Application of Prazosin in preparation of medicine for treating anorexia nervosa

Abstract

The invention provides an innovative AN drug treatment strategy, and based on a prazosin targeted LC-NE neural circuit, the weight is increased and the AN symptom is improved by reducing LC-NE neuron over-excitation, restoring appetite and improving the anxiety state. The application is characterized in that: different from the traditional antidepressant or antipsychotic drug, the pazosin can directly regulate and control the feeding loop. The safety is high, clinical use experience exists, and indications can be directly expanded. Individual treatment schemes are provided and can be independently used or combined for treatment, and the curative effect is improved. The application is expected to provide a new thought and a new drug choice for AN treatment, and promote the research of the NE system in eating disorders.

Description

Technical Field

[0001] This specification relates to the field of biomedicine, and particularly to the use of Prazosin in the preparation of drugs for the treatment of anorexia nervosa. Background Art

[0002] Anorexia Nervosa (AN) is a severe eating disorder characterized by persistent reduction in energy intake, extreme fear of weight gain, and abnormal perception of one's own weight and body shape. AN not only leads to significant weight loss, but also is accompanied by metabolic disorders, cardiovascular abnormalities, and cognitive function impairment, and can even lead to death. Due to the complexity of this disease, its treatment still faces major challenges.

[0003] Existing treatment methods and their limitations: Currently, the main treatment methods for AN include psychological intervention (such as cognitive behavioral therapy CBT), nutritional supplementation therapy, drug therapy, and neuromodulation therapy. 1) Psychological intervention and behavioral therapy: Cognitive behavioral therapy (CBT) is the main psychological intervention means for the treatment of AN, aiming to help patients correct distorted cognitions about eating, weight, and body image. However, the efficacy of CBT has large individual differences, and the treatment cycle is long, and the patient compliance is relatively low, especially for severe patients who are difficult to adhere to the treatment. 2) Existing drug therapies and their deficiencies: Antidepressants (such as fluoxetine): Although some AN patients are accompanied by anxiety and depressive symptoms, SSRI antidepressants are effective in improving mood, but have limited effects in promoting weight recovery. Antipsychotics (such as olanzapine): Studies have found that olanzapine can increase the weight of AN patients, but its side effects (such as drowsiness, increased risk of metabolic syndrome) limit its long-term use. Mirtazapine: It can improve anxiety and eating behavior, but some patients have problems such as sedation and insignificant weight gain. 3) Neuromodulation therapy: In recent years, neuromodulation methods such as transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) have been explored for the treatment of AN, but the high cost of equipment, invasiveness (DBS), or unstable individual efficacy limit their widespread application. Summary of the Invention

[0004] To solve the above technical problems, the present application proposes to use the α1-adrenergic receptor antagonist - Prazosin in the treatment of anorexia nervosa. The advantages of this strategy include: 1) Novel mechanism of action: Prazosin is a centrally permeable α1-adrenergic receptor antagonist that can directly act on the norepinephrine (NE) system and improve AN-related feeding inhibition by regulating the locus coeruleus (LC)-hypothalamus and reward circuitry. Prazosin can target the central nervous system, reduce the overexcitation of LC neurons, and thus improve appetite. 2) Improve the core symptoms of AN (promote feeding and weight recovery): Animal experiments show that Prazosin can reduce the hyperactivity of anorectic model mice, increase food intake, and promote weight recovery. Compared with traditional antidepressants, Prazosin has a weaker sedative effect, does not significantly affect cognitive function or cause drowsiness, and is more suitable for long-term treatment. 3) Potential neuroprotective effect: Studies have shown that α1 receptor antagonists can reduce the damage of chronic stress to brain structure and may play a role in reducing cognitive and emotional disorders caused by chronic stress in AN patients. 4) Good safety and tolerability: Prazosin has been approved by the FDA for the treatment of hypertension and post-traumatic stress disorder (PTSD), and its safety has been clinically verified. Its new uses can be expanded on the basis of existing indications. Low-dose Prazosin has a relatively small effect on blood pressure, making it more suitable for AN patients with low body weight and low blood pressure itself.

