CN108837144B - Application of triptorelin - Google Patents

Application of triptorelin Download PDF

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CN108837144B
CN108837144B CN201811144930.9A CN201811144930A CN108837144B CN 108837144 B CN108837144 B CN 108837144B CN 201811144930 A CN201811144930 A CN 201811144930A CN 108837144 B CN108837144 B CN 108837144B
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曹文宇
万炜
王贞
徐杨
牛磊
钟小林
刘政海
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Abstract

The application belongs to the field of medicines, and discloses application of triptorelin, in particular application of triptorelin in preparation of a medicine for treating depression. Experiments show that in forced swimming experiments, triptorelin can obviously reduce chronic restriction stress, lipopolysaccharide, plantar injection CFA and early social isolation induced immobility time of depression model mice, and has obvious improvement effect on the depression model mice. Meanwhile, triptorelin can obviously increase the expression of mouse hippocampal BDNF and neuron synaptic plasticity related genes c-fos, egr1, arc and npas4 induced by chronic limiting stress. Therefore, the triptorelin has obvious anti-depression activity, can be used for preparing the medicament for treating depression, and has higher clinical application value and development prospect.

Description

Application of triptorelin
Technical Field
The invention belongs to the field of medicines, particularly relates to application of triptorelin, and particularly relates to application of triptorelin in preparation of a medicine for treating depression.
Background
Depression is an affective disorder mental disease which seriously affects physical and mental health, and is a group of mood disorder, affective disorder and cognitive disorder which are caused by various reasons and take depression as main symptoms, and the clinical symptoms of depression which take depressed mood and self situation as the center are related to the occurrence, development and outcome of the depression and biological, psychological and social factors. Depression has high morbidity, high recurrence rate, high disease burden and high suicide mortality. According to global disease burden survey and estimation, depression will become the second largest disease after cardiovascular disease in China by 2020, and the research on the pathogenesis, prevention approach and treatment method of depression has great medical significance and practical requirements.
Drug therapy is the primary treatment for depression episodes above moderate. The traditional tricyclic and tetracyclic antidepressants and monoamine oxidase inhibitors have larger adverse reactions and obviously reduced application. The current first-line clinical antidepressants mainly comprise selective 5-hydroxytryptamine reuptake inhibitors, 5-hydroxytryptamine and norepinephrine reuptake inhibitors and the like, but the drugs have slow effect, narrow action spectrum and easy relapse after drug withdrawal. At present, the whole industry develops more effective therapeutic drugs with quick response, small side effect. Studies have shown that multiple levels of physiological systems are involved in the pathogenesis of depression, but current drug therapy for the treatment of depression is completely dependent on drugs acting on the monoamine transmitter system. However, it has been reported statistically that such drugs are not only of limited effectiveness in the treatment of patients with depression, but also have considerable side effects.
For the pathogenesis of depression, the academia proposed a new concept in the 21 st century, namely the neurotrophic hypothesis that depression is closely related to central brain-derived neurotrophic factor (BDNF) (Duman RS, Monteggia LM. a neuropathic model for stress-related moods disorders, Biol psychiatry.2006, 59, 1116-1127). BDNF is widely distributed in brain, and regulates important physiological processes in vivo such as nerve growth and development, synaptic plasticity and the like. BDNF is known to bind to its receptor tyrosine kinase B (TrkB), and is activated by downstream mitogen-activated protein kinase (MAPK)/Extracellular Regulated Kinase (ERK), phosphatidylinositol-3-kinase (PI-3K)/protein kinase B (AKT), and Ca2+Several signaling pathways by calmodulin kinase (CaM) activate the nuclear adenosine monophosphate response element binding protein (CREB), which in turn promotes synaptic plasticity (Qi X, Lin W, Wang D, et al. a role for the extracellular signal-regulated signal pathway in depression-like promoter. Behav Brain res.2009,199: 203-. Multiple research reports prove that the expression quantity of BDNF (brain derived neurotrophic factor) protein in serum and hippocampus of depression patients and depression animal models is obviously lower than that of normal individuals; clinical applicationLong-term administration of antidepressants and electroshock therapy (ECT) have been shown to reverse these changes (Molteni R, Calabrese F, Bedogni F, et al. chrononic treatment with fluorooxetine up-regulated cells BDNF mRNA expression in a rat dopathogenic regions. Int J Neuropsychharmacol. 2006, 9, 307 channels 317). Therefore, considering the importance of the brain-derived neurotrophic factor and neuronal synaptic plasticity in depression, it is possible to treat depression by up-regulating the brain-derived neurotrophic factor and promoting neuronal synaptic plasticity.
