阅读说明：本技术 左旋一叶萩碱及其可药用盐在制备抗抑郁症药物中的应用 (Application of L-securinine and its medicinal salt in preparing antidepressant drug ) 是由 师蕾 叶文才 王英 吴振龙 彭颖慧 陶丽君 张清华 肖涵琳 于 2020-08-11 设计创作，主要内容包括：本发明公开了左旋一叶萩碱及其可药用盐在制备抗抑郁症药物中的应用。本发明专利所述的抗抑郁药物为单一成分的左旋一叶萩碱及其可药用盐或含有左旋一叶萩碱及其可药用盐的药物组合物；上述药物或药物组合物所采用的剂型为片剂、胶囊剂、溶液剂、颗粒剂、散剂、丸剂、喷雾剂、悬浮液、注射剂或滴注液。该类药物或药物组合物及其可药用盐可应用于急性抑郁和慢性抑郁症的治疗,具有疗效显著、起效快、毒副作用小的特点。(The invention discloses application of L-securinine and a medicinal salt thereof in preparing an anti-depression medicament. The antidepressant drug disclosed by the invention is single-component L-securinine and a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the L-securinine and the pharmaceutically acceptable salt thereof; the medicament or the pharmaceutical composition adopts the dosage forms of tablets, capsules, solutions, granules, powder, pills, sprays, suspensions, injections or instillations. The medicine or the medicine composition and the medicinal salt thereof can be applied to the treatment of acute depression and chronic depression and have the characteristics of obvious curative effect, quick response and small toxic and side effect.)

1. Application of L-securinine and its pharmaceutically acceptable salt in preparing antidepressant is provided.

2. L-securineine and its pharmaceutically acceptable salts according to claim 1, wherein pharmaceutically acceptable salts include hydrochloride, sulfate and nitrate.

3. The use of L-securinega suffruticosa alkaloid and its pharmaceutically acceptable salt in the preparation of antidepressant according to claims 1-2, wherein the antidepressant is L-securinega suffruticosa alkaloid and its pharmaceutically acceptable salt or pharmaceutical composition containing the above components.

4. The use of L-securinenine and its pharmaceutically acceptable salts for the preparation of antidepressant for the treatment of depression of claims 1-3, wherein said antidepressant or pharmaceutical composition can be administered in a pharmaceutically acceptable manner and dosage form.

5. The administration mode and dosage form of the L-securinine and the pharmaceutically acceptable salt thereof or the pharmaceutical composition containing the above components in the preparation of antidepressant drug according to claim 4 are characterized in that the administration mode and dosage form can be realized by tablets, capsules, solutions, granules, powders, pills, sprays, suspensions, injections or instillations and the like.

Technical Field

The invention belongs to the field of medicines, and particularly relates to application of L-securinega suffruticosa alkaloid and pharmaceutically acceptable salts thereof in preparation of anti-depression drugs.

Background

Depression is a common mental disorder characterized primarily by a depressed mood, often accompanied by a suicidal tendency (FerrariA J, et al.PLoS Medicine2013, 10(11): e 1001547). According to the data published by the world health organization, about 3.5 million people worldwide have depression, about 100 million depression patients suicide each year, and about 6100 tens of thousands of depression patients in China. With the development of society and the acceleration of life rhythm, the number of patients is expected to increase continuously, which brings heavy economic burden to society (Phillips MR, et al,Lancet, 2009, 373(9680): 2041-2053). The first-line antidepressant drugs used in clinic at present are mainly selective 5-hydroxytryptamine reuptake inhibitors, such as fluoxetine, paroxetine, sertraline and other drugs, and the basic principle is that the 5-hydroxytryptamine level in the brain of depression patients is considered to be lower based on early researches. However, these drugs have two distinct limitations: 1) the drug effect is slow, and the effect is generally generated after the patient takes the drug for 5 to 7 weeks; 2) the response was low, with only about one third of patients responding to the drug. More notably, in some cases, the drug exerts antidepressant therapeutic effects but no increase in 5-hydroxytryptamine is detected. These evidence suggest that levels of 5-hydroxytryptamine may not be directly linked to levels of depression, nor are they the most effective targets for antidepressant drugs.

