CN114848619B - Application of sertraline in preparing medicine for preventing and treating iron death related diseases - Google Patents

Application of sertraline in preparing medicine for preventing and treating iron death related diseases Download PDF

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CN114848619B
CN114848619B CN202110151743.9A CN202110151743A CN114848619B CN 114848619 B CN114848619 B CN 114848619B CN 202110151743 A CN202110151743 A CN 202110151743A CN 114848619 B CN114848619 B CN 114848619B
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epilepsy
sertraline
iron death
related diseases
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CN114848619A (en
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胡文辉
孙平
杨忠金
郝颖
熊兮
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The invention relates to application of sertraline in preparing a medicament for preventing and treating iron death related diseases, which can effectively inhibit intracellular and lipid active oxygen increase generated by iron death, reduce GPX4 expression, have good preventing and treating effects on iron death related diseases, particularly epilepsy, and have remarkable preventing and treating effects.

Description

Application of sertraline in preparing medicine for preventing and treating iron death related diseases
Technical Field
The invention relates to the technical field of chemical medicines, in particular to application of sertraline in medicines for treating iron death related diseases.
Background
Iron death (ferrovision) is a completely new mode of cell death by iron or lipid reactive oxygen species, which was discovered in 2012 by the stock well-known university of columbia, and is a novel mode of apoptosis distinguished from apoptosis, necrosis, autophagy, etc. The essence of iron death is the metabolic disorder of intracellular lipid peroxide, i.e. Glutathione (GSH) is depleted, glutathione peroxidase (Glutathione Peroxidase, GPX 4) activity is reduced, lipid peroxide cannot be metabolized by the GSH reduction reaction catalyzed by GPX4, and abnormal metabolism is further catalyzed by iron ions, so that lipid peroxide accumulates, thereby triggering cell death. Morphologically, iron death is typically characterized by smaller mitochondria, increased membrane density, and the like.
Research has found that various diseases are associated with iron death, including neurological diseases (parkinson's disease, alzheimer's disease, cerebral apoplexy, huntington's disease, epilepsy) and the like; tumors (breast cancer, esophageal cancer, liver cancer, pancreatic cancer, renal cancer, etc.); ischemia reperfusion injury (myocardial, liver and kidney, etc.); acute renal failure and iron metabolism related diseases (atherosclerosis, diabetes, etc.). Therefore, iron death is targeted, and the iron death is inhibited through the targeting of the drug capable of inhibiting iron death, so that the method has great significance for treating iron death-related diseases. Currently, there are reported iron death inhibitors such as ethyl 3-amino-4-cyclohexylaminobenzoate (Ferrostatin-1, fer-1), N- [ (3-chlorophenyl) methyl ] -spiro [ piperidine-4, 2' (1 ' h) -quinoxaline ] -3' -amine (Liproxstatin-1), 1, 8-diaza-9-fluorenone (DFO), etc., but no iron death inhibitors have been put into clinical study.
The structural formula of the sertraline (seratrodast) isIts molecular formula is C 22 H 26 O 4 The molecular weight is 354.44, the CAS number is 112665-43-7, and the thromboxane A2 receptor (TP) antagonist is effective and selective, and is mainly used for treating bronchial asthma, cough, excessive phlegm and other symptoms. At present, whether the cetrimide can prevent and treat iron death related diseases, particularly epilepsy is not explicitly reported.
Disclosure of Invention
Based on this, it is an object of the present invention to provide the use of sertraline in the manufacture of a medicament for the prevention and treatment of iron-death related disorders.
The specific technical scheme is as follows.
The application of the sertraline in preparing the medicine for preventing and treating iron death related diseases.
In some embodiments, the iron-death-related disorder is a neurological disorder; the nervous system diseases are Parkinson's disease, alzheimer's disease, cerebral apoplexy, huntington's disease, epilepsy or depression.
In some embodiments, the iron death-related disorder is epilepsy.
In some embodiments, the epilepsy is primary or secondary.
In some embodiments, the epilepsy is temporal lobe epilepsy or refractory epilepsy.
In some embodiments, the epilepsy is convulsion or status epilepticus.
In some embodiments, the epilepsy is seizure phase epilepsy.
In some embodiments, the medicament is an injection or an oral formulation, and the oral formulation may be, for example, a capsule, a granule, an enema, an oral powder, a granule, a tablet, an oral powder, a film-coated tablet, a soft capsule, a granule (sugar-free).
In some embodiments, the pharmaceutical dosage form is a capsule, granule, injection, pill, syrup, powder, paste, emulsion, solution, suspension, or tincture.
Another object of the present invention is to provide a medicament for preventing and treating iron-death-related diseases.
The specific technical scheme is as follows.