Triptorelin belongs to GnRH agonist, and has the chemical structure as shown in the specification, and the molecular formula is C64H82N18O13(ii) a The molecular weight is 1311.45; CAS number 57773-63-4, as a white powder. The chemical formula is as follows:
Figure 713574DEST_PATH_IMAGE001
triptorelin is commonly used to treat patients who require lowering of steroid hormones, such as androgens and oestrogens, to low levels. There is no report in the literature that triptorelin can treat depression, and therefore, relevant research on the treatment of central nervous system diseases is available.
Disclosure of Invention
In view of this, the invention provides the application of the GnRH agonist triptorelin, namely the application of the triptorelin in preparing the medicament for treating the depression.
In one embodiment, the real-time fluorescent quantitative PCR method examines the effect of triptorelin on the expression of the chronic restrictive stress induced depression model mouse hippocampal BDNF and neuronal synaptic plasticity associated genes c-fos, egr1, arc, npas 4. The results show that chronic restriction stress limits down-regulate the expression of hippocampal BDNF and the genes c-fos, egr1, arc and npas4 related to neuronal synaptic plasticity, and triptorelin can reversely up-regulate the expression of hippocampal BDNF and the genes c-fos, egr1, arc and npas4 related to neuronal synaptic plasticity. Therefore, the invention provides the application of triptorelin in preparing the medicine for promoting the expression of the brain-derived neurotrophic factor BDNF and the application of triptorelin in preparing the medicine for promoting the expression of the genes c-fos, egr1, arc and npas4 related to the neuronal synaptic plasticity.
Further, in one embodiment, the invention takes triptorelin as a research object, firstly, lipopolysaccharide is adopted to establish a depression model of a mouse, GnRH agonist triptorelin is injected into the abdominal cavity of the mouse, and the depression resistance effect of the GnRH agonist triptorelin is evaluated through a forced swimming experiment. The results show that the mouse immobility time in forced swimming experiments can be obviously increased by intraperitoneal LPS injection, and the mice immobility time in forced swimming experiments can be obviously reduced by triptorelin (0.2 mg/kg) pretreatment. The triptorelin is shown to be capable of obviously improving the mouse depression-like behavior induced by LPS.
In one embodiment, the method takes triptorelin as a research object, adopts Chronic Restrictive Stress (CRS) to establish a depression model of a mouse, injects GnRH agonist triptorelin into the abdominal cavity of the mouse, and evaluates the depression resistance effect of the GnRH agonist triptorelin through a forced swimming experiment. The results show that chronic restriction stress can significantly increase the immobility time of mice in forced swimming experiments. Triptorelin (0.2 mg/kg) pretreatment significantly reduced immobility time in forced swim experiments in mice. The GnRH agonist triptorelin is shown to be capable of obviously improving the depression-like behavior of mice induced by chronic limiting stress.
In one embodiment, the invention takes triptorelin as a research object, adopts plantar injection CFA to establish a mouse depression model, injects GnRH agonist triptorelin into the abdominal cavity of a mouse, and evaluates the antidepressant effect of the GnRH agonist triptorelin through forced swimming experiments. The results show that plantar injection of CFA can significantly increase the immobility time of mice in forced swimming experiments. Triptorelin (0.2 mg/kg) pretreatment significantly reduced immobility time in forced swim experiments in mice. The triptorelin is shown to be capable of obviously improving the depression-like behavior of the mice induced by sole injection of CFA.
In one embodiment, the invention takes triptorelin as a research object, adopts early social isolation to establish a mouse depression model, injects GnRH agonist triptorelin into the abdominal cavity of a mouse, and evaluates the depression resistance effect of the GnRH agonist triptorelin through forced swimming experiments. The results show that early social isolation enables mice to have a significant increase in immobility time in forced swim experiments. Triptorelin (0.2 mg/kg) pretreatment significantly reduced immobility time in forced swim experiments in mice. The triptorelin is shown to be capable of obviously improving the depression-like behavior of mice induced by early social isolation.
