CN114767690A - Application of cephalothin acid in preparation of antidepressant drug - Google Patents
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- CN114767690A CN114767690A CN202210712283.7A CN202210712283A CN114767690A CN 114767690 A CN114767690 A CN 114767690A CN 202210712283 A CN202210712283 A CN 202210712283A CN 114767690 A CN114767690 A CN 114767690A
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- antidepressant
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Abstract
The invention relates to the technical field of biological medicines, in particular to application of cephalothin acid in preparation of antidepressant drugs. The application of the cephalothin acid in the preparation of antidepressant drugs is provided. The cephalothin acid can effectively relieve PC12 cell injury caused by corticosterone induction and relieve neuroinflammation. The corticosterone-induced depression model can simulate the pathological process of depression, and can be used for the efficacy evaluation and mechanism exploration of antidepressant medicaments. The patent can provide scientific basis for clinical medication of depression.
Description
Technical Field
The invention relates to the technical field of biological medicines, and in particular relates to application of cephalothin acid in preparation of antidepressant medicines.
Background
Depression is a type of mood disorder characterized clinically primarily by a marked and persistent depression, the most common affective disorder. It has the characteristics of high disease incidence, high recurrence rate and high disability rate. The world health organization investigative study in 2021 showed that about 3.5 million people worldwide suffer from depression, which will be the second leading cause of premature death or disability. Depression not only affects the quality of life of patients, but also places a heavy economic burden on patients and families.
Researchers believe that inflammatory cytokines, neurotrophic factors, hypothalamic-pituitary-adrenal Hormone (HPA) axons may be present as biomarkers of depression. At present, one of the accepted theories of the pathogenesis of depression is HPA axial hyperactivity. Corticosterone is an important hormone at the end of the HPA axis, and its abnormal increase can lead to depressive features. Nerve cell damage is one of important indexes of nerve cell apoptosis, and rat adrenal pheochromocytoma cell PC12 is a common nerve cell strain for researching depression and has the general characteristics of neuroendocrine cells. Apoptosis refers to the autonomous, ordered death of cells under the control of genes in order to maintain homeostasis, and a decrease in mitochondrial membrane potential is a marker event in the early stages of apoptosis. Corticosterone-induced poorly differentiated PC12 cells are used as an in vitro research model for depression, apoptosis-related indexes are detected, and the protective effect of the medicine on nerve cells can be observed.
At present, first-line antidepressant drugs mainly comprise fluoxetine, paroxetine, sertraline, fluvoxamine and citalopram, target serotonin and noradrenaline pathways, can relieve depression symptoms to a certain extent, but have the limitations that the drugs are easy to relapse after stopping treatment and the like. Therefore, it is important to obtain a drug which can relieve depression by protecting nerve cells with little side effects.
The cephalothin acid is a broad-spectrum sterilization type antibiotic in the breeding period, is stable to penicillinase and has strong gram-positive bacteria resistance. The antibacterial and anti-infective activities of antibiotics have been widely used clinically. In addition, antibiotics have a series of neuroprotective functions, such as prevention of occurrence of nerve infection, prevention of mitochondria-mediated cytochrome C release, prevention of microglial activation, reduction of cytotoxicity due to accumulation of glutamic acid, and the like. Antibiotics have potential therapeutic significance for partial types of neurological diseases and mental disorders, such as neurological damage caused by cerebral ischemia, mental diseases, depression, schizophrenia and the like. Through retrieval, no relevant report of antidepressant effect of cephalothin acid is found at present.
The Chinese patent application with application publication number CN201010283126.6 discloses a method for synthesizing cephalothin acid by 7-ACA, which takes one or more of n-hexane, cyclohexane and petroleum ether as a crystallization solvent to crystallize to separate out the cephalothin acid, thereby achieving the characteristics of quick drying, light color and high yield, and the treatment effect of the cephalothin acid for resisting depression by inhibiting inflammation is not clear.
Disclosure of Invention
The application aims to provide an application of cephalothin acid in preparation of antidepressant drugs, and aims to solve the problem that a drug which can relieve depression symptoms by reducing inflammation level and has small side effect is absent in the prior art.
In order to achieve the purpose of the application, the technical scheme adopted by the application is as follows:
in a first aspect, the present application provides the use of cephalothin acid for the preparation of a medicament for use as an antidepressant.