A medicament for preventing and treating iron death-related diseases, which comprises an active substance and pharmaceutically acceptable auxiliary materials, wherein the active substance comprises sertraline.
In some of these embodiments, the adjuvant comprises an excipient, filler, compatibilizer, binder, humectant, disintegrant, slow solvent, absorption accelerator, adsorbent, diluent, solubilizer, emulsifier, lubricant, wetting agent, suspending agent, flavoring agent, or perfume.
The inventor of the invention discovers in the research that the sertraline can effectively inhibit the increase of intracellular and lipid active oxygen generated by iron death, the expression of GPX4 is reduced, and the sertraline has good prevention and treatment effects on iron death related diseases, especially epilepsy, and has remarkable prevention and treatment effects.
Drawings
FIG. 1 is a graph of results of concentration-dependent inhibition of statin (erastin) induced cell death by sertraline, where A is a graph of cell viability and B is a graph of cells taken by microscopy.
FIG. 2 is a graph of the concentration-dependent inhibition of erastin-induced intracellular and lipid reactive oxygen species formation of sertraline, where A is intracellular reactive oxygen species level and B is lipid reactive oxygen species level.
FIG. 3 is a graph showing the effect of immunoblotting (WB) detection on the concentration-dependent inhibition of the erbtin-induced decrease in GPX4 expression by the celebrate, wherein A is a Western immunoblotting (western blot) detection graph of GPX4 expression, and B is a gray-scale analysis graph of a western blot result of GPX4 expression.
Fig. 4 is a graph showing the effect of sertraline on a pentatetrazolium-induced acute epileptic model, where a is myoclonus latency, B is tonic spasticity latency, C is tonic spasticity onset time, D is severity score, and E is a representative graph of nikohlrabi staining of brain sections.
Detailed Description
The following examples of the invention do not address the specific conditions of the experimental procedure, and are generally conducted under conventional conditions, or under conditions recommended by the manufacturer. The various chemicals commonly used in the examples are commercially available.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The terms "comprising" and "having" and any variations thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, apparatus, article, or device that comprises a list of steps is not limited to the elements but may, in the alternative, include additional steps or elements not listed or inherent to such process, method, article, or device.
In the present invention, the term "plurality" means two or more. "and/or", describes an association relationship of an association object, and indicates that there may be three relationships, for example, a and/or B, and may indicate: a exists alone, A and B exist together, and B exists alone. The character "/" generally indicates that the context-dependent object is an "or" relationship.
As used herein, the terms "first and second …" are used merely to distinguish between names and not to represent a particular number or order unless otherwise specified or defined.
The embodiment provides an application of the sertraline in preparing a medicament for preventing and treating iron death related diseases.
In some embodiments, the epilepsy is primary or secondary.
Primary (also referred to as idiopathic) epilepsy refers to epilepsy that has no underlying etiology other than genetic factors.
Secondary epilepsy, also known as symptomatic epilepsy, refers to epilepsy caused by other diseases.
In some of these embodiments, the epilepsy is simple epilepsy, complex epilepsy, or secondary epilepsy.
The simple partial seizure (simplepartialeizure) of epilepsy is of short duration, typically no more than 1min, with abrupt onset and end, and retained consciousness unless complicated partial seizures or tonic-clonic seizures (secondary generalization) are secondary.
Complex Partial Seizures (CPS) of epilepsy, also known as temporal lobe seizures, psychomotor seizures, represent a partial occurrence with varying degrees of disturbance of consciousness. Epilepsy discharges originate from the temporal lobe or forehead She Nace, have different origins, diffusion routes and speeds, can have large differences in clinical manifestations, can first have simple partial attacks (the time can be long or short), and then have conscious disturbance. Special sensations or purely autonomic symptoms are often precursors, attacks of deep structure (temporal lobe inner side, limbic system, etc.) origin, such as psychotic attacks (precursors), can be short and conscious disturbance occurs rapidly; consciousness disorder can also begin to exist, and even simply manifest.
In some embodiments, the epilepsy is temporal lobe epilepsy or refractory epilepsy.
Temporal lobe epilepsy, localized seizures affecting all or part of the temporal lobe, are affected by neuronal firing or damage resulting in seizures.
Refractory epilepsy (intractable epilepsy): the anti-epileptic drugs have poor therapeutic response and seizures are difficult to control, also known as refractory seizures.
In some of these embodiments, the seizure behavior is a major seizure, minor seizure, psychomotor seizure, or localized seizure.
Large seizures, also known as generalized tonic-clonic seizures, are characterized by loss of consciousness and generalized tics, and the type of seizures of frontal lobe origin are often manifested as epileptic large seizures.
Small seizures, as opposed to large seizures, involve a variety of seizures that have a smaller scope of involvement and are of shorter duration.