In conclusion, triptorelin has obvious improvement effect on depression model mice. Meanwhile, triptorelin can obviously increase the expression of mouse hippocampal BDNF and neuron synaptic plasticity related genes c-fos, egr1, arc and npas4 induced by chronic limiting stress. The triptorelin can be used for preparing the medicament for treating the depression. Therefore, the invention provides the application of triptorelin in preparing the medicament for treating depression.
Wherein the depression is depression induced by Lipopolysaccharide (LPS), depression induced by chronic stress limitation, depression induced by sole injection of CFA, and depression induced by early social isolation.
Preferably, the medicament comprises effective dose of triptorelin and pharmaceutically acceptable auxiliary materials.
The triptorelin can be directly or indirectly added into various pharmaceutically acceptable common auxiliary materials required by the preparation of different dosage forms by the technicians in the field, and the triptorelin can be prepared into common injection preparations by a conventional pharmaceutical preparation method.
Preferably, the injection preparation is injection or powder injection.
According to the technical scheme, the invention provides the application of triptorelin, in particular to the application of triptorelin in preparing the medicament for treating depression. Experiments show that in forced swimming experiments, triptorelin can obviously reduce chronic restriction stress, lipopolysaccharide, plantar injection CFA and early social isolation induced immobility time of depression model mice, and has obvious improvement effect on the depression model mice. Meanwhile, triptorelin can obviously increase the expression of mouse hippocampal BDNF and neuron synaptic plasticity related genes c-fos, egr1, arc and npas4 induced by chronic limiting stress. Therefore, the triptorelin has obvious anti-depression activity, can be used for preparing the medicament for treating depression, and has higher clinical application value and development prospect.
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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.
FIG. 1 is a graph showing the statistical results of the effect of triptorelin on Lipopolysaccharide (LPS) -induced depression model mouse behavior of example 1;
FIG. 2 is a graph showing the statistical results of the effect of triptorelin on the behavior of chronic stress-limited-induced depression model mice of example 2;
FIG. 3 is a graph showing the statistical results of the effect of triptorelin on the behavior of plantar injection of CFA-induced depression model mice of example 3;
FIG. 4 is a graph showing the statistical results of the effect of triptorelin on early social isolation-induced depression model mouse behavior of example 4;
FIG. 5 is a graph showing the statistical results of the effects of triptorelin on the expression of the hippocampal BDNF and neuronal synaptic plasticity associated genes c-fos, egr1, arc, npas4 in a model mouse with chronic stress-induced depression in example 5.
Detailed Description
The invention discloses application of triptorelin. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the art that the techniques of the invention can be implemented and applied by modifying or appropriately combining the methods described herein without departing from the spirit, scope and spirit of the invention.
In order to further understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to 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 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.
Unless otherwise specified, the reagents involved in the examples of the present invention are all commercially available products, and all of them are commercially available.
Example 1: effect of triptorelin on LPS-induced Depression model mouse behavior
Experimental animals: 36 male C57 mice, 3 months of age, weighing about 25 g. Animals are raised in an environment with room temperature (22 +/-2) DEG C, humidity (45-65%) and alternate light and shade (12 h:12 h) and are free to eat and drink water. Animal grouping and treatment mice were divided into 3 groups according to the random number table method: normal control group (NS, n = 12), lipopolysaccharide model group (LPS, n = 12), triptorelin (LPS + TRIP, n = 12), i.p. intraperitoneal injection (i.p.) 1 time a day for 1 week of treatment, i.p. intraperitoneal injection 0.83mg/kg LPS 1h after the last drug injection in LPS group and LPS + TRIP group, and open field and forced swimming experiments started on day 8. The results are shown in FIG. 1.
Because the shortening of the animal immobility time in the classical depression animal model may be caused by the central excitability of the drug, the invention also performs a mouse Open field test (Open field test) to check the autonomous activity of the mouse and avoid the interference of the central excitant. Forced swimming of mice has been used for screening of many antidepressants, and most clinically therapeutic antidepressants have also been shown to be effective in reducing immobility time in forced swimming experiments. By immobile, it is meant that "the animal stops struggling in water, or is in a floating state, only exposing nostrils to keep breathing, and only having small limb movements to keep the head floating on the water". Animals cannot escape from the harsh environment due to downstream swimming in a forced state, resulting in despair behavior of the animals. The model method is simple, convenient and reliable, and is widely used for evaluating antidepressant drugs.
