示与对照组比较p<0.01；*示与对照组比较p<0.05** showed p<0.01 compared with the control group; * showed comparison with the control group p<0.05
由表10可见，芍药内酯苷能缩短巴比妥钠诱导的实验小鼠睡眠潜伏期。As can be seen from Table 10, paeoniflorin can shorten the sleep latency of experimental mice induced by barbital sodium.
以上对本发明具体实施方式的描述并不限制本发明，本领域技术人员可以根据本发明作出各种改变或变形，只要不脱离本发明的精神，均应属于本发明所附权利要求的范围。
The above description of the specific embodiments of the present invention is not intended to limit the invention, and various modifications and changes may be made by those skilled in the art without departing from the spirit and scope of the invention.
Claims (10)
- 芍药内酯苷或其药学上可接受的盐、或者包含芍药内酯苷或其药学上可接受的盐的提取物在制备改善褪黑素系统功能的产品中的用途；Use of paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract comprising paeoniflorin or a pharmaceutically acceptable salt thereof, for the manufacture of a product for improving the function of a melatonin system;优选地，所述改善褪黑素系统功能的产品为内源性褪黑素分泌促进剂和/或褪黑素受体激动剂，其中所述褪黑素受体激动剂提高生物体内褪黑素受体的浓度和/或增加生物体内褪黑素受体的活性。Preferably, the product for improving the function of the melatonin system is an endogenous melatonin secretion promoter and/or a melatonin receptor agonist, wherein the melatonin receptor agonist enhances melanin in vivo The concentration of the receptor and/or increase the activity of the melatonin receptor in the organism.
- 根据权利要求1所述的用途，其中所述改善褪黑素系统功能的产品以选自药物、食品、保健品、食品添加剂或营养补充剂的形式提供。The use according to claim 1, wherein the product for improving the function of the melatonin system is provided in the form of a drug, a food, a health supplement, a food additive or a nutritional supplement.
- 根据权利要求1或2所述的用途，其中所述改善褪黑素系统功能为预防和/或治疗由褪黑素系统功能障碍引起的亚健康状态和/或疾病；The use according to claim 1 or 2, wherein said improving the melatonin system function is to prevent and/or treat a sub-health state and/or disease caused by melatonin system dysfunction;优选地，所述亚健康状态选自生物节律紊乱性睡眠障碍、老年睡眠障碍、情感障碍、认知功能障碍和免疫系统功能障碍中的一种或多种；Preferably, the sub-health state is selected from one or more of a biological rhythm disorder sleep disorder, an elderly sleep disorder, an affective disorder, a cognitive dysfunction, and an immune system dysfunction;优选地，所述疾病选自失眠、抑郁症、焦虑症、阿尔茨海默症和帕金森症中的一种或多种。Preferably, the disease is selected from one or more of insomnia, depression, anxiety, Alzheimer's disease, and Parkinson's disease.
- 一种用于改善褪黑素系统功能的方法，所述方法包括给予对象有效量的芍药内酯苷或其药学上可接受的盐、或者包含芍药内酯苷或其药学上可接受的盐的提取物；A method for improving the function of a melatonin system, the method comprising administering to a subject an effective amount of a paeoniflorin or a pharmaceutically acceptable salt thereof, or comprising a paeoniflorin or a pharmaceutically acceptable salt thereof Extract;优选地，所述改善褪黑素系统功能为促进内源性褪黑素分泌和/或激活褪黑素受体，其中所述激活褪黑素受体为提高褪黑素受体的浓度和/或增加褪黑素受体的活性。Preferably, said improving melatonin system functions to promote endogenous melatonin secretion and/or activate melatonin receptor, wherein said activation of melatonin receptor is to increase melatonin receptor concentration and / Or increase the activity of melatonin receptors.
- 根据权利要求4所述的方法，其中所述改善褪黑素系统功能为预防和/或治疗由褪黑素系统功能障碍引起的亚健康状态和/或疾病；The method according to claim 4, wherein said improving melatonin system function is for preventing and/or treating a sub-health state and/or disease caused by melatonin system dysfunction;优选地，所述亚健康状态选自生物节律紊乱性睡眠障碍、老年睡眠障碍、情感障碍、认知功能障碍和免疫系统功能障碍中的一种或多种；Preferably, the sub-health state is selected from one or more of a biological rhythm disorder sleep disorder, an elderly sleep disorder, an affective disorder, a cognitive dysfunction, and an immune system dysfunction;优选地，所述疾病选自失眠、抑郁症、焦虑症、阿尔茨海默症和帕金森症中的一种或多种。Preferably, the disease is selected from one or more of insomnia, depression, anxiety, Alzheimer's disease, and Parkinson's disease.
- 一种用于改善褪黑素系统功能的组合物，其包含芍药内酯苷或其药学 上可接受的盐、或者包含芍药内酯苷或其药学上可接受的盐的提取物；A composition for improving the function of a melatonin system, comprising a paeoniflorin or a pharmaceutically acceptable thereof An acceptable salt, or an extract comprising paeoniflorin or a pharmaceutically acceptable salt thereof;优选地，所述改善褪黑素系统功能为促进内源性褪黑素分泌和/或激活褪黑素受体，其中所述激活褪黑素受体为提高褪黑素受体的浓度和/或增加褪黑素受体的活性。Preferably, said improving melatonin system functions to promote endogenous melatonin secretion and/or activate melatonin receptor, wherein said activation of melatonin receptor is to increase melatonin receptor concentration and / Or increase the activity of melatonin receptors.