Studies have shown that multiple regions of the brain in depression patients develop lesions, the most stable of which are neuronal loss, atrophy, decreased dendritic protein expression, decreased dendritic spines and synaptic numbers in the hippocampal and prefrontal cortex sites (Krishnan Vand nester EJ,Nature, 2008, 455(7215): 894; Kang HJ, et al,Nature Medicine, 2012, 18(9): 1413-1417). In animal models of depression, pathological features of the brain consistent with the patient also appear, such as decreased branching of hippocampal neurons, shorter length, decreased dendritic spines, synaptic atrophy and the like (Duman RS, oral,Nature Medicine, 2016, 22(3): 238). The mTOR molecular signaling pathway is used as an important regulation pathway in neurons and can be adjusted by itselfThe processes of phagocytosis, transcription, translation and the like improve the expression of the neurosynaptic protein so as to promote the synaptic function, and various traditional antidepressants also have certain effect of activating mTOR; therefore, mTOR may be an important target for antidepressants (Ign cio ZM, et al, Br J Clin Pharmacol, 2016, 82(5): 1280-1290). The first antidepressant discovered in recent years, ketamine, which is different from a reuptake inhibitor of 5-hydroxytryptamine, has the advantages of quick response and high response. Ketamine can regulate the function of neural networks and neuronal synapses by inhibiting NMDA receptor function and activating mTOR pathway, but the overdose of ketamine can cause hallucinogenic and addictive properties to patients, and the clinical use is limited. Therefore, the development of a novel antidepressant with high efficiency and low toxicity is urgently needed.

Securinine (securinine) belongs to indolizidine alkaloids, and natural securinine includes levo-securinine and dextro-securinine. L-securinega suffruticosa has been found to antagonize neurotransmitter receptor GABA_AThe action of the receptors to excite central nerves (Beutler JA, et al,Brain Res1985, 3310(1):135-140), and can be used for treating facial paralysis, neurasthenia, lethargy, and poliomyelitis sequela. However, the application of the L-securinega suffruticosa alkaloid in depression has not been reported. The inventor finds that the L-securinine can improve the mTOR pathway level and the synaptic protein level of the brains of depressed mice, has obvious curative effect on the mice with acute depression and chronic depression, and is expected to be developed into a novel medicament for treating depression.

Disclosure of Invention

The invention aims to provide the application of the L-securinega suffruticosa alkaloid or the medicinal salt thereof in preparing the anti-depression medicament.

In order to achieve the purpose, the invention adopts the following technical scheme:

a L-securinine has a chemical structure as shown in formula (1):

。

the preparation method of the L-securinine and the pharmaceutically acceptable salt thereof comprises the following steps:

drying and pulverizing the plant raw material of the securinega suffruticosa, percolating and extracting by using 95% ethanol, and concentrating under reduced pressure to obtain a total extract of the securinega suffruticosa extract; suspending the total extract with water, adding 10% hydrochloric acid water solution to adjust pH to 2-3, extracting with chloroform, adding ammonia water to adjust pH to 9-10, extracting with chloroform, and concentrating chloroform layer under reduced pressure to obtain total alkaloids; purifying the total alkaloids by silica gel column chromatography to obtain an enriched part of L-securinine, and recrystallizing the enriched part to obtain L-securinine crystal.

Slowly adding dilute acid solution into the L-securinine crystal to completely dissolve the L-securinine crystal, cooling in ice water bath, drying under reduced pressure to obtain salt of L-securinine, dissolving with anhydrous ethanol, standing for recrystallization, filtering, and drying to obtain pure product of pharmaceutically acceptable salt of L-securinine.

The pharmaceutically acceptable salts described above include, but are not limited to: inorganic anions such as chloride, bromide, iodide, sulfate, sulfite, nitrate, nitrite, phosphate, and hydrogenphosphate, and the like; organic anions such as acetate, propionate, cinnamate, phenylmethanesulfonate, citrate, lactate, gluconate, and the like.

