CN114748472B - Application of mitomycin C in preparation of antidepressant - Google Patents
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- CN114748472B CN114748472B CN202210675330.5A CN202210675330A CN114748472B CN 114748472 B CN114748472 B CN 114748472B CN 202210675330 A CN202210675330 A CN 202210675330A CN 114748472 B CN114748472 B CN 114748472B
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Abstract
The invention relates to the technical field of biological medicines, in particular to application of mitomycin C in preparation of an antidepressant. The application of mitomycin C in preparing antidepressant is provided. Mitomycin C can effectively inhibit the increase of the level of PC12 cell inflammation caused by corticosterone induction, relieve inflammatory reaction and further exert the antidepressant effect. 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.
Description
Technical Field
The invention relates to the technical field of biological medicines, and in particular relates to application of mitomycin C in preparation of an antidepressant.
Background
The depression is the fourth disease in the world, the medical prevention and treatment of the depression in China are in the situation of low recognition rate, the recognition rate of hospitals above grade city is less than 20%, and only less than 10% of patients receive related drug treatment; in addition, the onset of depression (and suicidal events) has begun to trend toward a lower age (university, or even a group of primary and secondary school students).
Current first-line antidepressant drugs mainly include fluoxetine, paroxetine, sertraline, fluvoxamine and citalopram, targeting the serotonin and norepinephrine pathways. Although the depression symptom can be relieved to a certain extent, the traditional Chinese medicine has the limitations of easy relapse after stopping treatment and the like. Thus, it is of great importance to have available a drug that can alleviate depression by reducing the level of inflammation with minimal side effects.
Mitomycin C is a broad-spectrum antitumor antibiotic separated and extracted from a streptomyces racemosus culture solution, has an anticancer effect on various cancers, and has the action principle of inhibiting tumor cell division by depolymerizing DNA in cells and simultaneously inhibiting the replication of the DNA. In addition to the antibacterial and anti-infective activities of antibiotics, antibiotics also have a series of neuroprotective functions, such as prevention of occurrence of nerve infection, prevention of mitochondria-mediated release of cytochrome C, prevention of activation of microglia, reduction of cytotoxicity caused by 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. At present, mitomycin C has not been reported in the aspect of depression resistance.
The Chinese patent application with application publication No. CN201610118928.9 discloses a combined drug use scheme of total ginsenoside extract and mitomycin C for anti-tumor, provides a drug use scheme that the total ginsenoside extract can enhance the anti-non-small cell lung cancer and anti-liver cancer drug effects of mitomycin C and cisplatin in an in vitro human non-small cell lung cancer cell strain A549 and a liver cancer cell strain HepG2, and simultaneously is verified on an in vivo A549 nude mouse transplanted tumor model, while the treatment effect of mitomycin C on anti-depression through inhibiting inflammation is unclear and is irrelevant to the requirements of the patent.
Disclosure of Invention
The application aims to provide application of mitomycin C in preparation of antidepressant drugs, and aims to solve the problem of lack of a drug which can relieve depression symptoms by reducing inflammation level and has small side effect in the prior art.
In a first aspect, the application provides the use of mitomycin C in the preparation of an antidepressant medicament.
Furthermore, mitomycin C can reduce inflammatory reaction by improving the activity of rat adrenal pheochromocytoma PC12 cells or reducing the expression level of inflammatory factors interleukin-1 beta and interleukin-6, thereby playing an anti-depression role.
Further, the step of down-regulating the expression levels of inflammatory factors interleukin-1 beta and interleukin-6 comprises: the mitomycin C is combined with at least one amino acid of LYS-65, SER-43, LEU-62, TYR-90, PRO-87 amino acid of the interleukin-1 beta or ALA-152 and ARG-154 amino acid of the interleukin-6 amino acid, thereby regulating the expression level of the interleukin-1 beta or the interleukin-6 or the concentration of the protein coded by the interleukin-6.
Further, the mitomycin C acts as the sole active ingredient of the antidepressant drug.
Further, the antidepressant drug comprises at least one of pharmaceutically acceptable salts, cocrystals, stereoisomers, prodrugs, solvates and metabolites of mitomycin C.
Further, the antidepressant drug also comprises pharmaceutically acceptable auxiliary materials.
Further, the auxiliary material comprises at least one of diluent, excipient, filler, adhesive, wetting agent, absorption enhancer, surfactant, lubricant, stabilizer, flavoring agent, sweetener and pigment which are conventional in the pharmaceutical field.
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 mitomycin C is 2.5-100 nM.
In a second aspect, the present application provides an antidepressant drug comprising mitomycin C or a pharmaceutically acceptable salt, co-crystal, stereoisomer, prodrug, solvate, metabolite thereof.
