WO2024131267A1 - Electronic cigarette atomization liquid having antidepressant effect, and preparation method therefor - Google Patents
Electronic cigarette atomization liquid having antidepressant effect, and preparation method therefor Download PDFInfo
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- WO2024131267A1 WO2024131267A1 PCT/CN2023/126570 CN2023126570W WO2024131267A1 WO 2024131267 A1 WO2024131267 A1 WO 2024131267A1 CN 2023126570 W CN2023126570 W CN 2023126570W WO 2024131267 A1 WO2024131267 A1 WO 2024131267A1
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Classifications
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- A—HUMAN NECESSITIES
- A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
- A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
- A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
- A24B15/10—Chemical features of tobacco products or tobacco substitutes
- A24B15/16—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes
- A24B15/167—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes in liquid or vaporisable form, e.g. liquid compositions for electronic cigarettes
-
- A—HUMAN NECESSITIES
- A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
- A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
- A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
- A24B15/18—Treatment of tobacco products or tobacco substitutes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the invention belongs to the technical field of electronic cigarette atomizer liquid preparation, and particularly relates to an electronic cigarette atomizer liquid with antidepressant effect and a preparation method thereof.
- Depression is a common and widespread mental illness worldwide, which has a significant impact on the quality of human life. Studies have shown that depression is the result of the combined effects of psychological, physiological, and social factors. Many factors may be the cause of depression, including genetics, external adverse stimuli or internal conflicts, smoking, alcohol and drug abuse, chronic diseases, and improper diet. According to the incidence, it can be divided into mild depression and severe depression, and severe depression poses a serious threat to human health. With the development of society, the increase in stress and the effects of various other factors have caused the incidence of depression to increase year by year. The World Health Organization ranks major depression as the third largest cause of disease burden in the world, and predicts that by 2030, the disease will become the first cause of disease burden.
- the treatment of depression is mainly with antidepressants, and the treatment goal is symptom relief and functional recovery.
- antidepressants the efficacy of antidepressants is not ideal. In fact, about 30-40% of patients are completely relieved after one course of treatment, while 30% of patients still have residual symptoms, increased risk of relapse, and affect social function after clinically significant relief.
- the treatment of depression mainly relies on chemical synthetic drugs. However, this method generally has the disadvantages of narrow antidepressant spectrum, slow onset, and large side effects. Compared with chemical synthetic drugs, natural drugs have unique advantages in the prevention and treatment of depression. It is reported that these many volatile oils containing limonene can easily pass through the blood-brain barrier into the brain, have good antidepressant effects, and have few toxic side effects.
- monoamine oxidase activity has been shown to be associated with neurological and psychiatric diseases, and monoamine oxidase has become a valuable therapeutic target in neuropharmacology.
- Monoamine oxidase-A inhibitors are currently used to treat anxiety and depression. Since the 1950s, the first monoamine oxidase inhibitor, epronil, has been used as an antidepressant treatment because the levels of the three major monoamine substances (such as norepinephrine, dopamine and serotonin) are regulated in the brain.
- the monoamine transmitter imbalance hypothesis is a widely accepted pathogenesis of depression.
- monoamine oxidase-A mainly metabolizes 5-HT and NE
- inhibitors of this enzyme are mainly used to treat depression.
- monoamine oxidase inhibitors inhibit the deamination or metabolism of neurotransmitters.
- Monoamine oxidase inhibitors are also determined by their selectivity: some inhibitors selectively inhibit MAO-A (such as moclobemide), some selectively inhibit MAO-B (such as pargyline and selegiline), and some are non-selective (such as phenelzine and tronicyclopropane) and can inhibit both MAO-A and MAO-B.
- MAO-A inhibitors are a therapeutic mechanism for treating mental illness, some adverse reactions may occur when MAO-A inhibitors are taken in excess or in combination with other drugs, dietary supplements, or botanicals, such as hepatotoxicity, sedation, cognitive impairment, movement disorders, aggression, sexual dysfunction, drug tolerance, and dependence.
- Limonene is a monoterpene from the Rubiaceae family that has biological properties such as antioxidant, anti-inflammatory, anticancer, antinociceptive, and gastroprotective properties. Recently, there has been a great interest in studying the pharmacological effects of limonene in various chronic diseases due to its mitigating effects on oxidative stress and inflammation and its role in regulating apoptotic cell death. Available antidepressants are designed to target and restore monoamine imbalances. Studies have found that current antidepressants are associated with severe adverse reactions and that their effects vary from individual to individual. Therefore, the discovery of new drugs with the ability to normalize mood is of vital importance.
- Monoterpenes have been found to have mood-improving and mood-improving effects by acting directly on the central nervous system and olfactory nerves.
- Citrus essential oil (OEO) which contains limonene as its main component, has been observed to have an antidepressant effect in a study of a chronic unpredictable mild stress model created in mice. The researchers found that the brains of treated mice had higher levels of limonene than other compounds. They observed that OEO inhalation significantly improved the depressive-like behavior of the model mice, with reduced weight loss, sucrose preference, curiosity, and activity, a shorter immobility time, and a reduction in dyslipidemia.
- Limonene is the most abundant compound in the brain of mice sniffing OEO environment and after sniffing, and it is not immediately metabolized in the brain.
- inhalation of limonene can significantly restore the depressive behavior induced by the model, the hyperactivity of the hypothalamic-pituitary-adrenal axis, and the reduction of monoamine neurotransmitter levels, downregulating the expression of brain-derived neurotrophic factor and its receptors in the hippocampus. Therefore, the researchers believe that the improvement of neuroendocrine, neurotrophic and monoaminergic systems is related to the antidepressant effect of limonene.
- limonene can prevent acute lung injury caused by intranasal LPS in mice. Limonene shows effective lung protection. The researchers believe that the effect of limonene is caused by improving lung function through its anti-inflammatory activity. Limonene is able to reduce inflammatory neutrophil infiltration and subsequent myeloperoxidase activity (MPO). Inflammatory cytokines such as TNF- ⁇ , IL-1 ⁇ , and IL-6 are considered therapeutic targets for acute lung injury; limonene treatment reduces the activity of these cytokines.
- MPO myeloperoxidase activity
- Limonene is able to attenuate the activation of NF- ⁇ B, ERK, JNK, and p38 MAPK signaling pathways, showing anti-inflammatory effects in preventing LPS-induced acute lung injury and demonstrating potential new biological activities for limonene.
- Bronchial asthma is a chronic inflammatory disease that affects 300 million people worldwide. The clinical characteristics of this disease are allergen-induced airway obstruction, chronic eosinophilic airway inflammation, excessive mucus secretion, airway remodeling, and nonspecific airway hyperresponsiveness. Due to these airway abnormalities, individuals susceptible to asthma or allergic airway disease are believed to be more sensitive to inhaled irritants.
- Mint is the above-ground part of the herbaceous plant mint of the Lamiaceae family. It is pungent and cool, and belongs to the lung and liver meridians. It has the effects of dispersing wind-heat, clearing heat and relieving sore throat, dispelling wind and rash, and soothing the liver and relieving depression.
- the aromatic compounds of mint such as L-menthol
- the content of L-menthol in mint oil can be as high as 87%.
- the aromatic smell of L-menthol can act on the brain nervous system.
- L-menthol can significantly inhibit the expression of glutamate receptor 1 and acetylcholinesterase in the hippocampus of rats, thereby improving the cognitive ability of rats and improving memory.
- Experimental results show that the aroma of L-menthol can enhance the short-term memory of cockroaches and is related to the storage and retrieval of thinking information.
- L-menthol can enhance the bioavailability of nerve growth factor in the hippocampus of rats.
- L-menthol acts on hippocampal neurons, which can delay the desensitization of ⁇ -aminobutyric acid receptors and selectively enhance the affinity of hippocampal neurons in rats.
- L-menthol can control the autonomic nervous system and also has an effect on low mood and depression symptoms.
- Nicotine is a major irritant contained in tobacco smoke, causing burning or stinging sensations in the oral or nasal mucosa [9]. Nicotine-induced sensations are thought to involve activation of nACh receptors, including those composed of the ⁇ 7 subunit, which are expressed in sensory fibers innervating these tissues as well as in the bronchial and tracheal epithelial cells of lung tissue. Menthol may reduce nicotine-induced irritation and sensory perception. More recently, menthol has been shown to act as a counterirritant to inhaled cigarette smoke, suggesting that menthol may reduce nicotine-induced responses.
- the European Medicines Agency has not included these indications in its herbal monographs and has approved peppermint for the following indications: mild gastrointestinal spasms, flatulence, abdominal pain, indigestion, mild headaches, coughs and colds, localized muscle pain, and itching of intact skin.
- the scent of peppermint has been reported to reduce fatigue and improve mood and sleep.
- peppermint infusions and fresh parts have a positive effect on the mental health of college students. Students in the treatment group reported better memory function and sleep quality, and reduced anxiety, but this study was not blinded.
- a recent study reported the beneficial effects of 7 days of peppermint oil aromatherapy on sleep quality scores in cancer patients.
- the zebrafish (Danio rerio) is a vertebrate model that is widely used in biomedical research, including neurotoxicology studies. Zebrafish exhibit an overall nervous system and neurotransmitter systems similar to humans, including glutamatergic, cholinergic, serotonergic, dopaminergic, adrenergic, GABA, and histamine.
- the mature zebrafish central nervous system (CNS) is well developed and more complex and can be used to model complex brain disorders, including anxiety and depression.
- CNS central nervous system
- zebrafish can discriminate colors and exhibit spontaneous approach or avoidance behaviors. Some studies support color-based learning and memory paradigms or experiments involving aversion, anxiety, or fear in zebrafish. Zebrafish prefer blue and green colors and avoid yellow and red.
- the visual system of zebrafish includes a retina with cone cells that are sensitive to red, green, blue, and ultraviolet light; in addition, zebrafish are diurnal animals, which makes them an ideal model for the study of developing cognitive responses to visual cues.
- reserpine has the effect of lowering blood pressure and slowing heart rate, and was originally a good antihypertensive and sedative. However, previous studies have shown that acute reserpine application can cause depression.
- Electronic cigarettes are mainly used to replace tobacco cigarettes. Electronic cigarettes can heat and evaporate the stored electronic cigarette atomizer liquid or electronic cigarette oil into aerosol for users to inhale.
- the nicotine-containing electronic cigarettes on the market do not contain effective antidepressant ingredients because their atomizer liquid does not contain antidepressant effects. Therefore, existing electronic cigarettes have no antidepressant effect or have no effect on improving depressive symptoms.