Further, the cephalothin acid can realize antidepressant by playing a role in protecting nerve cells.
Further, the exerting of the nerve cell protection effect comprises improving the activity of rat adrenal pheochromocytoma PC12 cells.
Further, the exerting of the neurocyte protective effect comprises reducing the apoptosis rate of the PC12 cell and increasing the mitochondrial membrane potential.
Further, the cephalothin acid is used as the only active ingredient of the antidepressant drug.
Further, the antidepressant drug comprises at least one of a pharmaceutically acceptable salt, a eutectic crystal, a stereoisomer, a prodrug, a solvate and a metabolite of the cephalothin acid.
Further, the antidepressant drug also comprises pharmaceutically acceptable auxiliary materials; wherein the adjuvants comprise at least one of diluent, excipient, filler, binder, humectant, absorption enhancer, surfactant, lubricant, stabilizer, flavoring agent, sweetener, and pigment.
Furthermore, the antidepressant medicament can be prepared into any pharmaceutically acceptable dosage form, and the dosage form comprises any one of emulsion, cream, pills, dripping pills, capsules, granules, powder, liniment, cataplasm, spray, oral liquid, decoction, injection, sustained release preparation or controlled release preparation.
Further, the drug concentration of the cephalothin acid is 0.1-10 nM.
In a second aspect, the present application provides an antidepressant drug comprising cephalothin acid or a pharmaceutically acceptable salt, cocrystal, stereoisomer, prodrug, solvate, metabolite thereof.
The application of cephalothin acid provided by the first aspect of the application in preparing antidepressant drugs. The cephalothin acid can effectively relieve PC12 cell injury caused by corticosterone induction and relieve neuroinflammation. The pathological process of the corticosterone-induced depression model is close to that of clinical patients, the actual curative effect of the antidepressant can be reflected, a new strategy and a clinical research basis are provided for the antidepressant, and a basis is further provided for guiding clinical medication of the depressive disorder.
An antidepressant drug provided in the second aspect of the present application, comprising cephalothin acid or a pharmaceutically acceptable salt, cocrystal, stereoisomer, prodrug, solvate, metabolite thereof. In the using process, the cephalothin acid is applied to the preparation of antidepressant drugs. The cephalothin acid can effectively relieve PC12 cell injury caused by corticosterone induction and relieve neuroinflammation. The pathological process of the corticosterone-induced depression model is close to that of clinical patients, the actual curative effect of the antidepressant can be reflected, a new strategy and a clinical research basis are provided for the antidepressant, and a basis is further provided for guiding clinical medication of the depressive disorder.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
Wherein:
FIG. 1 shows the effect of cephalothin acid on the activity of PC12 cells at different concentrations;
FIG. 2 is a graph of the effect of cephalothin acid on the cell viability of corticosterone-induced PC12 cell injury at different concentrations;
FIG. 3 is a graph showing the effect of cephalothin acid on the rate of corticosterone-induced apoptosis of PC12 cells at various concentrations.
FIG. 4 is a graph showing the effect of cephalothin acid on the rate of PC12 apoptosis induced by corticosterone at different concentrations.
FIG. 5 is a graph showing the effect of cephalothin acid on corticosterone-induced mitochondrial membrane potential of PC12 cells at various concentrations.
FIG. 6 is a graph showing the effect of cephalothin acid on corticosterone-induced mitochondrial membrane potential of PC12 cells at different concentrations.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive step based on the embodiments of the present invention, are within the scope of protection of the present invention.
In a first aspect of the embodiments herein there is provided the use of cephalothin acid in the manufacture of an antidepressant medicament.
The application of cephalothin acid provided by the first aspect of the embodiment of the application in preparing antidepressant drugs. The cephalothin acid can effectively relieve PC12 cell injury caused by corticosterone induction and relieve neuroinflammation. The pathological process of the corticosterone-induced depression model is close to that of clinical patients, can reflect the real curative effect of depression resistance, provides a new strategy and clinical research basis for depression resistance, and further provides a basis for guiding clinical medication of depression.