The use of mitomycin C as provided in the first aspect of the application in the manufacture of an antidepressant medicament. Mitomycin C can effectively inhibit the increase of the level of PC12 cell inflammation caused by corticosterone induction, and relieve inflammatory reaction. The corticosterone-induced depression model can simulate the pathological process of depression, 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.
An antidepressant drug provided in a second aspect of the present application, said antidepressant drug comprising mitomycin C or a pharmaceutically acceptable salt, co-crystal, stereoisomer, prodrug, solvate, metabolite thereof. In the using process, mitomycin C can effectively inhibit the increase of the level of PC12 cell inflammation caused by corticosterone induction, relieve inflammatory reaction and further achieve the effect of anti-depression; the patent provides a new treatment strategy for depression and further guides the clinical reasonable medication of depression.
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 is a graph showing the effect of mitomycin C on the viability of PC12 cells at various concentrations;
FIG. 2 is a graph of the effect of mitomycin C on the cell viability of corticosterone-induced PC12 cell injury at various concentrations;
FIG. 3 is a graph of the effect of mitomycin C at various concentrations on corticosterone-induced levels of the cytokine interleukin-1 β of PC 12;
FIG. 4 is a graph showing the effect of mitomycin C at various concentrations on corticosterone-induced levels of the cytokine interleukin-6 PC 12;
FIG. 5 shows the docking results of mitomycin C with interleukin-1 beta;
FIG. 6 shows the docking results of mitomycin C with the interleukin-6 molecule, an inflammatory factor.
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 derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In a first aspect, the embodiments herein provide the use of mitomycin C in the preparation of an antidepressant medicament.
The use of mitomycin C as provided in the first aspect of the embodiments herein for the preparation of an antidepressant. Mitomycin C can effectively inhibit the increase of the level of PC12 cell inflammation caused by corticosterone induction, and relieve inflammatory reaction. The corticosterone-induced depression model can simulate the pathological process of depression and reflect the curative effect of the medicament on depression, and the patent can provide a new treatment strategy for depression and further guide the clinical reasonable medication of depression.
In some embodiments, mitomycin C has the formula C 15 H 18 N 4 O 5 The molecular weight is 334.3, and the structure is shown as formula (I):
formula (I).
In some embodiments, the mitomycin C exerts an antidepressant effect by increasing the viability of rat adrenal pheochromocytoma PC12 cells or down-regulating the expression levels of the inflammatory factors interleukin-1 β and interleukin-6, reducing the inflammatory response.
In some embodiments, the medicament is antidepressant by reducing inflammatory response.
In some embodiments, the reducing the inflammatory response is increasing the viability of rat adrenal pheochromocytoma PC12 cells.
In some embodiments, the reducing the inflammatory response is downregulating the expression levels of the inflammatory factors interleukin-1 β and interleukin-6.
In some embodiments, the step of down-regulating the expression levels of the inflammatory factors interleukin-1 β and interleukin-6 comprises: the mitomycin C is combined with at least one amino acid of LYS-65, SER-43, LEU-62, TYR-90, PRO-87 amino acid of the interleukin-1 beta or ALA-152 and ARG-154 amino acid of the interleukin-6 amino acid, thereby regulating the expression level of the interleukin-1 beta or the interleukin-6 or the concentration of the protein coded by the interleukin-6.
In some embodiments, the mitomycin C is the only active ingredient of the antidepressant drug.
In some embodiments, the antidepressant drug comprises at least one of a pharmaceutically acceptable salt, co-crystal, stereoisomer, prodrug, solvate, metabolite of mitomycin C.
In some embodiments, the antidepressant further comprises a pharmaceutically acceptable excipient.
In some embodiments, the excipient includes at least one of a diluent, an excipient, a filler, a binder, a wetting agent, an absorption enhancer, a surfactant, a lubricant, a stabilizer, a flavoring agent, a sweetener, and a pigment, which are conventional in the pharmaceutical field.
In some embodiments, the antidepressant drug can be prepared 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 drug concentration of mitomycin C is 2.5 to 100 nM.
In a second aspect of the embodiments herein there is provided an antidepressant drug including mitomycin C or a pharmaceutically acceptable salt, co-crystal, 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 mitomycin C or a pharmaceutically acceptable salt, co-crystal, stereoisomer, prodrug, solvate, metabolite thereof. In the using process, mitomycin C can effectively inhibit the increase of the level of PC12 cell inflammation caused by corticosterone induction, relieve inflammatory reaction and further achieve the effect of anti-depression; provides a new strategy and clinical research basis for resisting depression, and further provides a basis for guiding clinical medication of depression.
Specific examples are provided below for illustration.