- the purpose of the present invention is to provide an electronic cigarette atomizer liquid with antidepressant effect and a preparation method thereof.
- the technical solution of the present invention is an electronic cigarette atomizer liquid with antidepressant effect, and its preparation components include: 0.1-4 parts of limonene, 0.1-5 parts of nicotine, 1-8 parts of menthol, 70-80 parts of propylene glycol, and 10-30 parts of glycerol in parts by weight.
- the limonene is 0.5 parts
- the nicotine is 4 parts
- the menthol is 3 parts
- the propylene glycol is 72.5 parts
- the glycerol is 20 parts.
- Another technical solution of the present invention is a method for preparing an electronic cigarette atomizer liquid having an antidepressant effect, comprising the following steps:
- the components are sequentially added to the centrifuge tube, stirred and mixed at a stirring rate of 200 rad / min;
- the electronic cigarette atomizer liquid with anti-depression as the main function prepared by using menthol and limonene as additives solves the defects that the electronic cigarette atomizer liquid containing nicotine currently on the market has no anti-depressant effect and no improvement effect on depressive symptoms.
- limonene since limonene has an anti-inflammatory effect on lung inflammation, it can reduce the inflammation and damage of the lungs, trachea and bronchus caused by long-term smoking in smokers; at the same time, since the electronic cigarette atomizer liquid composed of limonene and menthol of the present invention has the effect of relieving anxiety, tension, irritability and the like to a certain extent after being absorbed by users through the atomization of electronic cigarettes, it can also increase memory, improve thinking, and have the effect of anti-depression, and also has a certain protective effect on lung damage.
- the present invention uses zebrafish as a model to establish a depression model using reserpine, observes the antidepressant effect of an electronic cigarette atomizer containing nicotine and menthol and limonene as main additives, and finds that the electronic cigarette atomizer has a very obvious antidepressant effect and can be used as an electronic cigarette atomizer with antidepressant effect.
- the invention discloses an electronic cigarette atomizer liquid with antidepressant effect, wherein the components thereof include, by weight: 0.1 to 4 parts of limonene, 0.1 to 5 parts of nicotine, 1 to 8 parts of menthol, 70 to 80 parts of propylene glycol, and 10 to 30 parts of glycerol.
- An electronic cigarette atomizer liquid with antidepressant effect wherein the prepared components include, by weight, 0.5 parts of limonene, 4 parts of nicotine, 3 parts of menthol, 72.5 parts of propylene glycol, and 20 parts of glycerol.
- the zebrafish broodstock used in the experiment were the AB strain introduced from the National Zebrafish Resource Center and were raised in a 28.5°C constant temperature water bath and a 14/10h light/dark cycle circulating water culture system. In this experiment, 6hpf embryos were selected as the fish for sample safety concentration testing.
- the toxicological endpoint selected for this study was mortality at 96 hours of embryonic development.
- the LC50 was calculated using the Spearmam-Karber method.
- the LC50 of the 96h acute toxicity test of limonene nicotine aerosol liquid is 0.24.
- LC50 refers to the concentration required to cause death in 50% of a group of subjects. According to the 96-hour acute toxicity test of limonene nicotine aerosol solution, the LC50 is 0.24. The results of calculating the safe concentrations LC50/10, LC50/5 and LC50/3 are shown in Table 2.
- LC50 refers to the concentration required to cause death of 50% of a group of subjects.
- the zebrafish broodstock used in the experiment were the AB strain introduced from the National Zebrafish Resource Center. In this chapter, 5 dpf fry were selected as the experimental fish.
- Preparation of working solution Use a 1/10,000 balance to weigh 2 mg of Reserpine, add 100 ⁇ l of DMSO, fully dissolve it, then add 500 ml of ultrapure water, the working solution concentration is 4 mg/L, and the DMSO concentration is 0.2 ⁇ .
- Preparation of working solution Use a 1/10,000 balance to weigh 50 mg of Toloxatone, add 965.11 ⁇ l of DMSO, concentration 250 mM, dilute 1250 times, working solution concentration 200 ⁇ M, DMSO concentration 0.8 ⁇ .
- the limonene nicotine atomized liquid was prepared according to the formula of Example 1. After preparation, it was divided into three concentrations for experiments:
- Low concentration group of limonene nicotine aerosol solution 23 ⁇ l of the test substance was aspirated with a pipette and dissolved in 100 ml of ultrapure water for later use.
- the working solution concentration was 0.023%.
- Limonene nicotine aerosol liquid concentration group use a pipette to draw 48 ⁇ l of the test substance and dissolve it in 100ml of ultrapure water for later use.
- the working solution concentration is 0.048%.
- High concentration group of limonene nicotine aerosol solution 80 ⁇ l of the test substance was aspirated with a pipette and dissolved in 100ml of ultrapure water for later use.
- the working solution concentration was 0.080%.
- methylene blue was added to the culture water from 5 hours after fertilization to the 5th day for incubation (methylene blue inhibits the growth of cultured water molds), and methylene blue, Reserpine, limonene nicotine aerosol solution, etc. were added to the culture water from the 5th day to the 6th day for co-administration efficacy evaluation.
- MAO Monoamine Oxidase
- MAO catalyzes the deamination of monoamine substrates to generate aldehydes, which are further oxidized to generate acids.
- the substrate has a characteristic absorption peak at 360nm.
- the rate of decrease in light absorption at 360nm is measured by an enzyme marker to calculate the MAO activity.
- SPSS was used to process the data and compare the significance of the differences between the experimental groups (* 0.01 ⁇ P ⁇ 0.05, ** P ⁇ 0.01). At least 90% of the fish embryos survived after the exposure of each test group, otherwise the results of the corresponding test group were invalid.
- the experimental results of MAO activity are shown in Table 5:
- the reserpine model group can significantly increase the amount of MAO in zebrafish, the increase is 591%, and the positive drug group (Toloxatone) can significantly reduce the MAO content in the model group, the enzyme activity is 86.25, and the enzyme activity is reduced by 13.8%.
- the three concentration groups of the sample can significantly reduce the MAO content in the model group.
- the enzyme activity of the low concentration group is reduced by 35.1%; compared with the model group, the enzyme activity of the medium concentration group is reduced by 72.0%, and the enzyme activity of the high concentration group is reduced by 79.2%.
- the zebrafish broodstock used in the experiment were the AB strain introduced from the National Zebrafish Resource Center. In this chapter, 5 dpf fry were selected as the experimental fish.
- Preparation of working solution Use a 1/10,000 balance to weigh 2 mg of Reserpine, add 100 ⁇ l of DMSO, fully dissolve it, then add 500 ml of ultrapure water, the working solution concentration is 4 mg/L, and the DMSO concentration is 0.2 ⁇ .
- Positive drug control Preparation of working solution: Use a 1/10,000 balance to weigh 50 mg of Toloxatone, add DMSO to a volume of 965.11 ⁇ l, a concentration of 250 mM, dilute 1250 times, working concentration 200 ⁇ M, DMSO concentration 0.8 ⁇ .
- the limonene nicotine atomized liquid was prepared according to the formula of Example 1. After preparation, it was divided into three concentrations for experiments:
- Low concentration group of limonene nicotine aerosol solution 23 ⁇ l of the test substance was aspirated with a pipette and dissolved in 100 ml of ultrapure water for later use.
- the working solution concentration was 0.023%.
- Limonene nicotine aerosol liquid concentration group use a pipette to draw 48 ⁇ l of the test substance and dissolve it in 100ml of ultrapure water for later use.
- the working solution concentration is 0.048%.
- High concentration group of limonene nicotine aerosol solution 80 ⁇ l of the test substance was aspirated with a pipette and dissolved in 100ml of ultrapure water for later use.
- the working solution concentration was 0.080%.
- Zebrafish behavior is based on the distance of swimming to judge the degree of depression. Long swimming distance means low depression, short swimming distance means high depression.
- the model group can significantly inhibit the activity of zebrafish (P ⁇ 0.05). According to the data of zebrafish activity trajectory in the figure, it can be seen that the activity trajectory and distance of zebrafish in the model group are significantly less than those in other groups.
- the positive drug group can significantly increase the activity of zebrafish (P ⁇ 0.05). All three concentrations of the sample can significantly increase the activity of zebrafish (P ⁇ 0.05).
- the behavioral data are basically consistent with the quantitative data of MAO.
- the activity distance of zebrafish in the medium concentration group increased significantly by 185%, which was 123% higher than that of the positive drug; the activity distance of the medium concentration group increased significantly by 141% compared with the control group, which was 127% higher than that of the positive drug; the activity distance of the high concentration group increased significantly by 145% compared with the control group, which was 196% higher than that of the positive drug.
- the electronic cigarette atomizer liquid prepared by the technical solution of the present invention has the effects of inhibiting the activity of monoamine oxidase and resisting depression, has high safety, and can be used as an atomizer for resisting depression.
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- Chemical & Material Sciences (AREA)
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Abstract
An electronic cigarette atomization liquid having an antidepressant effect, prepared from the following components in parts by weight: 0.1-4 parts of limonene, 0.1-5 parts of nicotine, 1-8 parts of menthol, 70-80 parts of propylene glycol, and 10-30 parts of glycerol. The electronic cigarette atomization liquid having the antidepressant effect overcomes the defects that existing electronic cigarette atomization liquids containing nicotine on the market do not have any antidepressant effect and depressive symptom alleviation effect; additionally, because limonene has an anti-inflammatory effect on lung inflammation, the inflammation and damage of lung, trachea, and bronchus caused by long-term smoking of smokers can be alleviated. In addition, a preparation method for the electronic cigarette atomization liquid having the antidepressant effect is provided.
Description
本发明属于电子烟雾化液制备技术领域,特别涉及一种具有抗抑郁作用的电子烟雾化液及其制备方法。The invention belongs to the technical field of electronic cigarette atomizer liquid preparation, and particularly relates to an electronic cigarette atomizer liquid with antidepressant effect and a preparation method thereof.