The results show that: in the open field experiment, the activity of each group of mice is not changed; intraperitoneal LPS injection can obviously increase the immobility time of mice in forced swimming experiments. Triptorelin (0.2 mg/kg) pretreatment significantly reduced immobility time in forced swim experiments in mice. Experimental results show that triptorelin can obviously improve the mouse depression-like behavior induced by LPS.
Example 2: effect of triptorelin on behavior of Chronic Restrictive Stress (CRS) -induced depressed model mice
Experimental animals: 36 male C57 mice, 3 months of age, weighing about 25 g. Animals are raised in an environment with room temperature (22 +/-2) DEG C, humidity (45-65%) and alternate light and shade (12 h:12 h) and are free to eat and drink water. Animal grouping and treatment mice were divided into 3 groups according to the random number table method: a normal Control group (Control, n = 12), a chronic restriction stress model group (CRS, n = 12), triptorelin (CRS + TRIP, n = 12), and chronic restriction stress mice were subjected to restriction stress for 6h per day for 3 weeks; triptorelin is intraperitoneally injected (i.p) 1 time a day for 3 weeks, the medicine is injected 1h before each stress limitation, and the open field experiment and forced swimming experiment are carried out 24h after the last stress. The results are shown in FIG. 2.
The results show that: in an open field experiment, the activity of a CRS group mouse is obviously reduced, and the activity of a model mouse can be obviously increased by pre-treating triptorelin (0.2 mg/kg); chronic limiting stress can significantly increase the immobility time of mice in forced swim experiments. Triptorelin (0.2 mg/kg) pretreatment significantly reduced immobility time in forced swim experiments in mice. Experimental results show that the GnRH agonist triptorelin can obviously improve the depression-like behavior of mice induced by chronic stress limitation.
Example 3: effect of triptorelin on behavior of plantar CFA-induced depressed model mice
Experimental animals: 24 male C57 mice, 3 months of age, weighing about 25 g. Animals are raised in an environment with room temperature (22 +/-2) DEG C, humidity (45-65%) and alternate light and shade (12 h:12 h) and are free to eat and drink water. Animal grouping and treatment mice were divided into 3 groups according to the random number table method: normal Control group (Control, n = 8), plantar injection CFA group (CFA, n = 8), triptorelin (CFA + TRIP, n = 8), plantar injection CFA being a classical model leading to chronic inflammatory pain and depressive behavior; triptorelin is treated for 3 weeks at i.p 1 time every day, and an open field experiment and a forced swimming experiment are started 24 hours after the last drug. The results are shown in FIG. 3.
The results show that: in an open field experiment, the activity of each group of mice is not different; plantar injection of CFA enabled mice to have a significant increase in immobility time in forced swim experiments. Triptorelin (0.2 mg/kg) pretreatment significantly reduced immobility time in forced swim experiments in mice. Experimental results show that triptorelin can obviously improve depression-like behaviors of mice induced by plantar injection of CFA.
Example 4: influence of triptorelin on behavior of early social isolation-induced depressed model mice
Animals: 30 male C57 mice, 3 weeks old, animals grouped and treated mice were divided into 3 groups according to the random number table method: normal Control group (Control, n = 10), early social isolation group (SI, n = 10), triptorelin (SI + TRIP, n = 10), early social isolation of mice 3 weeks after birth is a classical model leading to depressive behavior; starting at week 8, the SI + TRIP group was treated with triptorelin 1 i.p times daily for 3 weeks, and the open field and forced swimming tests were started 24h after the last drug. The results are shown in FIG. 4.
The results show that: in an open field experiment, the activity of each group of mice is not different; early social isolation enabled mice to have a significant increase in immobility time in forced swim experiments. Triptorelin (0.2 mg/kg) pretreatment significantly reduced immobility time in forced swim experiments in mice. Experimental results show that triptorelin can obviously improve the depression-like behavior of mice induced by early social isolation.