In some embodiments, cephalothin acid has the formula C16H16N2O6S2The molecular weight is 396.438, and the structure is shown in formula (I):
（I）。
in some embodiments, the cephalothin acid achieves antidepressant effects by exerting a neurocytoprotective effect.
In some embodiments, the exerting the neuroprotective effect comprises increasing the viability of rat adrenal pheochromocytoma PC12 cells.
In some embodiments, the exerting a neuroprotective effect comprises decreasing the rate of apoptosis of PC12 cells and increasing the mitochondrial membrane potential.
In some embodiments, the cephalothin acid is the only active ingredient of the antidepressant drug.
In some embodiments, the antidepressant drug includes at least one of a pharmaceutically acceptable salt, co-crystal, stereoisomer, prodrug, solvate, metabolite of cephalothin acid.
In some embodiments, the antidepressant further comprises a pharmaceutically acceptable excipient; wherein the adjuvants comprise at least one of diluent, excipient, filler, binder, humectant, absorption enhancer, surfactant, lubricant, stabilizer, flavoring agent, sweetener, and pigment.
In some embodiments, the antidepressant may be formulated into any one of pharmaceutically acceptable dosage forms, including any one of emulsion, cream, pill, drop pill, capsule, granule, powder, liniment, cataplasm, spray, oral liquid, decoction, injection, sustained release preparation or controlled release preparation.
In some embodiments, the cephalothin acid drug concentration is 0.1-10 nM.
In a second aspect of the embodiments herein there is provided an antidepressant drug comprising cephalothin acid or a pharmaceutically acceptable salt, cocrystal, stereoisomer, prodrug, solvate, metabolite thereof.
An antidepressant drug as provided in the second aspect of the embodiments of the present application, said antidepressant drug comprising cephalothin acid or a pharmaceutically acceptable salt, cocrystal, stereoisomer, prodrug, solvate, metabolite thereof. In the using process, the cephalothin acid is applied to the preparation of antidepressant drugs. The cephalothin acid can effectively relieve PC12 cell injury caused by corticosterone induction and relieve neuroinflammation. The pathological process of the corticosterone-induced depression model is close to that of clinical patients, the actual curative effect of the antidepressant can be reflected, a new strategy and a clinical research basis are provided for the antidepressant, and a basis is further provided for guiding clinical medication of the depressive disorder.
Specific examples are provided below for illustration.
Cell lines used in the examples: PC12 cells were purchased from Biotech limited, Jones and Xinzhou, Shanghai, by culturing in RPMI-1640 medium containing 10% fetal bovine serum and 1% double antibody at 37 deg.C and 5% CO2Culturing in a cell culture box.
The drugs used in the examples: cephalothin acid, provided by Shanghai-sourced leaf Biotechnology Limited, product batch number: B12O10D 99935.
Example 1
(one)) experimental method
The used corticosterone-induced PC12 cell injury model is a well-known ideal external model of depression, simulates the pathological state of depression, and is suitable for inspecting the antidepressant action characteristics of cephalothin acid.
The invention adopts a CCK8 method to evaluate the protective activity of cephalothin acid on corticosterone damage PC12 cells. PC12 cells are digested with trypsin and cultured in a complete medium to obtain a cell content of 1 × 10/ml5The suspension was inoculated into a 96-well plate at 100. mu.L/well, incubated at 37 ℃ with 5% CO2And (5) culturing in an incubator. After 24h, cell sap is discarded, a blank group is added with a complete culture medium, an administration group is added with the complete culture medium with the concentration of 0.1, 0.25, 0.5, 1, 2.5, 5, 10nM cephalothin acid respectively, and each concentration is provided with 6 multiple wells; after incubation for 24h, 10. mu.L of CCK8 solution was added to each well, and after further incubation for 1.5 h, the absorbance (OD) of each well was measured at 450nm using a microplate reader, and the cell viability of each group was calculated.
After 24h of plating culture, removing cell sap, adding complete culture medium into the blank group and the model group, adding complete culture medium with the concentrations of 0.25, 0.5, 1, 2.5, 5, 10nM cephalothin acid into the administration group, and setting 6 multiple holes for each concentration; after 24h incubation, the medium was discarded, the blank group was added with complete medium, and the model group and the administration group were added with complete medium containing 150 μ M corticosterone; after incubation for 24h, 10. mu.L of CCK8 solution was added to each well, and after further incubation for 1.5 h, the absorbance (OD) of each well was measured at 450nm using a microplate reader, and the cell viability of each group was calculated.