The L-securinine and its pharmaceutically acceptable salt can be made into various dosage forms, including tablet, pill, lozenge, granule, gel, unguent, solution, suppository, injection, inhalant and spray. These dosage forms can be used for both local or systemic administration and for immediate or sustained release administration. When administered by injection, the compounds can be formulated into solutions, suspensions, and emulsions with water-soluble or lipid-soluble solvents. When administered orally, they can be formulated into a complex with pharmaceutically acceptable excipients using conventional techniques. These excipients can be used to formulate the compounds into a variety of dosage forms acceptable to the patient, such as tablets, pills, capsules, suspensions, gels, and the like.

Compared with the prior art, the invention has the following advantages and beneficial effects:

the invention provides a new application of L-securinine and a medicinal salt thereof in treating depression. The experimental data show that the L-securinega suffruticosa alkaloid has obvious curative effect on mice with acute depression and chronic depression, has effect after single administration, takes effect quickly and has no influence on the autonomous movement of animals. Therefore, the anti-depression drug prepared from the L-securinine and the pharmaceutically acceptable salt thereof has the characteristics of obvious curative effect, quick response and good safety.

Drawings

FIG. 1: the pharmacokinetics curve of single intraperitoneal administration of the L-securinine for blood inflow and brain inflow is shown in the specification, wherein A is the blood concentration of the L-securinine after different time of intraperitoneal administration, and B is the brain concentration of the L-securinine after different time of intraperitoneal administration.

FIG. 2: securinine levorotatory reduced the level of acute depression in mice in a forced swim model: after intraperitoneal administration of L-securinine for 30min (A) or 90min (B), the result of immobility time in the experiment is forced. The result of 15 mice per group experiment is the mean value + -SEM, and the statistical method is one-way ANOVA; p <0.05, p < 0.01.

FIG. 3: l-securinenine activates AKT-mTOR-S6K, ERK and p38 pathways in mouse brain: (A) performing intraperitoneal injection of L-securinine for 90min, homogenizing forebrain parts (mainly including cerebral cortex and hippocampus), performing Western blot experiment, and detecting response of each signal channel. (B-G) statistics of different signaling pathway protein changes; the result is the mean value + -SEM of 6 groups of samples, and the statistical method is one-way ANOVA; p <0.01, p < 0.001.

FIG. 4: the oral administration of the L-securinine has the following effects of resisting acute depression: statistics of forced swimming immobility time after 3 hours of oral administration of securinega suffruticosa alkali. Results are mean ± SEM for 15 mice per group, one-way ANOVA, p <0.05 as statistical method.

FIG. 5: therapeutic effect of securinine levorotatory on chronic depression model mice: after administration of securinine, mice, a chronic depression model, were tested for carbohydrate preference (a), forced swimming (B), mTOR pathway activation (C), and PSD95 expression (D). It can be seen that a single administration improves carbohydrate bias and increases immobility time in forced swimming; the effect is more obvious after multiple times of administration. For the aspects of mTOR pathway activation and PSD95 expression, the effect of single administration is not obvious, and the effect of multiple administrations is obvious. Results were mean ± SEM for 15 mice per group, statistical methods one-way ANOVA, p <0.01, p <0.001, depression model + DMSO vs normal mice group; # p <0.05, # p <0.01, # p <0.001, depressive model + Securinegine levogyration group vs depressive model + DMSO group; a depression model, a single levorotatory securinine group vs depression model and a multiple levorotatory securinine group.

FIG. 6: the L-securinine does not generate toxic and side effects on the autonomous behavior of the mice: after the administration of the L-securinine for 60min, various indexes of the movement of the mice in an open field are tested: (A) a central zone residence time; (B) peripheral zone dwell time; (C) a center region movement distance; (D) peripheral zone movement distance; (E) a total movement distance; (F) a central region movement speed; (G) peripheral region

The speed of movement; (H) the total speed of movement. All indexes have no statistical difference. Results are mean ± SEM of 15 mice per group, one-way ANOVA is the statistical method.

Detailed Description

The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the present invention are not limited thereto.