Example 5: influence of triptorelin on expression of hippocampal BDNF and neuronal synaptic plasticity related genes c-fos, egr1, arc and npas4 of chronic restrictive stress induced depression model mice
Experimental animals: 24 male C57 mice, 3 months of age, weighing about 25 g. Animals are raised in an environment with room temperature (22 +/-2) DEG C, humidity (45-65%) and alternate light and shade (12 h:12 h) and are free to eat and drink water. Animal grouping and treatment mice were divided into 3 groups according to the random number table method: a normal Control group (Control, n = 8), a chronic restriction stress model group (CRS, n = 8), triptorelin (CRS + TRIP, n = 8), and chronic restriction stress mice were subjected to restriction stress for 6h per day for 3 weeks; triptorelin is i.p 1 time a day for 3 weeks, and the drug is injected 1h before each stress limitation.
The mice were anesthetized by intraperitoneal injection with 4% chloral hydrate 24h after the last stress, and after complete anesthesia, hippocampal tissues were taken for RNA extraction. Extracting total RNA of tissues, carrying out reverse transcription, and detecting the influence of triptorelin on the expression of chronic restriction stress induced depression model mouse hippocampal BDNF and neuron synaptic plasticity related genes c-fos, egr1, arc and npas4 by a real-time fluorescent quantitative PCR method.
The method for RNA extraction and reverse transcription comprises the following steps:
(a) mRNA extraction and reverse transcription into cDNA by Trizol: adding 0.8 ml Trizol, homogenizing the tissue fully, and standing in an EP tube for 10 min; centrifuging at 12,000 g for 15min, and discarding the precipitate; adding 300 μ l chloroform, mixing, standing at room temperature for 15 min; centrifuging at 4 deg.C for 15min at 12,000 g, and sucking the upper water phase into another centrifuge tube without sucking the middle layer; adding isopropanol with equal volume, mixing, and standing at room temperature for 5-10 min; centrifuging at 4 deg.C for 10min at 12,000 g, removing supernatant, and precipitating RNA at the bottom of the tube; adding 1ml of 75% ethanol, and suspending RNA precipitate; centrifuging at 4 deg.C and 8000g for 5min, and removing supernatant; drying at room temperature or vacuum drying for 5-10 min; adding 20 mul DEPC water, and dissolving in water bath at 60 ℃; reverse transcription into cDNA was performed according to the Reveraid TM First Strand cDNA Synthesis Kit.
(b) RT-PCR: reaction system: SYBR Green Mix 10. mu.l; 2 mul of each of the upstream and downstream primers (2 muM); 1 μ l of cDNA; ddH2O5. mu.l (20. mu.l total system)
Reaction procedure: step 1, 5min at 95 ℃; step 2: at 95 ℃ for 15s, at 60 ℃ for 15s, at 72 ℃ for 45s, for 40 cycles; and step 3: dissolution Curve analysis
The amplification of the target gene was normalized by the internal control GAPDH, and the relative expression level of the target gene was calculated by the 2-ddct method.
The Q-PCR primers used are shown in Table 1.
Table 1: Q-PCR primer
Figure 896293DEST_PATH_IMAGE002
The results of real-time fluorescence quantitative PCR method for detecting the expression levels of triptorelin on the BDNF and the c-fos, egr1, arc and npas4 genes of the chronic restrictive stress-induced depression model mouse hippocampus and the neuronal synaptic plasticity are shown in FIG. 5.
The results show that chronic restriction stress limits down-regulated expression of hippocampal BDNF, c-fos, egr1, arc, npas4, which triptorelin can reverse its expression.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (5)

1. Application of triptorelin in preparation of drugs for promoting expression of brain-derived neurotrophic factor BDNF under chronic stress-limiting conditions.
2. Application of triptorelin in preparing medicines for promoting expression of genes c-fos, arc and npas4 related to synaptic plasticity of neurons under chronic limited stress conditions.
3. The use of triptorelin in the manufacture of a medicament for the treatment of depression; the depression is depression induced by lipopolysaccharide, chronic stress-limiting depression, depression induced by sole injection of CFA (circulating fluid injection), and depression induced by early social isolation.
4. The use according to any one of claims 1 to 3, wherein the medicament comprises an effective amount of triptorelin and a pharmaceutically acceptable excipient.
5. The use of claim 4, wherein the medicament is an injectable formulation.
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Differential expression of the immediate early genes c-Fos, Arc, Egr-1, and Npas4 during long-term memory formation in the context preexposure facilitation effect (CPFE);Nicholas等;《Neurobiology of Learning and Memory》;20171206;第128-138页 *
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