- 根据权利要求6所述的组合物，其中所述用于改善褪黑素系统功能的组合物为药物、食品、保健品、食品添加剂或营养补充剂。The composition according to claim 6, wherein the composition for improving the function of the melatonin system is a medicine, a food, a health supplement, a food additive or a nutritional supplement.
- 根据权利要求6或7所述的组合物，其中所述改善褪黑素系统功能为预防和/或治疗由褪黑素系统功能障碍引起的亚健康状态和/或疾病；The composition according to claim 6 or 7, wherein said improving melatonin system function is for preventing and/or treating a sub-health state and/or disease caused by melatonin system dysfunction;优选地，所述亚健康状态选自生物节律紊乱性睡眠障碍、老年睡眠障碍、情感障碍、认知功能障碍和免疫系统功能障碍中的一种或多种；Preferably, the sub-health state is selected from one or more of a biological rhythm disorder sleep disorder, an elderly sleep disorder, an affective disorder, a cognitive dysfunction, and an immune system dysfunction;优选地，所述疾病选自失眠、抑郁症、焦虑症、阿尔茨海默症和帕金森症中的一种或多种。Preferably, the disease is selected from one or more of insomnia, depression, anxiety, Alzheimer's disease, and Parkinson's disease.
- 用于改善褪黑素系统功能的芍药内酯苷或其药学上可接受的盐、或者包含芍药内酯苷或其药学上可接受的盐的提取物；a paeoniflorin or a pharmaceutically acceptable salt thereof for improving the function of a melatonin system, or an extract comprising a paeoniflorin or a pharmaceutically acceptable salt thereof;优选地，所述改善褪黑素系统功能为促进内源性褪黑素分泌和/或激活褪黑素受体，其中所述激活褪黑素受体为提高褪黑素受体的浓度和/或增加褪黑素受体的活性。Preferably, said improving melatonin system functions to promote endogenous melatonin secretion and/or activate melatonin receptor, wherein said activation of melatonin receptor is to increase melatonin receptor concentration and / Or increase the activity of melatonin receptors.
- 根据权利要求9所述的芍药内酯苷或其药学上可接受的盐、或者包含芍药内酯苷或其药学上可接受的盐的提取物，其中所述改善褪黑素系统功能为预防和/或治疗由褪黑素系统功能障碍引起的亚健康状态和/或疾病；The paeoniflorin or a pharmaceutically acceptable salt thereof according to claim 9, or an extract comprising paeoniflorin or a pharmaceutically acceptable salt thereof, wherein the melatonin system function is improved for prevention and / or treatment of sub-health status and / or disease caused by melatonin system dysfunction;优选地，所述亚健康状态选自生物节律紊乱性睡眠障碍、老年睡眠障碍、情感障碍、认知功能障碍和免疫系统功能障碍中的一种或多种；Preferably, the sub-health state is selected from one or more of a biological rhythm disorder sleep disorder, an elderly sleep disorder, an affective disorder, a cognitive dysfunction, and an immune system dysfunction;优选地，所述疾病选自失眠、抑郁症、焦虑症、阿尔茨海默症和帕金森症中的一种或多种。 Preferably, the disease is selected from one or more of insomnia, depression, anxiety, Alzheimer's disease, and Parkinson's disease.
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| WO2010133015A1 (en) * | 2009-05-21 | 2010-11-25 | 陈婷 | Pharmaceutical composition for treating depression and preparative method and use thereof |
| WO2011003226A1 (en) * | 2009-07-10 | 2011-01-13 | 陈婷 | Pharmaceutical composition for treating depression and preparative method and use thereof |
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| WO2012068958A1 (en) * | 2010-11-25 | 2012-05-31 | Zhang Zuoguang | Antianxiety and sleep disorder improving use of albiflorin or metabolite thereof in |
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2017
- 2017-08-04 CN CN201710660037.0A patent/CN107412244A/en active Pending
- 2017-08-04 WO PCT/CN2017/095985 patent/WO2018068565A1/en active Application Filing
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| WO2010133015A1 (en) * | 2009-05-21 | 2010-11-25 | 陈婷 | Pharmaceutical composition for treating depression and preparative method and use thereof |
| WO2011003226A1 (en) * | 2009-07-10 | 2011-01-13 | 陈婷 | Pharmaceutical composition for treating depression and preparative method and use thereof |
| WO2011047576A1 (en) * | 2009-10-20 | 2011-04-28 | Zhang Zuoguang | Use of albiflorin for anti-depression |
| WO2011088715A1 (en) * | 2010-01-19 | 2011-07-28 | Zhang Zuoguang | Use of albiflorin for anti-parkinson's disease |
| WO2012068958A1 (en) * | 2010-11-25 | 2012-05-31 | Zhang Zuoguang | Antianxiety and sleep disorder improving use of albiflorin or metabolite thereof in |
| WO2016134563A1 (en) * | 2015-02-26 | 2016-09-01 | 张作光 | Use of albiflorin or pharmaceutically acceptable salt for prevention and/or treatment of irritable bowel syndrome |
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| CN107412244A (en) | 2017-12-01 |
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