Cell lines used in the examples: PC12 cells were obtained from Shanghai Joseph Biotech limited by using 10% fetal bovine serum and 1% double antibody in RPMI-1640 medium at 37 deg.C and 5% CO 2 Culturing in a cell culture box.
The drugs used in the examples: mitomycin C, supplied by shanghai-derived phyllo biotechnology limited, product lot no: t43319.
Example 1
(I) Experimental method
The corticosterone-induced PC12 cell injury model is a well-known ideal external model of depression, can simulate the pathological state of depression, and is suitable for investigating the antidepressant action characteristics of mitomycin C.
The invention adopts a CCK8 method to evaluate the protective activity of mitomycin C on PC12 cells damaged by corticosterone. PC12 cells are digested with trypsin and cultured in a complete medium to obtain a cell content of 1 × 10/ml 5 The suspension was inoculated into a 96-well plate at 100. mu.L/well, incubated at 37 ℃ with 5% CO 2 And (5) incubator culture. Discarding cell sap after 24h, adding complete culture medium into blank group, and adding concentrate into administration groupComplete culture medium with mitomycin C degree of 0.1, 0.5, 2.5, 5,10,20, 40, 80, 160 μ M, 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, cell sap is removed, a blank group and a model group are added with complete culture media, an administration group is added with complete culture media with the concentrations of 2.5, 5,10, 25, 50 and 100nM mitomycin C respectively, and each concentration is provided with 3 multiple holes; 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 24h incubation, 10. mu.L of CCK8 solution was added to each well, and after further 1.5 h incubation, 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/ml 5 The suspension of (4) was inoculated into a 24-well plate at 500. mu.L/well, and placed at 37 ℃ in 5% CO 2 And (5) incubator culture. After 24h, the cell fluid was discarded, and the blank group and the model group were added to complete medium, and the administration group was added to complete medium at concentrations of 2.5, 5, and 10nM mitomycin C, respectively, with 3 duplicate wells per concentration. After 24h incubation, the culture medium is discarded, the blank group is added with the complete culture medium, the model group and the administration group are added with the complete culture medium containing 150 mu M corticosterone, and after 24h incubation, the levels of inflammatory factors interleukin-1 beta and interleukin-6 are detected by taking cell supernatant through an ELISA method.
Downloading PDB files of 3D structures of interleukin-1 beta and interleukin-6 through a PDB database; acquiring a mol2 file of a mitomycin C2D structure from a PubChem database; and (2) performing pretreatment operations such as compound 3D structure conversion, compound and target protein format conversion, ligand extraction and format conversion, protein dehydration, hydrogenation and the like by using AutoDockTools and OpenBabel software, and performing molecular docking on mitomycin C, interleukin-1 beta and interleukin-6 respectively by using the AutoDock software to determine the binding targets of the mitomycin C, the interleukin-1 beta and the interleukin-6.
(II) results of experiment
2.1 mitomycin C concentrations below 0.5. mu.M were not significantly toxic to PC12 cells.
The effect of mitomycin C on the viability of PC12 cells is shown in FIG. 1 ( *** P<0.001vs blank). The result shows that when the concentration is lower than 0.5 mu M, mitomycin C has no obvious cytotoxicity to PC12 cells, and provides a safe range reference for the use concentration of mitomycin C in subsequent experiments.
2.2 mitomycin C significantly ameliorated corticosterone-induced PC12 cell damage.
The protective effect of mitomycin C on corticosterone-damaged PC12 cells is shown in FIG. 2 ( ### P<0.001vs blank; ** P<0.01， *** P<0.001vs model group). The results show that the cell survival rate of the administration group is improved to a certain extent compared with that of the model group at the concentration of 2.5, 5,10 and 25 nM, and a significant difference exists, which indicates that the compound can effectively relieve PC12 cell injury induced by corticosterone.
2.3 mitomycin C significantly reduced corticosterone-induced inflammation of PC12 cells.
The effect of mitomycin C on corticosterone-induced PC12 cytokine interleukin-1 beta is shown in FIG. 3, and the effect on inflammatory factor interleukin-6 is shown in FIG. 4 ( # P<0.05， ## P<0.01vs blank; * P<0.05vs model set). Compared with a blank control group, the model group has obviously increased levels of inflammatory factors interleukin-1 beta and interleukin-6; compared with a model group, the mitomycin C administration group has obvious reduction of inflammatory factors interleukin-1 beta and interleukin-6 and obvious difference; the application of mitomycin C administration treatment has obvious anti-inflammatory effect on PC12 cells damaged by corticosterone.
2.4 mitomycin C stably binds to the inflammatory factors interleukin-1 beta and interleukin-6.