Psychomotor attacks, also known as complex partial attacks, are also known as temporal lobe seizures because they are mostly caused by temporal lobe lesions. Clinically, it is mainly manifested as disturbance of consciousness, mental symptoms and automatic symptoms, and a few of them can develop into systemic attacks.
Localized seizures are seizures caused by organic lesions in a certain part of the cerebral cortex (e.g., anterior and posterior central), and the external side of the brain hemisphere is internationally classified as simple partial seizures.
In some embodiments, the epilepsy is convulsion or status epilepticus.
Convulsions, also known as convulsions, are manifested as paroxysmal cramps of the limbs and facial muscles, accompanied by the upward turning of the eyes, staring or strabismus of the two sides, and mental confusion. Sometimes accompanied by white spit or mouth angle pulling, apnea, dark purple complexion, and recurrent attacks or even continuous attacks within 3-5 minutes.
Status epilepticus is a condition in which consciousness between consecutive seizures is not completely restored but frequently recurred, or seizures persist for more than 30 minutes without stopping by itself.
In some embodiments, the pharmaceutical dosage form is a capsule, granule, injection, pill, syrup, powder, paste, emulsion, solution, suspension, or tincture.
In some embodiments, the pharmaceutical dosage form is an oral solution; and/or the drug is administered orally; and/or the medicament is for use in a mammal or a human.
In some of these embodiments, the adjuvant comprises an excipient, filler, compatibilizer, binder, humectant, disintegrant, slow solvent, absorption accelerator, adsorbent, diluent, solubilizer, emulsifier, lubricant, wetting agent, suspending agent, flavoring agent, or perfume.
The present invention will be described more fully hereinafter in order to facilitate an understanding of the present invention. This invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
The sertraline is purchased from Shanghai source foliar organisms.
Erastin,2',7' -dichlorofluorescein diacetate (2 ',7' -Dichlorofluorescin diacetate, DCFH-DA) and anti-Tubulin antibody (T6199) were purchased from Sigma.
Iron death inhibitor Fer-1 was purchased from selleck corporation.
BODIPY C11 581/591 was purchased from Invitrogen corporation.
Sodium valproate was purchased from MCE company.
anti-GPX 4 antibodies (ab 125066) were purchased from abcam corporation.
C57BL/6J male mice were purchased from Experimental animal center in Guangdong province.
HT22 cells were purchased from Guangzhou Ji Ni European Biotech Co.
In order to verify the effect of the sertraline, the inventor of the invention firstly carries out in vitro experiments on inhibiting the iron death of the cells induced by the ervstin by the sertraline, then establishes an animal model of iron death related diseases, and prevents and treats the diseases by the sertraline so as to observe the effect and the drug effect of the sertraline on resisting the iron death at animal level.
Example 1 in vitro studies of the inhibition of erastin by sertraline induced cell iron death.
1. On the first day, HT22 cells were divided into 96-well plates, each well approximately 2X 10 4 A cell;
2. plates were left overnight, the supernatant was discarded, and different concentrations (0. Mu.M, 2.5. Mu.M, 5. Mu.M, 10. Mu.M) of cetrimide were added to each well for 2 hours, and 100. Mu.L of 1. Mu.M aerostin in DMEM medium containing 2% serum was added again for 8 hours;
3. after the treatment in step 2, the cells were photographed using a microscope. Subsequently, 10. Mu.L of CCK8 was added to each well, and the procedure was followed according to the instructions for the reagents, the results of which are shown in FIG. 1.
The results in FIG. 1A show that erastin can inhibit cell growth and promote cell death by iron production. With the addition of different concentrations of sertraline, cell death was effectively inhibited and this inhibition effect was dose dependent. FIG. 1B is a photograph of a light field taken by a microscope showing an increase in cell death in the erastin treated model compared to the negative control, whereas both sertraline and Fer-1 inhibited cell death.
Example 2 sertraline can inhibit erastin-induced intracellular and lipid reactive oxygen species formation in a concentration-dependent manner.
1. On the first day, HT22 cells were divided into 96-well plates, each well approximately 2X 10 4 A cell;
2. plates were left overnight, supernatants were discarded, and different concentrations (0. Mu.M, 5. Mu.M, 10. Mu.M) of sertraline were added to each well for 2 hours, and 100. Mu.L of 1. Mu.M perastin in DMEM medium with 2% serum was added again for 8 hours;
3. after the treatment in the step 2, 10 mu M of intracellular active oxygen probe DCFH-DA or lipid active oxygen probe BODIPY C11 581/591 ℃ is added into each hole to incubate for 30min at the constant temperature of the cell, then a fluorescence value is detected by a fluorescence enzyme-labeled instrument, and the intracellular active oxygen and lipid active oxygen generation conditions of the cell are observed, wherein the result is shown in figure 2.