抑郁症是一种全球常见的广泛存在的精神疾病,对人类的生活质量有重大影响。研究表明,抑郁症是心理、生理、社会等因素综合作用的结果。许多因素可能是导致抑郁的原因,包括遗传、外部不利刺激或内部冲突、吸烟、酒精和药物滥用、慢性疾病和不适当的饮食。按发病率可分为轻度抑郁症和重度抑郁症,重度抑郁症对人体健康构成严重威胁。随着社会的发展,压力的增加以及其他各种因素的作用使得抑郁症的发病率逐年增加。世卫组织将重度抑郁症列为全球第三大疾病负担原因,并预计到2030年,该病将成为第一大疾病负担原因。全球超过3.5亿人受到重度抑郁症的影响,其特征是情绪的显著变化(持续抑郁或快感不足),并伴有明显的心理和营养变化,如嗜睡、厌食症、主观疲劳、失去动力、内疚和绝望良心、难以保持注意力集中、自杀念头和行为。在全球范围内,抑郁症的负担正在增加,尤其是在女性中。Depression is a common and widespread mental illness worldwide, which has a significant impact on the quality of human life. Studies have shown that depression is the result of the combined effects of psychological, physiological, and social factors. Many factors may be the cause of depression, including genetics, external adverse stimuli or internal conflicts, smoking, alcohol and drug abuse, chronic diseases, and improper diet. According to the incidence, it can be divided into mild depression and severe depression, and severe depression poses a serious threat to human health. With the development of society, the increase in stress and the effects of various other factors have caused the incidence of depression to increase year by year. The World Health Organization ranks major depression as the third largest cause of disease burden in the world, and predicts that by 2030, the disease will become the first cause of disease burden. More than 350 million people worldwide are affected by major depression, which is characterized by significant changes in mood (persistent depression or lack of pleasure), accompanied by obvious psychological and nutritional changes, such as drowsiness, anorexia, subjective fatigue, loss of motivation, guilt and despair of conscience, difficulty maintaining concentration, suicidal thoughts and behaviors. Globally, the burden of depression is increasing, especially among women.
目前对抑郁症的治疗主要是用抗抑郁药物,治疗目标是症状缓解和功能恢复,然而,实验和临床证据表明,抗抑郁药物的疗效并不理想。事实上,约30 -40%的患者在一个疗程后完全缓解,而30%的患者仍有残留症状,复发风险增加,在临床显著缓解后影响社会功能。目前抑郁症的治疗主要依靠化学合成药物。但这种方法普遍存在抗抑郁药谱窄、起效慢、副作用大等缺点。与化学合成药物相比,天然药物在预防和治疗抑郁症方面具有独特的优势。据报道,这些许多含有柠檬烯的挥发油,很容易通过血脑屏障进入大脑,具有良好的抗抑郁作用,毒副作用小。At present, the treatment of depression is mainly with antidepressants, and the treatment goal is symptom relief and functional recovery. However, experimental and clinical evidence shows that the efficacy of antidepressants is not ideal. In fact, about 30-40% of patients are completely relieved after one course of treatment, while 30% of patients still have residual symptoms, increased risk of relapse, and affect social function after clinically significant relief. At present, the treatment of depression mainly relies on chemical synthetic drugs. However, this method generally has the disadvantages of narrow antidepressant spectrum, slow onset, and large side effects. Compared with chemical synthetic drugs, natural drugs have unique advantages in the prevention and treatment of depression. It is reported that these many volatile oils containing limonene can easily pass through the blood-brain barrier into the brain, have good antidepressant effects, and have few toxic side effects.
单胺氧化酶活性和神经递质水平之间的关系被证实与神经和精神疾病相关,单胺氧化酶已成为神经药理学中极具价值的治疗靶点。单胺氧化酶-A 抑制剂目前被用来治疗焦虑症和抑郁症,自20世纪50年代第一个单胺氧化酶抑制剂依普罗尼嗪被用作抗抑郁药治疗,因为三种主要单胺类物质(如去甲肾上腺素、多巴胺和血清素)的水平在大脑中受到调节。单胺类递质失衡假说是被广泛认可的抑郁症发病机制,在抑郁症患者中,脑内去甲肾上腺素和5-羟色胺水平的降低以及诱导表达MAO-A 是抑郁症最重要的致病因素。此外,抑郁症与单胺氧化酶-A 功能多态性基因和5-羟色胺基因信号通路有关。在抑郁症情况下,脑内单胺氧化酶A 的水平增加。因此传统抗抑郁药物抑制单胺氧化酶A使5-HT信号通路活性降低而发挥治疗效应。单胺氧化酶-A的抑制剂已被发现有抗抑郁的特性,在抑郁症治疗中的应用已有50多年的历史,由于单胺氧化酶-A主要代谢5-HT和NE,因此这种酶的抑制剂主要用于治疗抑郁症。研究表明,单胺氧化酶抑制剂抑制神经递质的脱氨或代谢。单胺氧化酶抑制剂也由其选择性决定:有些抑制剂选择性地抑制MAO-A(如吗氯贝胺),有些选择性地抑制MAO-B(如帕吉林和塞来吉林),有些是非选择性的(如苯乙嗪和曲尼环丙烷),可同时抑制MAO-A和MAO-B。早期的单胺氧化酶抑制剂不可逆地抑制单胺氧化酶,当它们与单胺氧化酶相互作用时,会使酶永久性地失活。之后研发的单胺氧化酶抑制剂,如吗氯贝胺是可逆的,意味着当抑制剂与酶分离时,MAO酶活性可被再次恢复。尽管MAO-A 抑制剂是治疗心理疾病的一种治疗机制,但当过量服用MAO-A抑制剂或与其他药物、膳食补充剂或植物药联合使用时,可能会出现一些不良反应,如肝毒性、镇静、认知障碍、运动失调、攻击性、性功能障碍、药物耐受性和依赖性等。同时,肝脏中过度的MAO-A 抑制会阻碍饮食中酪胺的代谢,最终导致高血压危机。因此,有必要去寻找替代传统MAO-A 抑制剂的天然无毒抑制剂。The relationship between monoamine oxidase activity and neurotransmitter levels has been shown to be associated with neurological and psychiatric diseases, and monoamine oxidase has become a valuable therapeutic target in neuropharmacology. Monoamine oxidase-A inhibitors are currently used to treat anxiety and depression. Since the 1950s, the first monoamine oxidase inhibitor, epronil, has been used as an antidepressant treatment because the levels of the three major monoamine substances (such as norepinephrine, dopamine and serotonin) are regulated in the brain. The monoamine transmitter imbalance hypothesis is a widely accepted pathogenesis of depression. In patients with depression, the reduction of norepinephrine and 5-hydroxytryptamine levels in the brain and the induction of MAO-A expression are the most important pathogenic factors of depression. In addition, depression is associated with monoamine oxidase-A functional polymorphism genes and 5-hydroxytryptamine gene signaling pathways. In the case of depression, the level of monoamine oxidase A in the brain increases. Therefore, traditional antidepressants inhibit monoamine oxidase A to reduce the activity of the 5-HT signaling pathway and exert a therapeutic effect. Inhibitors of monoamine oxidase-A have been found to have antidepressant properties and have been used in the treatment of depression for more than 50 years. Since monoamine oxidase-A mainly metabolizes 5-HT and NE, inhibitors of this enzyme are mainly used to treat depression. Studies have shown that monoamine oxidase inhibitors inhibit the deamination or metabolism of neurotransmitters. Monoamine oxidase inhibitors are also determined by their selectivity: some inhibitors selectively inhibit MAO-A (such as moclobemide), some selectively inhibit MAO-B (such as pargyline and selegiline), and some are non-selective (such as phenelzine and tronicyclopropane) and can inhibit both MAO-A and MAO-B. Early monoamine oxidase inhibitors inhibited monoamine oxidase irreversibly, and when they interacted with monoamine oxidase, they permanently inactivated the enzyme. Later developed monoamine oxidase inhibitors, such as moclobemide, are reversible, meaning that when the inhibitor is separated from the enzyme, MAO enzyme activity can be restored again. Although MAO-A inhibitors are a therapeutic mechanism for treating mental illness, some adverse reactions may occur when MAO-A inhibitors are taken in excess or in combination with other drugs, dietary supplements, or botanicals, such as hepatotoxicity, sedation, cognitive impairment, movement disorders, aggression, sexual dysfunction, drug tolerance, and dependence. At the same time, excessive MAO-A inhibition in the liver can hinder the metabolism of tyramine in the diet, ultimately leading to a hypertensive crisis. Therefore, it is necessary to find natural, non-toxic inhibitors that can replace traditional MAO-A inhibitors.