[0005] The present application provides the use of Prazosin in the preparation of a product having one or more of the following functions:

[0006] Treat anorexia;

[0007] Reduce the overactivation of locus coeruleus neurons;

[0008] Reverse or inhibit the overactivation of locus coeruleus norepinephrine neurons;

[0009] Reduce locus coeruleus c-Fos positive cells and TH / c-Fos co-expressing cells;

[0010] Promote feeding and weight recovery;

[0011] Reduce anxiety-like hyperactive behavior and reduce total activity;

[0012] Protect brain nerves and reduce brain damage caused by chronic stress;

[0013] Reduce anxiety and metabolic disorders;

[0014] Improve individual survival rate;

[0015] Alleviate the degree of body temperature drop.

[0016] The present application also provides a method for treating anorexia nervosa, which is characterized by administering a therapeutically effective amount of a pharmaceutical composition containing prazosin to an individual with anorexia nervosa.

[0017] The beneficial effects brought by the present application include but are not limited to:

[0018] 1) Improved efficiency: Significantly enhanced therapeutic effect: Traditional AN treatments (such as psychotherapy, antidepressant drugs) usually take months or even years to show effects, while the method of the present application using prazosin can significantly improve food intake and weight recovery within a short period (4 - 8 weeks). More direct neuromodulatory effect: Different from SSRIs (such as fluoxetine) that indirectly regulate emotions, prazosin restores the feeding motivation by directly reducing the overexcitation of LC-NE neurons, with a more precise action and more stable curative effect. Shorter adaptation period: AN patients are usually highly sensitive to drug side effects, while prazosin has a shorter adaptation period, higher patient compliance, and is easier to adhere to treatment.

[0019] 2) Reduced side effects and improved safety: Avoidance of adverse reactions of traditional antipsychotic drugs: Drugs such as olanzapine and risperidone may cause metabolic syndrome, sedative effects, and movement disorders, while prazosin does not cause similar side effects. Non-addictive and safe for long-term use: Compared with some sedative drugs (such as benzodiazepines), prazosin does not produce drug dependence and has a lower risk for long-term use. Applicable to a wider population of AN patients: Suitable for patients with low body weight and low blood pressure (because its α1-receptor antagonistic effect is relatively mild and low doses do not cause severe hypotension). Applicable to AN patients with anxiety symptoms, which can simultaneously improve the anxiety state and enhance the overall therapeutic effect.

[0020] 3) Innovative mechanism of action: Unique targeting of the NE system: The method of the present application uses prazosin to reduce the excitability of LC-NE neurons. This strategy is different from traditional 5-HT (antidepressants) or dopamine (antipsychotics) regulation methods, opening up a new AN treatment target. Precise action on the neural circuits related to feeding: By inhibiting the abnormal overexcitation of LC, it improves appetite and energy balance. By regulating LC → medial septal nucleus (reward system), it restores the positive stimulation effect of food and reduces food avoidance behavior. Filling the research gap of the norepinephrine system (NE) in the treatment of AN and providing a new research direction for future treatment of eating disorders

[0021] 4) Convenient application and improved patient compliance: Oral administration is convenient to use. This method mainly uses oral tablets or capsules, without the need for injection or invasive treatment, and is easier to promote on a large scale clinically than methods such as TMS (transcranial magnetic stimulation) or DBS (deep brain stimulation). Flexible treatment plan: It can be used alone or in combination with psychotherapy (CBT), nutritional support, and anti-anxiety drugs, and is suitable for different groups of AN patients. Sustained-release preparations can be used to reduce the daily dosing frequency and improve patient compliance.

[0022] 5) Low production cost and great promotion potential: Prazosin is an existing drug approved by the FDA, and there is a mature production process. There is no need to develop new molecules, the R & D cost is low, and the market access is fast. Compared with expensive antipsychotic drugs (such as olanzapine) or neuromodulation techniques (TMS / DBS), the production and use costs of prazosin are lower, making it more suitable for clinical promotion. Suitable for areas with limited medical resources: Since AN patients have a high incidence rate globally (especially in developed countries), and existing treatment methods (such as CBT and neuromodulation therapy) are costly and have low coverage, this method provides a more accessible drug treatment option.

[0023] 6) Environmentally friendly: The existing production process of prazosin is mature, and there is no need to develop new production processes additionally, avoiding the generation of a large amount of experimental waste during the new drug development process, meeting environmental protection requirements. Oral administration has no pollution risk, and compared with injectable drugs, it reduces the problem of medical waste disposal.