Figure 2A shows that as sertraline is effective in reducing the formation of erastin-induced intracellular reactive oxygen species. The results in fig. 2B show that estramustine is effective in inhibiting the formation of erbtin-induced cellular lipid reactive oxygen species and that this inhibition effect is dose dependent.
Example 3 sertraline can inhibit the reduction of GPX4 expression in cells induced by erastin.
1. On the first day, HT22 cells were divided into 6 well plates, each well approximately 5X 10 5 A cell;
2. plates were left overnight, the supernatant was discarded, 3mL of different concentrations of cetrimide (0, 5, 10. Mu.M) containing 2% serum DMEM medium was added to each well, then the supernatant was discarded, and 1. Mu.M erastin was added for 8h;
3. after the treatment in the step 2, cell lysate is collected, protein is extracted according to a conventional method, then western blot analysis is carried out by using an anti-GPX 4 antibody, and tubulin is taken as an internal reference, and the result is shown in FIG. 3.
FIG. 3A is a representative graph of a western blot analysis of GPX 4. Fig. 3B shows the result of gray level analysis on western blot, and from the result, it can be seen that the expression level of GPX4 in the control group treated with erastin is significantly reduced, while administration of the pre-treated sertraline group can effectively inhibit the reduction of GPX4, and the inhibition effect is dose-dependent.
Example 4 in vivo study of the inhibition of iron death by sertraline-sertraline alleviating tebuconazole-induced epilepsy.
1. C57BL/6 male mice of 6-8 weeks old are weighed, grouped and numbered. The mice were then given gavage, estramustine (3, 9,18 mg/kg), and the positive drug sodium valproate (100 mg/kg) was given physiological saline as a parallel control once a day for five consecutive days. After the last gastric lavage administration, each mouse was given an intraperitoneal injection of 60mg/kg of pentatetrazole, observed for 30min, and the behavioral state, seizure grade, of each mouse was recorded with reference to the rating standard of Racine. Myoclonus latency is the time when the phase from intraperitoneal injection of pentatetrazole to grade 2 behavior occurs, tonic spasticity latency is the time when the phase from intraperitoneal injection of pentatetrazole to grade 5 behavior occurs, and the behavioral results are shown in fig. 4;
after 2.12 h, the mice were perfused and stained for brain and sections were prepared and the results are shown in FIG. 4.
From the results of fig. 4, the sertraline prolonged myoclonus latency (fig. 4A), tonic spasticity latency (fig. 4B), reduced tonic spasticity onset time (fig. 4C) and reduced seizure score (fig. 4D) in mice to some extent as compared to the model control group. Fig. 4E shows that the hippocampal dentate gyrus of the model group mice show atrophy, darkening, etc., indicating that neurons are damaged, while sertraline is able to reduce the number of damaged neurons.
From the above experiments, it is known that the sertraline can effectively inhibit the increase of intracellular and lipid active oxygen generated by iron death, reduce GPX4 expression, and has good prevention and treatment effects on iron death related diseases, especially epilepsy, and has remarkable prevention and treatment effects.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments have not been described for the sake of brevity, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (10)

1. The application of the sertraline in preparing the medicine for preventing and treating the iron death related disease, wherein the iron death related disease is epilepsy.
2. The use according to claim 1, wherein the epilepsy is primary or secondary.
3. The use according to claim 1, wherein the epilepsy is temporal lobe epilepsy.
4. The use according to claim 1, wherein the epilepsy is refractory epilepsy.
5. The use according to claim 1, wherein the epilepsy is convulsions or status epilepticus.
6. The use according to claim 1, wherein the epilepsy is seizure phase.
7. The use according to any one of claims 1 to 6, wherein the medicament is in the form of a capsule, or a granule.
8. The use according to any one of claims 1 to 6, wherein the medicament is in the form of an injection.
9. The use according to any one of claims 1 to 6, wherein the medicament is in the form of a pill, powder, or paste.
10. The use according to any one of claims 1 to 6, wherein the medicament is in the form of a syrup, emulsion, suspension or tincture.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016150971A1 (en) * 2015-03-24 2016-09-29 Almirall, S.A. Aminoindazole derivatives as sodium channel inhibitors
WO2016170009A1 (en) * 2015-04-21 2016-10-27 Almirall, S.A. Amino-substituted heterocyclic derivatives as sodium channel inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016150971A1 (en) * 2015-03-24 2016-09-29 Almirall, S.A. Aminoindazole derivatives as sodium channel inhibitors
WO2016170009A1 (en) * 2015-04-21 2016-10-27 Almirall, S.A. Amino-substituted heterocyclic derivatives as sodium channel inhibitors

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