柠檬烯是茜草科的一种单萜,具有抗氧化、抗炎、抗癌、抗伤害和胃保护等生物学特性。最近,由于柠檬烯对氧化应激和炎症的减轻作用以及调节凋亡细胞死亡的作用,人们对研究柠檬烯在各种慢性疾病中的药理作用产生了浓厚的兴趣。可用的抗抑郁药旨在靶向和恢复单胺失衡。研究发现,目前的抗抑郁药与严重的不良反应有关,而且它们对不同个体的效果并不相同。因此,发现具有情绪正常化能力的新药至关重要。通过直接作用于中枢神经系统和嗅觉神经,发现单萜具有改善情绪和情绪的作用。有人观察了含柠檬烯为主要成分的柑橘精油(OEO)对小鼠身上创建的慢性不可预测的轻度应激模型的研究中,证明了其有抗抑郁作用,研究者发现接受治疗的小鼠大脑中的柠檬烯含量高于其他化合物,他们观察到OEO 吸入显着改善了模型小鼠的抑郁样行为,体重减轻、蔗糖偏好、好奇心和活动能力下降,不动时间缩短,血脂异常减轻。柠檬烯是嗅探OEO 环境和嗅探后小鼠大脑中最丰富的化合物,它不会立即在大脑中代谢。此外,吸入柠檬烯可显着恢复模型引起的抑郁行为、下丘脑-垂体-肾上腺轴的过度活跃以及单胺类神经递质水平的降低,下调脑源性神经营养因子及其在海马中的受体表达。因此,研究者认为神经内分泌、神经营养和单胺能系统的改善与柠檬烯的抗抑郁作用有关。[ Zhang LL, Yang ZY, Fan G., Ren JN, Yin KJ, Pan SY Antidepressant-like Effect of Citrus sinensis (L.) Osbeck Essential Oil and Its Main Component Limonene on Mice.J Agric Food Chem. 2019 Dec 18;67(50):13817-13828.]。还有研究者证明了口服D-柠檬烯可降低保留的神经损伤诱导的对机械性痛觉过敏表现,表现出抗痛觉过敏作用,并且具有抗抑郁作用。吸入EO 可以调节与情绪和神经退化相关的大脑健康和功能,反映它们在大脑中的生物利用度。[Piccinelli AC, Antihyperalgesic and antidepressive actions of (R)-(+)-limonene, α-phellandrene, and essential oil from Schinus terebinthifolius fruits in a neuropathic pain model.Nutr Neurosci. 2015 Jul;18(5):217-24]。还有研究证明了柠檬烯可提高大鼠大脑中GABA 水平的能力,具有抗焦虑作用,还有一些研究证明了柠檬烯在神经退行性疾病中的神经保护作用,包括阿尔茨海默病、多发性硬化症、癫痫、焦虑症和中风。我们注意到柠檬烯对呼吸道的影响,特别是对急性肺损伤的影响,急性肺损伤是一种严重的疾病与炎症有关,发病率和死亡率都很高,没有可用于治疗的特定药物。有研究发现柠檬烯可以预防小鼠鼻内LPS 引起的急性肺损伤,柠檬烯显示出有效的肺保护作用,研究者认为柠檬烯的作用是通过其抗炎活性改善肺功能导致的。柠檬烯能够减少炎症性中性粒细胞浸润和随后的髓过氧化物酶活性(MPO)。炎症细胞因子如TNF-α、IL-1β和IL-6 被认为是急性肺损伤的治疗靶点;柠檬烯处理降低了这些细胞因子的活性。柠檬烯能够减弱NF-κB、ERK、JNK 和p38 MAPK 信号通路的激活,显示出对预防LPS 诱导的急性肺损伤的抗炎作用,并证明了潜在的新生物活性为柠檬烯。支气管哮喘是一种慢性炎症性疾病,影响全球3亿人。这种疾病的临床特征是过敏原引起的气道阻塞、慢性嗜酸性气道炎症、粘液分泌过多、气道重塑和非特异性气道高反应性。由于这些气道异常,易患哮喘或过敏性气道疾病的个体被认为对吸入的刺激剂更敏感。有人进行了一项研究,旨在评估柠檬烯是否可以减少粉尘螨引起的(DER) 气道炎症模型中的过敏性气道和改善哮喘症状。获得的结果表明,用柠檬烯口服治疗显着降低了免疫球蛋白E (IgE)(过敏性炎症的重要标志物)、代表性Th-2 细胞类型(负责产生促炎细胞因子)、趋化细胞因子MCP-1(重要用于炎症细胞的流入)和TGF-β1(与哮喘气道重塑的发展有关)。组织病理学变化还表明,柠檬烯治疗有效地减少了嗜酸性粒细胞流入肺部、气道纤维化并减轻胶原蛋白沉积。此外,柠檬烯治疗能够减轻DER小鼠因施用乙酰胆碱引起的支气管收缩,这些结果表明,柠檬烯对过敏性气道和哮喘具有有效的治疗作用。Limonene is a monoterpene from the Rubiaceae family that has biological properties such as antioxidant, anti-inflammatory, anticancer, antinociceptive, and gastroprotective properties. Recently, there has been a great interest in studying the pharmacological effects of limonene in various chronic diseases due to its mitigating effects on oxidative stress and inflammation and its role in regulating apoptotic cell death. Available antidepressants are designed to target and restore monoamine imbalances. Studies have found that current antidepressants are associated with severe adverse reactions and that their effects vary from individual to individual. Therefore, the discovery of new drugs with the ability to normalize mood is of vital importance. Monoterpenes have been found to have mood-improving and mood-improving effects by acting directly on the central nervous system and olfactory nerves. Citrus essential oil (OEO), which contains limonene as its main component, has been observed to have an antidepressant effect in a study of a chronic unpredictable mild stress model created in mice. The researchers found that the brains of treated mice had higher levels of limonene than other compounds. They observed that OEO inhalation significantly improved the depressive-like behavior of the model mice, with reduced weight loss, sucrose preference, curiosity, and activity, a shorter immobility time, and a reduction in dyslipidemia. Limonene is the most abundant compound in the brain of mice sniffing OEO environment and after sniffing, and it is not immediately metabolized in the brain. In addition, inhalation of limonene can significantly restore the depressive behavior induced by the model, the hyperactivity of the hypothalamic-pituitary-adrenal axis, and the reduction of monoamine neurotransmitter levels, downregulating the expression of brain-derived neurotrophic factor and its receptors in the hippocampus. Therefore, the researchers believe that the improvement of neuroendocrine, neurotrophic and monoaminergic systems is related to the antidepressant effect of limonene. [Zhang LL, Yang ZY, Fan G., Ren JN, Yin KJ, Pan SY Antidepressant-like Effect of Citrus sinensis (L.) Osbeck Essential Oil and Its Main Component Limonene on Mice.J Agric Food Chem. 2019 Dec 18;67(50):13817-13828.]. Other researchers have demonstrated that oral D-limonene can reduce the mechanical hyperalgesia induced by preserved nerve injury, showing anti-hyperalgesia and antidepressant effects. Inhaled EOs may modulate brain health and function related to mood and neurodegeneration, reflecting their bioavailability in the brain. [Piccinelli AC, Antihyperalgesic and antidepressive actions of (R)-(+)-limonene, α-phellandrene, and essential oil from Schinus terebinthifolius fruits in a neuropathic pain model. Nutr Neurosci. 2015 Jul;18(5):217-24]. Other studies have demonstrated the ability of limonene to increase GABA levels in the rat brain, with an anxiolytic effect, and others have demonstrated neuroprotective effects in neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis, epilepsy, anxiety, and stroke. We note the effects of limonene on the respiratory tract, particularly acute lung injury, a serious disease associated with inflammation, high morbidity and mortality, and no specific drugs available for treatment. Studies have found that limonene can prevent acute lung injury caused by intranasal LPS in mice. Limonene shows effective lung protection. The researchers believe that the effect of limonene is caused by improving lung function through its anti-inflammatory activity. Limonene is able to reduce inflammatory neutrophil infiltration and subsequent myeloperoxidase activity (MPO). Inflammatory cytokines such as TNF-α, IL-1β, and IL-6 are considered therapeutic targets for acute lung injury; limonene treatment reduces the activity of these cytokines. Limonene is able to attenuate the activation of NF-κB, ERK, JNK, and p38 MAPK signaling pathways, showing anti-inflammatory effects in preventing LPS-induced acute lung injury and demonstrating potential new biological activities for limonene. Bronchial asthma is a chronic inflammatory disease that affects 300 million people worldwide. The clinical characteristics of this disease are allergen-induced airway obstruction, chronic eosinophilic airway inflammation, excessive mucus secretion, airway remodeling, and nonspecific airway hyperresponsiveness. Due to these airway abnormalities, individuals susceptible to asthma or allergic airway disease are believed to be more sensitive to inhaled irritants. A study was conducted to evaluate whether limonene could reduce allergic airways and improve asthma symptoms in a dust mite-induced (DER) airway inflammation model. The results obtained showed that oral treatment with limonene significantly reduced immunoglobulin E (IgE), an important marker of allergic inflammation, representative Th-2 cell types, responsible for the production of proinflammatory cytokines, the chemotactic cytokine MCP-1, important for the influx of inflammatory cells, and TGF-β1, which is associated with the development of asthmatic airway remodeling. Histopathological changes also showed that limonene treatment effectively reduced the influx of eosinophils into the lungs, airway fibrosis, and alleviated collagen deposition. In addition, limonene treatment was able to alleviate bronchoconstriction induced by the administration of acetylcholine in DER mice. These results suggest that limonene has an effective therapeutic effect on allergic airways and asthma.
薄荷为唇形科草本植物薄荷的地上部分,辛、凉,归肺、肝经,具有疏散风热、清热利咽、祛风透疹、疏肝解郁的功效。其中薄荷的芳香类化合物如L-薄荷醇具有芳香开窍,提神醒脑的作用,L-薄荷醇在薄荷油中含量可高达87%。L-薄荷醇的芳香气味可以作用在脑神经系统,文献报道L-薄荷醇能明显抑制大鼠海马区谷氨酸受体1 和乙酰胆碱酯酶的表达量从而改善大鼠的认知能力,提高记忆力。有实验结果显示L-薄荷醇的芳香味能够使蜚蠊的短期记忆增强,并与的思维信息的存储和检索相关。L-薄荷醇可以使大鼠海马区神经生长因子的生物利用度增强。L-薄荷醇作用在海马神经元,可以迟缓脱敏γ-氨基丁酸受体,选择性增强大鼠脑部海马神经元的亲和度。L-薄荷醇可以控制自主神经系统,对情绪低落,抑郁症状也有作用。薄荷醇和nACh受体之间的相互作用已经在一些早期的研究中进行了研究。尼古丁是烟草烟雾中含有的一种主要刺激物,会引起口腔或鼻粘膜的灼痛或刺痛感[9]。尼古丁诱导的感觉被认为涉及nACh受体的激活,包括那些由α7 亚基组成的受体,在支配这些组织的感觉纤维以及肺组织的支气管和气管上皮细胞中表达。薄荷醇可降低尼古丁引起的刺激和感官知觉. 最近,薄荷醇已被证明可作为吸入香烟烟雾的抗刺激剂,这表明薄荷醇可降低尼古丁诱导的反应。除了感觉反应,尼古丁的主要生理作用之一是由于皮肤血管舒张导致体温降低,这种作用起源于大脑,可能由下丘脑烟碱受体介导。慢性和急性薄荷醇给药都会降低尼古丁对体温的影响。研究已经证明,含有薄荷的中药复方逍遥散对抑郁症有明显的疗效,其中薄荷与柴胡被认为是方中抗抑郁的主药,目前关于使用薄荷治疗焦虑症和抑郁症的数据有限。欧洲药品管理局未将这些适应症纳入草药专论中,已批准薄荷可用于以下适应症:轻度胃肠道痉挛、胃肠胀气、腹痛、消化不良、轻度头痛、咳嗽和感冒、局部肌肉疼痛和局部肌肉疼痛完整皮肤的瘙痒情况。有报道薄荷气味可以减轻疲劳,改善情绪和睡眠。还有报道薄荷浸液和新鲜部位对大学生心理健康的有较好影响,治疗组的学生报告了更好的记忆功能和睡眠质量,并减少了焦虑,但这项研究并不是采用盲法观察的。最近的有研究报告了应用7天薄荷油芳香疗法对癌症患者睡眠质量评分的有益影响。Mint is the above-ground part of the herbaceous plant mint of the Lamiaceae family. It is pungent and cool, and belongs to the lung and liver meridians. It has the effects of dispersing wind-heat, clearing heat and relieving sore throat, dispelling wind and rash, and soothing the liver and relieving depression. Among them, the aromatic compounds of mint, such as L-menthol, have the effects of aromatic awakening and refreshing the mind. The content of L-menthol in mint oil can be as high as 87%. The aromatic smell of L-menthol can act on the brain nervous system. Literature reports that L-menthol can significantly inhibit the expression of glutamate receptor 1 and acetylcholinesterase in the hippocampus of rats, thereby improving the cognitive ability of rats and improving memory. Experimental results show that the aroma of L-menthol can enhance the short-term memory of cockroaches and is related to the storage and retrieval of thinking information. L-menthol can enhance the bioavailability of nerve growth factor in the hippocampus of rats. L-menthol acts on hippocampal neurons, which can delay the desensitization of γ-aminobutyric acid receptors and selectively enhance the affinity of hippocampal neurons in rats. L-menthol can control the autonomic nervous system and also has an effect on low mood and depression symptoms. The interaction between menthol and nACh receptors has been investigated in several early studies. Nicotine is a major irritant contained in tobacco smoke, causing burning or stinging sensations in the oral or nasal mucosa [9]. Nicotine-induced sensations are thought to involve activation of nACh receptors, including those composed of the α7 subunit, which are expressed in sensory fibers innervating these tissues as well as in the bronchial and tracheal epithelial cells of lung tissue. Menthol may reduce nicotine-induced irritation and sensory perception. More recently, menthol has been shown to act as a counterirritant to inhaled cigarette smoke, suggesting that menthol may reduce nicotine-induced responses. In addition to sensory responses, one of the major physiological effects of nicotine is a decrease in body temperature due to cutaneous vasodilation, an effect that originates in the brain and may be mediated by hypothalamic nicotinic receptors. Both chronic and acute menthol administration reduce the effects of nicotine on body temperature. Studies have shown that the traditional Chinese medicine compound Xiaoyaosan containing mint has significant therapeutic effects on depression, with mint and bupleurum being considered the main antidepressant drugs in the formula. There is limited data on the use of mint in the treatment of anxiety and depression. The European Medicines Agency has not included these indications in its herbal monographs and has approved peppermint for the following indications: mild gastrointestinal spasms, flatulence, abdominal pain, indigestion, mild headaches, coughs and colds, localized muscle pain, and itching of intact skin. The scent of peppermint has been reported to reduce fatigue and improve mood and sleep. There are also reports that peppermint infusions and fresh parts have a positive effect on the mental health of college students. Students in the treatment group reported better memory function and sleep quality, and reduced anxiety, but this study was not blinded. A recent study reported the beneficial effects of 7 days of peppermint oil aromatherapy on sleep quality scores in cancer patients.