[0024] 7) Wide range of applicable populations: Suitable for AN patients of all ages (especially adult patients), without the need for special gene screening or expensive personalized treatment plans. It can be used for long-term AN patients, patients with recurrent conditions, or those with poor tolerance to existing treatments, providing new treatment options. The application in other eating disorders (such as stress eating disorder, avoidant restrictive food intake disorder ARFID) can be further explored to expand the indication range.

[0025] 8) Economic and social value: ① Reducing the medical burden: The long-term treatment cost of AN is high, especially for severe patients who need hospitalization. This application provides a more economical and effective drug intervention means, which can reduce the long-term medical cost. ② Improving the quality of life of patients: Compared with mandatory eating interventions, prazosin can help patients naturally regain their appetite, reduce food avoidance, and improve their daily social and living abilities. ③ Enhancing the overall level of the AN treatment field: Currently, the drug treatment options for AN are limited. The solution of this application provides a new breakthrough point for this field, promoting future research and treatment innovation for eating disorders. Brief Description of the Drawings

[0026] This application will be further described by way of exemplary embodiments, which will be described in detail through the drawings. These embodiments are not restrictive, and among them:

[0027] Figure 1 showed a significant activation of noradrenergic neurons in the locus coeruleus of anorectic mice ( Figure 1 A: locus coeruleus of normal mice, Figure 1 B: locus coeruleus of anorectic mice) Green (TH): marker for noradrenergic neurons in the locus coeruleus; Red (cFos): marker for neuron activation; Yellow (TH / cFos): proportion of noradrenergic neurons in the locus coeruleus that are activated.

[0028] Figure 2 showed a decrease in the activation level of locus coeruleus neurons after injection of the NE receptor Adra1a antagonist prazosin (left: saline, right: prazosin).

[0029] Figure 3 showed that daily injection of 1 mg / kg of the NE receptor Adra1a antagonist prazosin could relieve the symptoms of anorectic mice (A) Schematic diagram of the drug treatment protocol; (B - E) Effects of intraperitoneal injection of prazosin on the activity, body weight, food intake, and body temperature of ABA mice; FR, fasting phase; BL, baseline data collected before drug administration and fasting intervention.

[0030] Figure 4 showed that daily injection of 2 mg / kg of the NE receptor Adra1a antagonist prazosin could relieve the symptoms of anorectic mice (A) Schematic diagram of the drug treatment protocol; (B - E) Effects of intraperitoneal injection of prazosin on the activity, body weight, food intake, and body temperature of ABA mice. Detailed implementation mode

[0031] To more clearly illustrate the technical solutions of the embodiments of this specification, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the drawings in the following description are only some examples or embodiments of this specification. For those of ordinary skill in the art, without creative efforts, this specification can also be applied to other similar scenarios based on these drawings. Unless obvious from the language context or otherwise stated, the same reference numerals in the figures represent the same structure or operation.

[0032] As shown in this specification and the claims, unless the context clearly indicates an exceptional situation, words such as "a", "an", "one", and / or "the" are not specifically singular and may also include the plural. Generally speaking, the terms "comprising" and "including" only indicate the inclusion of the clearly identified steps and elements, and these steps and elements do not constitute an exclusive list. The method or device may also include other steps or elements.

[0033] Flowcharts are used in this specification to illustrate the operations performed by the systems according to the embodiments of this specification. It should be understood that the operations before or after do not necessarily have to be executed precisely in order. On the contrary, the steps can be processed in reverse order or simultaneously. Also, other operations can be added to these processes, or one or more steps can be removed from these processes.

[0034] This application provides the use of prazosin in the preparation of a product having one or more of the following functions:

[0035] Treating anorexia;

[0036] Reducing the overactivation of locus coeruleus neurons;

[0037] Reversing or inhibiting the overactivation of locus coeruleus noradrenergic neurons;

[0038] Reducing locus coeruleus c-Fos positive cells and TH / c-Fos co-expressing cells;

[0039] Promoting food intake and weight recovery;

[0040] Reducing anxiety-like hyperactive behavior and decreasing total activity;

[0041] Protecting brain nerves and reducing brain damage caused by chronic stress;

[0042] Reducing anxiety and metabolic disorders;

[0043] Increasing individual survival rate;

[0044] Alleviating the degree of body temperature drop.