PC12 cells are digested with pancreatin and then cultured in complete medium to obtain cells with a cell content of 1 × 10/ml5Inoculating to 24-well culture plate (500 μ L per well), placing at 37 deg.C and 5% CO2And (5) incubator culture. After 24h, cell sap is discarded, complete culture media are added into the blank group and the model group, complete culture media with the concentrations of 2.5, 5 and 10nM cephalothin acid are added into the administration group, and 3 multiple wells are arranged at each concentration. Incubating for 24h, removing culture medium, adding complete culture medium to blank group, adding complete culture medium containing 150 μ M corticosterone to model group and administration group, incubating for 24h, digesting cells with pancreatin, collecting cells, centrifuging for 5 min at 1000 g, removing supernatant, washing with PBS once, centrifuging for 5 min at 1000 g, removing supernatant, adding binding solution to cell precipitate for resuspension, adding Annexin in dark place, and adding AnnexinAnd (3) incubating the V-FITC/PI double staining agent for 15 min at room temperature in a dark place, and detecting the apoptosis rate on a computer.
After cell precipitation is prepared as above, JC-1 staining working solution is added, incubation is carried out for 20 min at 37 ℃, centrifugation is carried out for 4 min at 600 g, cells are collected, 1 mL of JC-1 staining buffer solution is added for washing twice, the cells are precipitated, 200 μ L of JC-1 staining buffer solution is added for resuspension, and mitochondrial membrane potential is detected on a machine.
(II) results of the experiment
2.1 the cephalothin acid concentration is not higher than 10nM and has no obvious toxicity to PC12 cell.
The effect of cephalothin acid on the activity of PC12 cells is shown in FIG. 1. The result shows that when the concentration is not higher than 10nM, the cephalothin acid has no obvious cytotoxicity to PC12 cells, and provides a safe range reference for the use concentration of the cephalothin acid in subsequent experiments.
2.2 cephalothin acid can obviously improve PC12 cell damage induced by corticosterone.
The protective effect of cephalothin acid on PC12 cells injured by corticosterone is shown in FIG. 2 (C: (C))### P<0.001vs blank;*** P<0.001vs model set). The result shows that the cell survival rate of the administration group under each concentration is improved to a certain extent compared with that of the model group, and statistical difference exists, which indicates that the compound can effectively relieve corticosterone-induced PC12 cell injury.
2.3 cephalothin acid can obviously reduce the PC12 cell apoptosis rate induced by corticosterone.
The effect of cephalothin acid on the rate of corticosterone-induced apoptosis of PC12 cells is shown in FIGS. 3 and 4: (### P<0.001vs blank;* P<0.05 vs model set). Compared with a blank control group, the apoptosis rate of the model group is obviously increased; compared with the model group, the apoptosis rate of the cephalothin acid administration group is obviously reduced, and the 5nM concentration shows obvious difference; the application of cephalothin acid to treatment shows that the cephalothin acid has obvious anti-apoptosis effect on PC12 cells damaged by corticosterone.
2.4 Cefthiophene acid can significantly reverse corticosterone-induced decrease in mitochondrial membrane potential of PC12 cells.
The effect of cephalothin acid on corticosterone-induced mitochondrial membrane potential of PC12 cells is shown in fig. 5 and 6. (### P<0.001vs blank;** P<0.01 vs model set). Compared with a blank control group, the cell mitochondrial membrane potential of the model group is obviously reduced; compared with a model group, the mitochondrial membrane potential of the cephalothin acid administration group is obviously increased, and the concentration of 10nM shows obvious difference; the method shows that the early apoptosis of PC12 cells damaged by corticosterone can be improved by adopting cephalothin acid for treatment.
In conclusion, the cephalothin acid provided by the application can be applied to the preparation of antidepressant drugs. The cephalothin acid can effectively relieve PC12 cell injury caused by corticosterone induction and relieve neuroinflammation. The corticosterone-induced depression model can simulate the pathological process of depression and can be used for evaluating the drug effect of antidepressant drugs and researching the mechanism of the antidepressant drugs. The patent can provide scientific basis for clinical medication of depression.