斑马鱼(Danio rerio)是一种脊椎动物模型,广泛用于生物医学研究,包括神经毒理学研究。斑马鱼表现出与人类相似的整体神经系统和神经递质系统,包括谷氨酸能、胆碱能、5-羟色胺能、多巴胺能、肾上腺素能、GABA和组胺。成熟的斑马鱼中枢神经系统(CNS)发育良好且更为复杂,可用于模拟复杂的脑部疾病,包括焦虑和抑郁。有几种实验测定可以测量成年斑马鱼的行为学习变化,例如旋转逃逸测试、咬伤测试、新型水箱测试、位置偏好测试、T 迷宫、加迷宫和Y 迷宫测定。大多数用于评估动物模型中学习和记忆的工具都涉及视觉刺激,包括颜色偏好。斑马鱼可以辨别颜色并表现出自发的接近或回避行为。一些研究支持基于颜色的学习和记忆范式或涉及斑马鱼厌恶、焦虑或恐惧的实验。斑马鱼偏爱蓝色和绿色,避免黄色和红色。斑马鱼的视觉系统包括具有对红、绿、蓝和紫外线敏感的视锥细胞的视网膜;此外,斑马鱼是昼夜活动的动物,这使它们成为发展对视觉信号的认知反应研究的理想模型,此外,利血平具有降低血压、减慢心率的作用,最初是一种良好的降压和镇静剂。然而,先前的研究表明,急性利血平应用会导致抑郁症。The zebrafish (Danio rerio) is a vertebrate model that is widely used in biomedical research, including neurotoxicology studies. Zebrafish exhibit an overall nervous system and neurotransmitter systems similar to humans, including glutamatergic, cholinergic, serotonergic, dopaminergic, adrenergic, GABA, and histamine. The mature zebrafish central nervous system (CNS) is well developed and more complex and can be used to model complex brain disorders, including anxiety and depression. There are several experimental assays that can measure behavioral learning changes in adult zebrafish, such as the rotational escape test, bite test, novel tank test, place preference test, T-maze, plus-maze, and Y-maze assays. Most of the tools used to assess learning and memory in animal models involve visual stimulation, including color preference. Zebrafish can discriminate colors and exhibit spontaneous approach or avoidance behaviors. Some studies support color-based learning and memory paradigms or experiments involving aversion, anxiety, or fear in zebrafish. Zebrafish prefer blue and green colors and avoid yellow and red. The visual system of zebrafish includes a retina with cone cells that are sensitive to red, green, blue, and ultraviolet light; in addition, zebrafish are diurnal animals, which makes them an ideal model for the study of developing cognitive responses to visual cues. In addition, reserpine has the effect of lowering blood pressure and slowing heart rate, and was originally a good antihypertensive and sedative. However, previous studies have shown that acute reserpine application can cause depression.
电子烟,主要用于取代烟草型的香烟而使用,电子烟可将存储的电子烟雾化液或称电子烟烟油进行加热蒸发成气溶胶供用户吸食。目前市面上的含尼古丁的电子烟,因其雾化液不含有抗抑郁的有效成分,因此现有的电子烟没有抗抑郁作用、或者说对抑郁症状没有改善作用。Electronic cigarettes are mainly used to replace tobacco cigarettes. Electronic cigarettes can heat and evaporate the stored electronic cigarette atomizer liquid or electronic cigarette oil into aerosol for users to inhale. Currently, the nicotine-containing electronic cigarettes on the market do not contain effective antidepressant ingredients because their atomizer liquid does not contain antidepressant effects. Therefore, existing electronic cigarettes have no antidepressant effect or have no effect on improving depressive symptoms.
本发明的目的是提供一种具有抗抑郁作用的电子烟雾化液及其制备方法,经过大量的实验药物组合及实验观察,我们发现,在含尼古丁的电子烟雾化液中,以柠檬烯和薄荷醇为主要添加剂的电子烟雾化液能够抑制单胺氧化酶的活性又能发挥抗抑郁的作用,这种含柠檬烯薄荷醇的烟碱雾化液具有抗抑郁作用,对患有轻度抑郁、焦虑症的人群可以取代单胺氧化酶A抑制剂的作用,减轻他们的症状。The purpose of the present invention is to provide an electronic cigarette atomizer liquid with antidepressant effect and a preparation method thereof. After a large number of experimental drug combinations and experimental observations, we found that in the electronic cigarette atomizer liquid containing nicotine, the electronic cigarette atomizer liquid with limonene and menthol as main additives can inhibit the activity of monoamine oxidase and play an antidepressant effect. This nicotine atomizer liquid containing limonene and menthol has an antidepressant effect and can replace the effect of monoamine oxidase A inhibitors for people suffering from mild depression and anxiety, thereby alleviating their symptoms.
本发明的技术解决方案是,一种具有抗抑郁作用的电子烟雾化液,其配制组分按重量份包括:柠檬烯0.1~4份,烟碱0.1~5份,薄荷醇1~8份,丙二醇70~80份,甘油10~30份。The technical solution of the present invention is an electronic cigarette atomizer liquid with antidepressant effect, and its preparation components include: 0.1-4 parts of limonene, 0.1-5 parts of nicotine, 1-8 parts of menthol, 70-80 parts of propylene glycol, and 10-30 parts of glycerol in parts by weight.
优选地,所述柠檬烯0.5份,所述烟碱4份,所述薄荷醇3份,所述丙二醇72.5份,所述甘油20份。Preferably, the limonene is 0.5 parts, the nicotine is 4 parts, the menthol is 3 parts, the propylene glycol is 72.5 parts, and the glycerol is 20 parts.
本发明的另一技术解决方案是,一种具有抗抑郁作用的电子烟雾化液的制备方法,包括以下步骤:Another technical solution of the present invention is a method for preparing an electronic cigarette atomizer liquid having an antidepressant effect, comprising the following steps:
S1.按所述配制组分的重量份配比称取各组分;S1. Weigh each component according to the weight ratio of the formulated components;
S2.将所述各组分依次添加到离心管中,以200rad/min的搅拌速率充分搅拌及混合均匀;S2. The components are sequentially added to the centrifuge tube, stirred and mixed at a stirring rate of 200 rad / min;
S3.在温度为40℃的条件下浸泡480分钟;S3. Soaking at 40°C for 480 minutes;
S4.加热升温至60℃,保持20分钟后降至室温;S4. Heat to 60°C, keep for 20 minutes and then cool to room temperature;
S5.过滤杂质后即得。S5. Filter out impurities and you are done.
本发明以薄荷醇和柠檬烯为添加剂制备的以抗抑郁为主要作用的电子烟雾化液,解决了以目前市面上的含尼古丁的电子烟雾化液没有抗抑郁作用,对抑郁症状没有改善作用的缺陷,同时由于柠檬烯对肺部炎症有抗炎作用,可以减轻抽烟人群长期吸烟造成肺与气管,支气管的炎症与损伤;同时,由于本发明由柠檬烯和薄荷醇组成的电子烟雾化液,经过电子烟的雾化被用户吸收后,具有一定程度的解除焦虑、紧张、烦躁等症状的作用,还可增加记忆、改善思维、对抗抑郁的作用,对肺损伤也具有一定的保护作用。The electronic cigarette atomizer liquid with anti-depression as the main function prepared by using menthol and limonene as additives solves the defects that the electronic cigarette atomizer liquid containing nicotine currently on the market has no anti-depressant effect and no improvement effect on depressive symptoms. At the same time, since limonene has an anti-inflammatory effect on lung inflammation, it can reduce the inflammation and damage of the lungs, trachea and bronchus caused by long-term smoking in smokers; at the same time, since the electronic cigarette atomizer liquid composed of limonene and menthol of the present invention has the effect of relieving anxiety, tension, irritability and the like to a certain extent after being absorbed by users through the atomization of electronic cigarettes, it can also increase memory, improve thinking, and have the effect of anti-depression, and also has a certain protective effect on lung damage.