The docking results of mitomycin C and interleukin-1 beta molecules are shown in FIG. 5, and the docking results of mitomycin C and interleukin-6 molecules are shown in FIG. 6. The interaction of the mitomycin C and LYS-65, SER-43, LEU-62, TYR-90 and PRO-87 of interleukin-1 beta or the amino acids ALA-152 and ARG-154 of interleukin-6 is further verified that the mitomycin C can be combined with the interleukin-1 beta and interleukin-6, and plays an anti-inflammatory role so as to resist depression.
In conclusion, the mitomycin C provided by the application in the preparation of the antidepressant drug can effectively inhibit the increase of the PC12 cell inflammation level caused by corticosterone induction and relieve the inflammatory reaction. 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.
The above disclosure is only for the purpose of illustrating the preferred embodiments of the present invention, and it is therefore to be understood that the invention is not limited by the scope of the appended claims.
Claims (9)
1. The use of mitomycin C in the preparation of an antidepressant medicament, wherein said antidepressant medicament comprises mitomycin C or a pharmaceutically acceptable salt thereof.
2. The use of claim 1, wherein mitomycin C exerts an antidepressant effect by increasing the viability of the adrenal pheochromocytoma PC12 cells or by down-regulating the expression levels of the inflammatory factors interleukin-1 β and interleukin-6, reducing the inflammatory response.
3. The use of claim 2, wherein the step of down-regulating the expression levels of the inflammatory factors interleukin-1 β and interleukin-6 comprises: the mitomycin C is combined with at least one amino acid of LYS-65, SER-43, LEU-62, TYR-90, PRO-87 or ALA-152 and ARG-154 of interleukin-6 of the amino acid of interleukin-1 beta, thereby regulating the expression level of interleukin-1 beta or interleukin-6 or the concentration of the protein coded by the interleukin-6.
4. The use according to any one of claims 1 to 3, wherein mitomycin C is the sole active ingredient of said antidepressant.
5. The use of any one of claims 1 to 3, wherein the antidepressant further comprises a pharmaceutically acceptable excipient.
6. The use of claim 5, wherein the excipient comprises at least one of a diluent, a filler, a binder, a wetting agent, an absorption enhancer, a surfactant, a lubricant, a stabilizer, a flavoring agent, a sweetener, and a pigment, which are conventional in the pharmaceutical field.
7. The use according to any one of claims 1 to 3, wherein the antidepressant is formulated into any one of pharmaceutically acceptable dosage forms, including any one of emulsion, cream, pill, capsule, granule, powder, liniment, cataplasm, spray, oral liquid, decoction, injection and controlled release preparation.
8. The use of any one of claims 1 to 3, wherein the antidepressant is formulated in any one of the pharmaceutically acceptable dosage forms, including a drop pill or a sustained release formulation.
9. The use according to any one of claims 1 to 3, wherein the drug concentration of mitomycin C is 2.5 to 25 nM.
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| WO1986007260A1 (en) * | 1985-06-06 | 1986-12-18 | Georgetown University | 1a-7-SUBSTITUTED DERIVATIVES OF MITOMYCIN AND USES THEREOF |
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| CN101732238A (en) * | 2010-02-09 | 2010-06-16 | 黄绳武 | Mitomycin c ophthalmic gel |
| CN102018686A (en) * | 2010-12-16 | 2011-04-20 | 浙江大学医学院附属邵逸夫医院 | Mitomycin-containing film agent and preparation method thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1986007260A1 (en) * | 1985-06-06 | 1986-12-18 | Georgetown University | 1a-7-SUBSTITUTED DERIVATIVES OF MITOMYCIN AND USES THEREOF |
| WO2005102280A1 (en) * | 2004-03-26 | 2005-11-03 | The Bankruptcy Estate Of Ferx Incorporated | Magnetically targetable mitomycin c compositions and methods of their use |
| CN101732238A (en) * | 2010-02-09 | 2010-06-16 | 黄绳武 | Mitomycin c ophthalmic gel |
| CN102018686A (en) * | 2010-12-16 | 2011-04-20 | 浙江大学医学院附属邵逸夫医院 | Mitomycin-containing film agent and preparation method thereof |
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| Title |
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| Effect of mitomocin C in eosinophilic nasal polyposis, in vivo: concentration of IL5 and GM-CSF, RT-PCR;Mirian Cabral Moreirade Castro等;《Brazilian Journal of Otorhinolaryngology》;20060228;第72卷(第1期);第38-42页 * |
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| 腺性膀胱炎采用经尿道汽化电切联合丝裂霉素治疗的效果观察;文曙光等;《航空航天医学杂志》;20180625;第29卷(第06期);第666-668页 * |
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