[0045] In some embodiments, the product can reduce the overactivation of locus coeruleus neurons in anorexic individuals.

[0046] In some embodiments, the product can reverse or inhibit the overactivation of locus coeruleus noradrenergic neurons in anorexic individuals.

[0047] In some embodiments, the product can reduce locus coeruleus c-Fos positive cells and TH / c-Fos co-expressing cells in anorexic individuals.

[0048] In some embodiments, the product can promote food intake and weight recovery in anorexic individuals.

[0049] In some embodiments, the product can reduce anxiety-like hyperactive behavior and decrease total activity in anorexic individuals.

[0050] In some embodiments, the product can protect the brain nerves of anorexic individuals and reduce cognitive and emotional disorders caused by chronic stress in anorexic individuals.

[0051] In some embodiments, the product can reduce anxiety and metabolic disorders in anorexic individuals.

[0052] In some embodiments, the product can increase the survival rate of anorexic individuals.

[0053] In some embodiments, the product can alleviate the degree of body temperature drop in anorexic individuals.

[0054] In some embodiments, the product does not affect cognitive function or cause drowsiness.

[0055] In some embodiments, the product does not affect the cognitive function of anorexic individuals or cause drowsiness.

[0056] In some embodiments, the anorexia may include at least one of anorexia nervosa, emotional anorexia, physiological anorexia, anorexia related to depression, or anorexia related to anxiety.

[0057] In some embodiments, the anorexia may be anorexia nervosa.

[0058] In some embodiments, the product may be a drug or a health product.

[0059] The present application also provides a method for treating anorexia, characterized in that a therapeutically effective amount of a pharmaceutical composition containing Prazosin is administered to an anorexic individual.

[0060] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0061] As used generally herein, "pharmaceutically acceptable" means such compounds, materials, compositions, and / or dosage forms that are suitable, within the scope of reasonable medical judgment, for contact with the tissues, organs, and / or body fluids of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0062] The excipients include various excipients and diluents, which are not essential active ingredients and have no excessive toxicity after administration. The excipients include sterile water or physiological saline, stabilizers, excipients, antioxidants (such as ascorbic acid), buffers (phosphoric acid, citric acid, other organic acids, etc.), preservatives, surfactants (PEG, Tween, etc.), chelating agents (EDTA, etc.) or binders. The excipients also include other low-molecular-weight polypeptides, serum albumin, glycine, glutamine, asparagine, arginine, polysaccharides, monosaccharides, mannitol or sorbitol. The excipients for aqueous solutions for injection are selected from physiological saline, glucose isotonic solution, D-sorbitol isotonic solution, D-mannose isotonic solution, D-mannitol or sorbitol isotonic solution. The aqueous solution for injection contains solubilizers. The solubilizers are selected from alcohols (ethanol), polyols (propylene glycol or PEG) and / or non-ionic surfactants (Tween 80 or HCO-50).

[0063] In the pharmaceutical composition, the Prazosin can be a single active ingredient or can be combined with one or more other active components useful for the treatment of diseases to form a combined preparation.

[0064] The content of the active component in the pharmaceutical composition is a safe and effective amount, and the safe and effective amount should be adjustable for those skilled in the art. For example, the dosage of the Prazosin and the active ingredient of the pharmaceutical composition depends on the patient's weight, the type of application, the condition and severity of the disease.

[0065] In some embodiments, the administration mode of the pharmaceutical composition can be selected from any one of oral administration, intraperitoneal injection, intravenous injection, subcutaneous injection or intramuscular injection.

[0066] In some embodiments, the anorexia can include at least one of anorexia nervosa, emotional anorexia, physiological anorexia, anorexia related to depression or anorexia related to anxiety disorder.

[0067] In some embodiments, the anorexia can be anorexia nervosa.

[0068] This application proposes a new use of Prazosin in the treatment of anorexia nervosa (AN), aiming to improve food intake and weight recovery of AN patients and reduce AN-related anxiety and metabolic disorders by regulating the norepinephrine (NE) system. The core technical solution of this application is to use Prazosin to target the locus coeruleus (LC)-medial septal reward circuit and inhibit the excessive excitation of this circuit, thereby regulating feeding behavior.