本发明通过以斑马鱼为模型,建立了采用利血平建立抑郁症的模型,观察了在含尼古丁的电子烟雾化液中,以薄荷醇和柠檬烯为主要添加剂的电子烟雾化液的抗抑郁作用,发现了这种电子烟雾化液有非常明显的抗抑郁作用,可以作为一种具有抗抑郁作用的电子烟雾化液。The present invention uses zebrafish as a model to establish a depression model using reserpine, observes the antidepressant effect of an electronic cigarette atomizer containing nicotine and menthol and limonene as main additives, and finds that the electronic cigarette atomizer has a very obvious antidepressant effect and can be used as an electronic cigarette atomizer with antidepressant effect.
本发明阐述的是一种具有抗抑郁作用的电子烟雾化液,其配制组分按重量份包括:柠檬烯0.1~4份,烟碱0.1~5份,薄荷醇1~8份,丙二醇70~80份,甘油10~30份。The invention discloses an electronic cigarette atomizer liquid with antidepressant effect, wherein the components thereof include, by weight: 0.1 to 4 parts of limonene, 0.1 to 5 parts of nicotine, 1 to 8 parts of menthol, 70 to 80 parts of propylene glycol, and 10 to 30 parts of glycerol.
下面将通过具体实施例对本发明进行详细说明。The present invention will be described in detail below through specific embodiments.
一种具有抗抑郁作用的电子烟雾化液,其配制组分按重量份包括:柠檬烯0.5份,烟碱4份,薄荷醇3份,丙二醇72.5份,甘油20份。An electronic cigarette atomizer liquid with antidepressant effect, wherein the prepared components include, by weight, 0.5 parts of limonene, 4 parts of nicotine, 3 parts of menthol, 72.5 parts of propylene glycol, and 20 parts of glycerol.
该具有抗抑郁作用的电子烟雾化液的制备方法,包括以下步骤:The method for preparing the electronic cigarette atomizer liquid having an antidepressant effect comprises the following steps:
S1.按上述各组分的重量份配比称取各组分;S1. Weigh each component according to the weight ratio of each component;
S2.将各组分依次添加到离心管中,以200rad/min的搅拌速率充分搅拌及混合均匀;S2. Add each component to the centrifuge tube in sequence, stir and mix thoroughly at a stirring rate of 200 rad/min;
S3.在温度为40℃的条件下浸泡480分钟;S3. Soaking at 40°C for 480 minutes;
S4.加热升温至60℃,保持20分钟后降至室温;S4. Heat to 60°C, keep for 20 minutes and then cool to room temperature;
S5.过滤杂质后即得。S5. Filter out impurities and you are done.
本发明具有抗抑郁作用的电子烟雾化液(以下实验中称为“柠檬烯烟碱雾化液”),其配方通过斑马鱼模型加以验证,主要的实验方法与结果如下:The formula of the electronic cigarette atomizer liquid with antidepressant effect of the present invention (hereinafter referred to as "limonene nicotine atomizer liquid") is verified by a zebrafish model. The main experimental methods and results are as follows:
实验柠檬烯烟碱雾化液抗抑郁功效评价Evaluation of the antidepressant efficacy of experimental limonene nicotine atomizer
一、柠檬烯烟碱雾化液安全浓度测试1. Test on safe concentration of limonene nicotine atomizing liquid
1材料方法1 Materials and methods
1.1 实验生物1.1 Experimental organisms
实验所用斑马鱼亲鱼为引种自国家斑马鱼资源中心的AB系,饲养在28.5℃恒温水浴和光/暗周期为14/10h循环水养殖系统中。本实验选用6hpf的胚胎作为样品安全浓度测试用鱼。The zebrafish broodstock used in the experiment were the AB strain introduced from the National Zebrafish Resource Center and were raised in a 28.5°C constant temperature water bath and a 14/10h light/dark cycle circulating water culture system. In this experiment, 6hpf embryos were selected as the fish for sample safety concentration testing.
1.2 受试物1.2 Test substances
1.3 仪器设备1.3 Instruments and Equipment
解剖镜,斑马鱼养殖系统(上海海圣生物实验设备有限公司),24孔板、各种规格吸头、巴氏吸管等,恒温培养箱。Dissecting microscope, zebrafish culture system (Shanghai Haisheng Biological Experiment Equipment Co., Ltd.), 24-well plate, various specifications of pipette tips, Pasteur pipettes, etc., constant temperature incubator.
1.4 实验方法1.4 Experimental methods
1.4.1斑马鱼胚胎收集:挑选出健壮的性成熟斑马鱼,在28℃恒温环境中,按照雌、雄2:3的比例在前一天晚上放入带孵化器的玻璃缸中,雌、雄用隔板分开,玻璃缸用黑布遮光。第二天,除去黑布,抽出隔板,以灯光照射。斑马鱼受光照的刺激雌鱼产卵,雄鱼排精。待其产卵完成后,去除未受精的胚胎并将受精胚胎上的异物去除,收集胚胎,在6孔细胞培养板、28 ℃恒温环境下孵化。1.4.1 Collection of zebrafish embryos: Select healthy and sexually mature zebrafish and place them in a glass tank with an incubator at a constant temperature of 28°C at a ratio of 2:3. The females and males are separated by a partition and the glass tank is shaded with a black cloth. On the second day, remove the black cloth, pull out the partition, and illuminate with light. Zebrafish are stimulated by light to lay eggs by females and ejaculate by males. After the spawning is completed, remove the unfertilized embryos and foreign bodies on the fertilized embryos, collect the embryos, and incubate them in a 6-well cell culture plate at a constant temperature of 28°C.
1.4.2安全浓度测试试验:预实验确定各药品对仔鱼致死的初步范围,即在能够使仔鱼全存活和全死亡临近的两个浓度范围,保证致死浓度的有效性。按一定比例设置0%、0.025%、0.05%、0.1%、0.2%、0.4% 6个浓度梯度。每个浓度设3个重复,每个重复10粒胚胎。使用巴士吸管随机挑选发育正常的受精卵平均放入有样品溶液的24孔板中,试验在28 ℃的恒温箱内进行,光周期的设定为12 h:12 h,定时观察并记录发育过程中的毒理学终点。观察记录胚胎的死亡率,每天至少两次在解剖显微镜下观察胚胎发育情况,在观察过程将肉眼看到白色或倒置显微镜下观察为黑色的卵被判断为死亡个体,从培养板中及时挑出。观察时尽可能在室温28 ℃时进行,动作迅速,完毕后放回恒温箱中。本试验选定的毒理学终点为胚胎发育96h的死亡率。1.4.2 Safety concentration test: The preliminary experiment determines the initial range of lethality of each drug to fry, that is, the two concentration ranges that can make the fry survive and die, to ensure the effectiveness of the lethal concentration. Set 6 concentration gradients of 0%, 0.025%, 0.05%, 0.1%, 0.2%, and 0.4% according to a certain proportion. Set 3 replicates for each concentration, and 10 embryos for each replicate. Use a bus pipette to randomly select normal fertilized eggs and put them evenly into a 24-well plate with sample solution. The experiment is carried out in a constant temperature box at 28 ℃, and the light cycle is set to 12 h:12 h. The toxicological endpoints during the development process are observed and recorded regularly. Observe and record the mortality rate of the embryos, observe the embryonic development under a dissecting microscope at least twice a day, and judge the eggs that are white to the naked eye or black under an inverted microscope as dead individuals during the observation process, and pick them out from the culture plate in time. The observation should be carried out at room temperature of 28 ℃ as much as possible, and the action should be quick, and the eggs should be put back into the constant temperature box after completion. The toxicological endpoint selected for this study was mortality at 96 hours of embryonic development.
1.5 数据统计1.5 Statistics
采用Spearmam-Karber法,计算LC50。The LC50 was calculated using the Spearmam-Karber method.
2. 实验结果2. Experimental results
2.1 柠檬烯烟碱雾化液96h的LC50和安全浓度确定2.1 Determination of LC50 and safe concentration of limonene nicotine atomized liquid for 96 hours
柠檬烯烟碱雾化液96h实验结果及LC50和安全浓度的计算结果见表1:The 96h experimental results of limonene nicotine atomized liquid and the calculation results of LC50 and safe concentration are shown in Table 1:
[根据细则26改正 05.12.2023]
表1:柠檬烯烟碱雾化液96h的实验结果及LC50的计算过程[Corrected 05.12.2023 in accordance with Rule 26]
Table 1: Experimental results of 96h limonene nicotine atomized liquid and calculation process of LC50
表1:柠檬烯烟碱雾化液96h的实验结果及LC50的计算过程[Corrected 05.12.2023 in accordance with Rule 26]
Table 1: Experimental results of 96h limonene nicotine atomized liquid and calculation process of LC50
[根据细则26改正 05.12.2023]
[Corrected 05.12.2023 in accordance with Rule 26]
[Corrected 05.12.2023 in accordance with Rule 26]
[根据细则26改正 05.12.2023]
[Corrected 05.12.2023 in accordance with Rule 26]
[Corrected 05.12.2023 in accordance with Rule 26]
根据实验结果计算,柠檬烯烟碱雾化液96h急性毒性试验LC50为0.24。According to the experimental results, the LC50 of the 96h acute toxicity test of limonene nicotine aerosol liquid is 0.24.
2.2 柠檬烯烟碱雾化液安全浓度计算2.2 Calculation of safe concentration of limonene nicotine atomizing liquid
LC50是指能引起一群受试对象50%个体死亡所需的浓度,根据柠檬烯烟碱雾化液96h急性毒性试验LC50为0.24。分别计算出安全浓度LC50/10、LC50/5和LC50/3的结果见表2LC50 refers to the concentration required to cause death in 50% of a group of subjects. According to the 96-hour acute toxicity test of limonene nicotine aerosol solution, the LC50 is 0.24. The results of calculating the safe concentrations LC50/10, LC50/5 and LC50/3 are shown in Table 2.
表2 柠檬烯烟碱雾化液急性毒性试验及安全浓度Table 2 Acute toxicity test and safe concentration of limonene nicotine atomized liquid
注:LC50:指能引起一群受试对象50%个体死亡所需的浓度Note: LC50: refers to the concentration required to cause death of 50% of a group of subjects.