While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not to be limited to the disclosed embodiment, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
Claims (10)
1. Application of cephalothin acid in preparing antidepressant is provided.
2. The use as claimed in claim 1, wherein said cephalosporanic acid is antidepressant by exerting a neurocytoprotective effect.
3. The use of claim 2, wherein said neuroprotective effect comprises increasing the viability of rat adrenal pheochromocytoma PC12 cells.
4. The use of claim 2, wherein said neuroprotective effect comprises decreasing the rate of apoptosis of PC12 cells and increasing mitochondrial membrane potential.
5. The use according to any one of claims 1 to 4, wherein cephalothin acid is used as the sole active ingredient of the antidepressant.
6. The use of any one of claims 1 to 4, wherein the antidepressant drug comprises at least one of a pharmaceutically acceptable salt, a cocrystal, a stereoisomer, a prodrug, a solvate and a metabolite of cephalothin acid.
7. The use of any one of claims 1 to 4, wherein the antidepressant further comprises a pharmaceutically acceptable excipient; wherein the adjuvants comprise at least one of diluent, excipient, filler, binder, humectant, absorption enhancer, surfactant, lubricant, stabilizer, flavoring agent, sweetener, and pigment.
8. The use of any one of claims 1 to 4, wherein the antidepressant is formulated into any one of pharmaceutically acceptable dosage forms, including emulsion, cream, pill, drop pill, capsule, granule, powder, liniment, cataplasm, spray, oral liquid, decoction, injection, sustained release preparation or controlled release preparation.
9. The use according to any one of claims 1 to 4, wherein the drug concentration of cephalothin acid is 0.1 to 10 nM.
10. An antidepressant drug, which is characterized in that the antidepressant drug comprises cephalothin acid or pharmaceutically acceptable salts, eutectic crystals, stereoisomers, prodrugs, solvates and metabolites thereof.
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Citations (7)
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| US5977090A (en) * | 1996-09-27 | 1999-11-02 | Guilford Pharmaceuticals Inc. | Pharmaceutical compositions and methods of treating compulsive disorders using NAALADase inhibitors |
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| US20100160300A1 (en) * | 2008-12-23 | 2010-06-24 | Brookhaven Science Associates, Llc | Method of Treating Depression |
| CN101979393A (en) * | 2010-09-16 | 2011-02-23 | 苏州中联化学制药有限公司 | Method for synthesizing cephalothin acid by using 7-aminocephalosporanic acid (ACA) |
| CN104151242A (en) * | 2014-06-06 | 2014-11-19 | 四川大学 | Dihydro isoquinoline compound and application thereof in preparation of nerve protection or antidepressant medicament |
| CN105820053A (en) * | 2016-04-23 | 2016-08-03 | 黄亦琼 | Pharmaceutical composition of cefalexin and application of pharmaceutical composition in biological medicine |
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- 2022-06-22 CN CN202210712283.7A patent/CN114767690B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5977090A (en) * | 1996-09-27 | 1999-11-02 | Guilford Pharmaceuticals Inc. | Pharmaceutical compositions and methods of treating compulsive disorders using NAALADase inhibitors |
| US20040014739A1 (en) * | 1999-08-16 | 2004-01-22 | Koppel Gary A. | Neurotherapeutic clavulanate composition and method |
| CN1871243A (en) * | 2003-08-25 | 2006-11-29 | 雷瓦尔克斯药品有限公司 | Oral neurotherapeutic cefazolin compositions |
| US20100160300A1 (en) * | 2008-12-23 | 2010-06-24 | Brookhaven Science Associates, Llc | Method of Treating Depression |
| CN101979393A (en) * | 2010-09-16 | 2011-02-23 | 苏州中联化学制药有限公司 | Method for synthesizing cephalothin acid by using 7-aminocephalosporanic acid (ACA) |
| CN104151242A (en) * | 2014-06-06 | 2014-11-19 | 四川大学 | Dihydro isoquinoline compound and application thereof in preparation of nerve protection or antidepressant medicament |
| CN105820053A (en) * | 2016-04-23 | 2016-08-03 | 黄亦琼 | Pharmaceutical composition of cefalexin and application of pharmaceutical composition in biological medicine |
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