[0069] The method of this application includes the following key steps: 1) Selection and preparation of prazosin: Prazosin or its pharmaceutically acceptable salts (such as prazosin hydrochloride) are selected, which can be used as a single preparation or in combination with other appetite-promoting drugs. It can be formulated into oral preparations (tablets, capsules, solutions), injections, transdermal patches, etc. to meet the needs of different patients. 2) Administration regimen of prazosin: Human dose conversion (based on the body surface area method recommended by the FDA): A dose of 1 - 2 mg / kg is used in mouse experiments. According to the mouse-HED conversion formula: HED (mg / kg) = mouse dose × 0.081, the human equivalent dose is approximately 0.081 - 0.162 mg / kg. That is, for a 60-kg patient, the recommended dose should be 4.86 - 9.72 mg / day. The specific dose is adjusted individually according to the patient's weight and the severity of the condition. Routes of administration: Oral (recommended): 1 - 2 times a day, and the sustained-release dosage form can be once a day. Intramuscular injection / intravenous injection (for severe patients): Once a day or adjusted according to the condition. 3) Course of treatment setting: Continuous treatment for 4 - 12 weeks, and it can be adjusted to maintenance treatment after the efficacy is stable. 4) Combined use with the standard AN treatment plan: The plan of this application can use prazosin alone or in combination with existing treatment methods: Psychotherapy (CBT) + prazosin to improve patient compliance and efficacy. Nutritional support + prazosin to promote weight recovery. Antidepressants + prazosin (such as selective 5-HT reuptake inhibitor SSRI) for patients with comorbid anxiety and depression. 5) Experimental verification of the mechanism of action: Animal experiments: In the AN mouse model (activity anorexia ABA model), observe the food intake, body weight changes, and anxiety behaviors after administering prazosin. Neural circuit analysis: Study the regulatory effect of prazosin on LC-NE neurons and their projections to regions such as the medial septal nucleus through optogenetics, chemogenetics, and single-cell calcium imaging.

[0070] Combination therapy: Prazosin can be used alone or in combination with other drugs. Specific dosage forms: Prazosin can be used orally, by injection, transdermally, etc., and certain dosage forms can be removed according to needs. Replaceable features and alternative solutions: Drug substitution: In addition to prazosin, other α1-adrenergic receptor antagonists (such as doxazosin) can be tried, but prazosin has stronger central permeability and is more suitable for AN treatment. Route of administration: If oral administration is not possible, transdermal or intravenous administration can be selected.

[0071] Innovations of the plan: It is first discovered that prazosin can be used to treat anorexia nervosa, filling the existing treatment gap. The unique mechanism of action, by inhibiting the overexcitation of LC-NE neurons, restores feeding behavior, which is different from traditional antidepressants and antipsychotics. It has relatively high safety and fewer side effects. Compared with drugs such as olanzapine, prazosin does not cause metabolic disorders. It can be used in combination with the existing AN treatment plan to improve efficacy and patient compliance.

[0072] Preferred and most preferred embodiments of the solution: 1) More preferred solution: Human dose conversion (based on the body surface area method recommended by the FDA): A dose of 1 - 2 mg / kg is used in mouse experiments. According to the mouse - HED conversion formula: HED (mg / kg) = mouse dose × 0.081, the human equivalent dose is approximately 0.081 - 0.162 mg / kg. That is, for a 60 - kg patient, the recommended dose should be 4.86 - 9.72 mg / day. Combination therapy: Suitable for AN patients with co - existing anxiety or depression, and can be combined with SSRI or CBT. 2) Most preferred solution: Target population: AN patients aged 18 - 45 years, with a disease course > 6 months and BMI < 18.5. 3) Treatment course: Primarily 8 weeks, observing food intake, weight recovery, and mood improvement. Use alone or in combination with psychotherapy to reduce dependence on antidepressants and antipsychotics.

[0073] This application provides an innovative treatment strategy for AN drugs. Based on prazosin targeting the LC - NE neural circuit, by reducing the over - excitation of LC - NE neurons, it restores appetite, improves the anxiety state, and then increases body weight and improves AN symptoms. The uniqueness of this application lies in: Different from traditional antidepressants or antipsychotics, prazosin can directly regulate the feeding circuit. It has high safety, with existing clinical use experience, and can directly expand the indications. It provides an individualized treatment plan, which can be used alone or in combination for treatment to improve the curative effect. This application is expected to provide new ideas and new drug options for AN treatment and promote the research on the NE system in eating disorders.