根据实验结果得出:柠檬烯烟碱雾化液可以获得有效96h的LC50,同时发现样品的安全浓度含量偏低,后续功效评价采用LC50的1/10,1/5,1/3作为测试浓度(具体参看表2),对柠檬烯雾化液进行进一步的功效评价。According to the experimental results, it was concluded that the limonene nicotine atomized liquid could obtain an effective LC50 of 96 hours. At the same time, it was found that the safe concentration of the sample was low. The subsequent efficacy evaluation used 1/10, 1/5, and 1/3 of the LC50 as the test concentration (see Table 2 for details) to further evaluate the efficacy of the limonene atomized liquid.
二、柠檬烯烟碱雾化液对单胺氧化酶活性影响2. Effect of limonene nicotine atomized liquid on monoamine oxidase activity
1材料方法1 Materials and methods
1.1 实验生物1.1 Experimental organisms
实验所用斑马鱼亲鱼为引种自国家斑马鱼资源中心的AB系,本章节评价选用5 dpf的仔鱼作为实验用鱼。The zebrafish broodstock used in the experiment were the AB strain introduced from the National Zebrafish Resource Center. In this chapter, 5 dpf fry were selected as the experimental fish.
1.2 受试物和主要试剂1.2 Test substances and main reagents
(1)Reserpine(4mg/L):(Sigma | Lot:83580)(1) Reserpine (4 mg/L): (Sigma | Lot: 83580)
工作液配制:用万分之一天平,称量2mg的Reserpine,加入DMSO体积100μl,充分溶解,再加入500ml超纯水,工作液浓度4mg/L,DMSO浓度0.2‰。Preparation of working solution: Use a 1/10,000 balance to weigh 2 mg of Reserpine, add 100 μl of DMSO, fully dissolve it, then add 500 ml of ultrapure water, the working solution concentration is 4 mg/L, and the DMSO concentration is 0.2‰.
(2)Toloxatone(托洛沙酮)(200μM):(MCE | Lot:HY-14196)(2)Toloxatone (200 μM): (MCE | Lot: HY-14196)
工作液配制:用万分之一天平,称量50mg的Toloxatone,加入DMSO体积965.11μl,浓度250mM,稀释1250倍,工作液浓度200μM,DMSO浓度0.8‰。Preparation of working solution: Use a 1/10,000 balance to weigh 50 mg of Toloxatone, add 965.11 μl of DMSO, concentration 250 mM, dilute 1250 times, working solution concentration 200 μM, DMSO concentration 0.8‰.
(3)单胺氧化酶(MAO)活性检测试剂盒:(Solarbio | Lot:BC0015);(3) Monoamine oxidase (MAO) activity detection kit: (Solarbio | Lot: BC0015);
(4)BCA蛋白浓度测定试剂盒(碧云天| Lot:P0012S)(4) BCA protein concentration assay kit (Biyuntian | Lot: P0012S)
(5)受试物溶液配制:(5) Preparation of test solution:
柠檬烯烟碱雾化液按照实施例一的配方配制,配好后,分为三种浓度进行实验:The limonene nicotine atomized liquid was prepared according to the formula of Example 1. After preparation, it was divided into three concentrations for experiments:
柠檬烯烟碱雾化液低浓度组:用移液枪抽吸23 µl受试物溶于100ml超纯水中备用,工作液浓度为0.023%。Low concentration group of limonene nicotine aerosol solution: 23 µl of the test substance was aspirated with a pipette and dissolved in 100 ml of ultrapure water for later use. The working solution concentration was 0.023%.
柠檬烯烟碱雾化液中浓度组:用移液枪抽吸48 µl受试物溶于100ml超纯水中备用,工作液浓度为0.048%。Limonene nicotine aerosol liquid concentration group: use a pipette to draw 48 µl of the test substance and dissolve it in 100ml of ultrapure water for later use. The working solution concentration is 0.048%.
柠檬烯烟碱雾化液高浓度组:用移液枪抽吸80µl受试物溶于100ml超纯水中备用,工作液浓度为0.080%。High concentration group of limonene nicotine aerosol solution: 80µl of the test substance was aspirated with a pipette and dissolved in 100ml of ultrapure water for later use. The working solution concentration was 0.080%.
1.3 仪器设备1.3 Instruments and Equipment
1.4 实验方法1.4 Experimental methods
1.4.1 药物处理给药设计(见表3);1.4.1 Drug treatment and administration design (see Table 3);
表3 待测药物检测给药顺序Table 3 Drug administration sequence for testing
注:“+”表示包含此种药物;“-”表示不添加此种药物;Note: “+” means that this drug is included; “-” means that this drug is not added;
例:在受精后5h到第5天培养水中添加亚甲基蓝进行孵化(亚甲基蓝抑制培养水霉菌生长),在第5天到第6天期间培养水中添加亚甲基蓝、Reserpine、柠檬烯烟碱雾化液等进行共给药功效评价。For example, methylene blue was added to the culture water from 5 hours after fertilization to the 5th day for incubation (methylene blue inhibits the growth of cultured water molds), and methylene blue, Reserpine, limonene nicotine aerosol solution, etc. were added to the culture water from the 5th day to the 6th day for co-administration efficacy evaluation.
1.4.2实验组设置;1.4.2 Experimental group settings;
实验组设置,根据检测需要MAO检测。每个浓度组两组重复,每组30尾,共60尾仔鱼,实验容器选择6孔板,每孔添加工作液10ml,功效评价实验组设置(见表4)。Experimental group setting, MAO detection according to the detection needs. Each concentration group was repeated in two groups, 30 fish in each group, a total of 60 fish larvae, the experimental container was a 6-well plate, 10 ml of working solution was added to each well, and the efficacy evaluation experimental group was set up (see Table 4).
表4 柠檬烯烟碱雾化液功效评价实验组设置Table 4 Experimental group settings for the efficacy evaluation of limonene nicotine atomizer liquid
注:所有实验组仔鱼均正常,没有出现死亡和发育畸形,但给药过程中,实验组仔鱼多浮于水面,轻微晃动会下沉,活动正常。Note: All larvae in the experimental groups were normal, with no mortality or developmental deformities. However, during the drug administration process, most of the larvae in the experimental groups floated on the water surface and sank with a slight shake. Their activities were normal.
1.4.3 MAO酶标检测1.4.3 MAO ELISA
参照《单胺氧化酶(MAO)活性检测试剂盒:(Solarbio| Lot:BC0015)》说明书进行,在测试终点取样,每个实验组60尾仔鱼,按照试剂盒说明书提取蛋白,进行MAO测试前需先进行蛋白定量,参照说明书《BCA蛋白浓度测定试剂盒(碧云天| Lot:P0012S)》。通过测定360nm处光吸收下降的速率,计算MAO活性。Refer to the instructions of the Monoamine Oxidase (MAO) Activity Detection Kit: (Solarbio | Lot: BC0015) and take samples at the end of the test. Each experimental group has 60 fry. Protein is extracted according to the instructions of the kit. Protein quantification is required before MAO testing. Refer to the instructions of the BCA Protein Concentration Determination Kit (Biyuntian | Lot: P0012S). MAO activity is calculated by measuring the rate of decrease in light absorption at 360nm.
1.5 结果与数据分析1.5 Results and Data Analysis
MAO催化单胺类底物脱氨生成醛,进一步氧化生成酸,底物在360nm处有特征吸收峰,利用酶标仪测定360nm处光吸收下降的速率,计算MAO活性。通过SPSS进行数据处理,比较各实验组间的差异显著性(* 0.01<P≤0.05,** P≤0.01)。各测试组暴露完成后至少90%鱼胚胎存活,否则对应测试组结果无效。实验结果MAO活性见表5:MAO catalyzes the deamination of monoamine substrates to generate aldehydes, which are further oxidized to generate acids. The substrate has a characteristic absorption peak at 360nm. The rate of decrease in light absorption at 360nm is measured by an enzyme marker to calculate the MAO activity. SPSS was used to process the data and compare the significance of the differences between the experimental groups (* 0.01<P≤0.05, ** P≤0.01). At least 90% of the fish embryos survived after the exposure of each test group, otherwise the results of the corresponding test group were invalid. The experimental results of MAO activity are shown in Table 5:
表5:各组MAO活性Table 5: MAO activity in each group
从表5的结果可见,利血平模型组可显著升高斑马鱼体内MAO量,升高量达到591%,阳性药组(Toloxatone)可显著降低模型组MAO含量,酶活性为86.25,降低酶的活性为13.8%。与模型组相比,样品的3个浓度组均能显著降低模型组的MAO含量,低浓度组酶的活性与模型组相比,酶的活性降低为35.1%;中浓度组酶的活性与模型组相比,酶的活性降低为72.0%,高浓度组酶的活性与模型组相比,酶的活性降低为79.2%。实验结果提示,柠檬烯烟碱雾化液对利血平导致的斑马鱼单胺氧化酶增高有明显的抑制作用,该作用与阳性对照药Toloxatone(托洛沙酮)相比,三种测试浓度均有更明显的抑制作用,这种抑制作用与药物的浓度相关。柠檬烯烟碱雾化液能够显著降低MAO量,并且随着浓度的增加,该效果也变得更加明显。From the results in Table 5, it can be seen that the reserpine model group can significantly increase the amount of MAO in zebrafish, the increase is 591%, and the positive drug group (Toloxatone) can significantly reduce the MAO content in the model group, the enzyme activity is 86.25, and the enzyme activity is reduced by 13.8%. Compared with the model group, the three concentration groups of the sample can significantly reduce the MAO content in the model group. Compared with the model group, the enzyme activity of the low concentration group is reduced by 35.1%; compared with the model group, the enzyme activity of the medium concentration group is reduced by 72.0%, and the enzyme activity of the high concentration group is reduced by 79.2%. The experimental results suggest that limonene nicotine atomized liquid has a significant inhibitory effect on the increase of zebrafish monoamine oxidase caused by reserpine. Compared with the positive control drug Toloxatone, the three test concentrations have a more obvious inhibitory effect, and this inhibitory effect is related to the concentration of the drug. Limonene nicotine aerosol liquid can significantly reduce the amount of MAO, and the effect becomes more obvious as the concentration increases.
三、柠檬烯烟碱雾化液抗抑郁功效行为学影响3. Behavioral effects of limonene nicotine atomizer on antidepressant efficacy
1材料方法1 Materials and methods
1.1 实验生物1.1 Experimental organisms
实验所用斑马鱼亲鱼为引种自国家斑马鱼资源中心的AB系,本章节评价选用5 dpf的仔鱼作为实验用鱼。The zebrafish broodstock used in the experiment were the AB strain introduced from the National Zebrafish Resource Center. In this chapter, 5 dpf fry were selected as the experimental fish.
1.2 受试物和主要试剂1.2 Test substances and main reagents
(1)Reserpine(4mg/L):(Sigma | Lot:83580)(1) Reserpine (4 mg/L): (Sigma | Lot: 83580)
工作液配制:用万分之一天平,称量2mg的Reserpine,加入DMSO体积100μl,充分溶解,再加入500ml超纯水,工作液浓度4mg/L,DMSO浓度0.2‰。Preparation of working solution: Use a 1/10,000 balance to weigh 2 mg of Reserpine, add 100 μl of DMSO, fully dissolve it, then add 500 ml of ultrapure water, the working solution concentration is 4 mg/L, and the DMSO concentration is 0.2‰.
(2)Toloxatone (200μM):(MCE | Lot:HY-14196)(2)Toloxatone (200μM): (MCE | Lot: HY-14196)
阳性药对照;工作液配制:用万分之一天平,称量50mg的Toloxatone,加入DMSO体积965.11μl,浓度250mM,稀释1250倍,工作浓度200μM,DMSO浓度0.8‰。Positive drug control; Preparation of working solution: Use a 1/10,000 balance to weigh 50 mg of Toloxatone, add DMSO to a volume of 965.11 μl, a concentration of 250 mM, dilute 1250 times, working concentration 200 μM, DMSO concentration 0.8‰.
(3)受试物配制:(3) Preparation of test substances:
柠檬烯烟碱雾化液按照实施例一的配方配制,配好后,分为三种浓度进行实验:The limonene nicotine atomized liquid was prepared according to the formula of Example 1. After preparation, it was divided into three concentrations for experiments:
柠檬烯烟碱雾化液低浓度组:用移液枪抽吸23 µl受试物溶于100ml超纯水中备用,工作液浓度为0.023%。Low concentration group of limonene nicotine aerosol solution: 23 µl of the test substance was aspirated with a pipette and dissolved in 100 ml of ultrapure water for later use. The working solution concentration was 0.023%.
柠檬烯烟碱雾化液中浓度组:用移液枪抽吸48 µl受试物溶于100ml超纯水中备用,工作液浓度为0.048%。Limonene nicotine aerosol liquid concentration group: use a pipette to draw 48 µl of the test substance and dissolve it in 100ml of ultrapure water for later use. The working solution concentration is 0.048%.
柠檬烯烟碱雾化液高浓度组:用移液枪抽吸80µl受试物溶于100ml超纯水中备用,工作液浓度为0.080%。High concentration group of limonene nicotine aerosol solution: 80µl of the test substance was aspirated with a pipette and dissolved in 100ml of ultrapure water for later use. The working solution concentration was 0.080%.
1.3 仪器设备1.3 Instruments and Equipment
主要仪器设备,见下表:Main instruments and equipment are shown in the table below:
1.4 实验方法1.4 Experimental methods
在MAO检测的同时,在实验结束时,对给药24h活体仔鱼,进行行为学监测,实验组设置与MAO活性检测的实验组相一致。用移液管将斑马鱼仔鱼转移到96孔板,每个组16孔重复,使用自动视频跟踪系统(Videotrack)记录斑马鱼仔鱼的运动轨迹和距离。轨迹记录参数设置为light 5min+black 5min,阈值为0(所有运动均统计),单位为mm,light 5min用于稳定仔鱼,分析black 5min的轨迹和运动距离。试验结果如下(* 0.01<P≤0.05,** P≤0.01)):At the same time as the MAO test, at the end of the experiment, behavioral monitoring was performed on the live larvae that had been administered for 24 hours, and the experimental group settings were consistent with the experimental groups for MAO activity detection. The zebrafish larvae were transferred to a 96-well plate with a pipette, and 16 wells were repeated in each group. The movement trajectory and distance of the zebrafish larvae were recorded using an automatic video tracking system (Videotrack). The trajectory recording parameters were set to light 5min + black 5min, the threshold was 0 (all movements were counted), the unit was mm, light 5min was used to stabilize the larvae, and the trajectory and movement distance of black 5min were analyzed. The experimental results are as follows (* 0.01<P≤0.05, ** P≤0.01)):
1.5 实验结果1.5 Experimental Results
斑马鱼行为学是按照游动距离来判断抑郁程度,游动距离长低抑郁,游动距离短高抑郁。模型组可显著抑制斑马鱼活跃度(P<0.05),根据图中斑马鱼活动轨迹数据可以看出,模型组的斑马鱼活动轨迹以及距离明显要少于其他组。阳性药组与模型组相比,可显著提升斑马鱼活跃度(P<0.05)。样品3个浓度中均能显著提升斑马鱼活跃度(P<0.05)。行为学数据与MAO定量数据基本一致。Zebrafish behavior is based on the distance of swimming to judge the degree of depression. Long swimming distance means low depression, short swimming distance means high depression. The model group can significantly inhibit the activity of zebrafish (P<0.05). According to the data of zebrafish activity trajectory in the figure, it can be seen that the activity trajectory and distance of zebrafish in the model group are significantly less than those in other groups. Compared with the model group, the positive drug group can significantly increase the activity of zebrafish (P<0.05). All three concentrations of the sample can significantly increase the activity of zebrafish (P<0.05). The behavioral data are basically consistent with the quantitative data of MAO.
2.1斑马鱼行为学结果:2.1 Zebrafish behavioral results:
斑马鱼行为学结果见表6:The zebrafish behavioral results are shown in Table 6:
表6斑马鱼仔鱼活动距离结果Table 6 Results of activity distance of zebrafish larvae
从表6结果可见,利血平模型组与对照组相比,活动距离明显减少,仅仅为对照组的74%,减少了26%;阳性药物Toloxatone活动距离明显增加,与对照组相比,增加了11.2%;与模型组相比,增加了50%;而3组柠檬烯烟碱雾化液斑马鱼的活动距离明显增高,低浓度组与对照组相比,活From the results in Table 6, it can be seen that the activity distance of the reserpine model group was significantly reduced compared with the control group, which was only 74% of the control group, a decrease of 26%; the activity distance of the positive drug Toloxatone was significantly increased, which increased by 11.2% compared with the control group; and increased by 50% compared with the model group; while the activity distance of zebrafish in the three groups of limonene nicotine atomized liquid was significantly increased, and the activity distance of the low concentration group was significantly increased compared with the control group.
动距离明显增加,为185%,与阳性药物相比,增加123%;中浓度组与对照组相比,活动距离明显增加,为141%,与阳性药物相比,增加127%;高浓度组与对照组相比,活动距离明显增加,为145%,与阳性药物相比,增加196%。这些结果提示,利血平可以导致斑马鱼活动距离明显减少,导致抑郁症状的出现,阳性药物Toloxatone可以使斑马鱼的活动距离明显增加,可以对抗斑马鱼的抑郁症状。而3组柠檬烯烟碱雾化液斑马鱼的活动距离明显增高,比阳性药物Toloxatone的作用更强,提示了在利血平导致的斑马鱼抑郁模型中,柠檬烯烟碱雾化液的作用比抗抑郁药物Toloxatone的作用更强。The activity distance of zebrafish in the medium concentration group increased significantly by 185%, which was 123% higher than that of the positive drug; the activity distance of the medium concentration group increased significantly by 141% compared with the control group, which was 127% higher than that of the positive drug; the activity distance of the high concentration group increased significantly by 145% compared with the control group, which was 196% higher than that of the positive drug. These results suggest that reserpine can cause a significant decrease in the activity distance of zebrafish, leading to the appearance of depressive symptoms, and the positive drug Toloxatone can significantly increase the activity distance of zebrafish, which can counteract the depressive symptoms of zebrafish. The activity distance of zebrafish in the three groups of limonene nicotine aerosol solution increased significantly, which was stronger than the effect of the positive drug Toloxatone, suggesting that in the zebrafish depression model caused by reserpine, the effect of limonene nicotine aerosol solution is stronger than that of the antidepressant drug Toloxatone.
本发明技术方案配制的电子烟雾化液,具有抑制单胺氧化酶的活性及抗抑郁症的作用,安全性高,可以作为抗抑郁症的雾化剂。The electronic cigarette atomizer liquid prepared by the technical solution of the present invention has the effects of inhibiting the activity of monoamine oxidase and resisting depression, has high safety, and can be used as an atomizer for resisting depression.
以上所述仅为本发明的较佳实施例,凡依本发明权利要求范围所做的均等变化与修饰,皆应属本发明权利要求的涵盖范围。The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made within the scope of the claims of the present invention should fall within the scope of the claims of the present invention.
Claims (3)
- .一种具有抗抑郁作用的电子烟雾化液,其特征在于,其配制组分按重量份包括:柠檬烯0.1~4份,烟碱0.1~5份,薄荷醇1~8份,丙二醇70~80份,甘油10~30份。.An electronic cigarette atomizer liquid with antidepressant effect, characterized in that its preparation components include, by weight: 0.1 to 4 parts of limonene, 0.1 to 5 parts of nicotine, 1 to 8 parts of menthol, 70 to 80 parts of propylene glycol, and 10 to 30 parts of glycerol.
- 根据权利要求1所述具有抗抑郁作用的电子烟雾化液,其特征在于,所述柠檬烯0.5份,所述烟碱4份,所述薄荷醇3份,所述丙二醇72.5份,所述甘油20份。The electronic cigarette atomizer liquid with antidepressant effect according to claim 1 is characterized by comprising 0.5 parts of limonene, 4 parts of nicotine, 3 parts of menthol, 72.5 parts of propylene glycol, and 20 parts of glycerol.
- 如权利要求1或2所述具有抗抑郁作用的电子烟雾化液的制备方法,其特征在于,包括以下步骤:The method for preparing the electronic cigarette atomizer liquid having an antidepressant effect as claimed in claim 1 or 2, characterized in that it comprises the following steps:S1.按所述配制组分的重量份配比称取各组分;S1. Weigh each component according to the weight ratio of the formulated components;S2.将所述各组分依次添加到离心管中,以200rad/min的搅拌速率充分搅拌及混合均匀;S2. The components are sequentially added to the centrifuge tube, stirred and mixed at a stirring rate of 200 rad / min;S3.在温度为40℃的条件下浸泡480分钟;S3. Soaking at 40°C for 480 minutes;S4.加热升温至60℃,保持20分钟后降至室温;S4. Heat to 60°C, keep for 20 minutes and then cool to room temperature;S5.过滤杂质后即得。S5. Filter out impurities and you are done.
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