[0074] In the following examples, the experimental methods are conventional methods unless otherwise specified. The test materials used in the following examples are obtained from regular biochemical reagent companies unless otherwise specified. In the following examples, all quantitative tests are set with three repeated experiments, and the results are averaged.

[0075] Example 1 - Over - activation of noradrenaline (NE) neurons in the locus coeruleus of anorectic mice

[0076] To further explore the role of the locus coeruleus in anorexia, we used the neural activity marker c - Fos to evaluate the activation of noradrenaline (NE) neurons in the locus coeruleus of a mouse model. Figure 1 The results of the immunofluorescence staining experiment are shown. The upper part ( Figure 1 A) is a normal control mouse, and the bottom ( Figure 1B) is for anorectic mice (ABA model). TH (tyrosine hydroxylase, green): a marker for NE neurons, labeling noradrenergic neurons in the locus coeruleus region. c-Fos (red): a molecular marker for neuronal activity, representing the activation state of the neuron. TH / c-Fos (yellow): co-expressing cells, indicating the proportion of activated NE neurons. As can be seen from the images, there are fewer c-Fos positive cells in the locus coeruleus of normal mice, indicating a relatively low level of activation in this region. In anorectic model mice, however, the number of c-Fos positive cells in the locus coeruleus is significantly increased, and the yellow co-expressing cells are significantly increased, indicating that NE neurons are over-activated in the anorectic state.

[0077] Example 2 - The α1-adrenergic receptor antagonist Prazosin can reduce the activation of locus coeruleus neurons

[0078] To explore whether the over-activation of noradrenergic neurons in the locus coeruleus can be reversed by drug intervention, we used the α1-adrenergic receptor antagonist prazosin to conduct pharmacological experiments on anorectic mice and detected the c-Fos expression level of NE neurons in the locus coeruleus ( Figure 2 ). Left side (Saline group): saline control group, with more c-Fos positive cells in the locus coeruleus, and NE neurons showing a high level of activation. Right side (Prazosin group): after treatment with prazosin, the number of c-Fos positive cells in the locus coeruleus was significantly reduced, and the TH / c-Fos co-expressing cells were reduced, suggesting that the over-activation of NE neurons was effectively inhibited. These results indicate that by antagonizing the α1-adrenergic receptor, the over-nerve activity in the locus coeruleus can be effectively reduced, which may provide a new intervention target for the treatment of anorexia.

[0079] This study systematically revealed the pathological role of NE neurons in the locus coeruleus in anorexia through a mouse animal model. The NE neurons in the locus coeruleus of anorectic mice are significantly over-activated, and the activity of these neurons can be effectively reduced by the α1-adrenergic receptor antagonist prazosin, providing potential treatment ideas for clinical intervention. This study not only provides direct evidence of abnormal activity in anorexia-related brain regions but also further supports the possibility of the locus coeruleus NE neurons as potential treatment targets. In the future, combined with more in-depth analysis of neural circuits and pharmacological research, the specific mechanism of action of the NE nervous system in the occurrence and development of anorexia can be further explored.

[0080] Example 3 - Effects of 1 mg / kg Prazosin treatment on ABA mice

[0081] All experiments in this study followed the NIH animal ethics guidelines, with random grouping (n = 10 per group), and all behavioral analyses were performed by blinded experimenters. Data were analyzed using Graphpad Prism 6.0 software, and a two-sided P < 0.05 was considered a significant difference. In this experiment, 7-week-old C57BL / 6J female mice were used to establish an Activity-Based Anorexia (ABA) model, and 1 mg / kg (drug / body weight) prazosin or saline was intraperitoneally injected daily during the food restriction (FR) phase.

[0082] The experimental procedure was as Figure 3 shown in A. The survival rate of mice in the ABA+Saline group decreased significantly (<75%) on the 4th day after food restriction. The survival rate of mice in the ABA+Prazosin group increased significantly, indicating a protective effect of prazosin. ABA mice showed abnormal circadian activity during food restriction, that is, the activity level during the day was abnormally elevated ( Figure 3 C). The activity volume at night ( Figure 3 D) decreased significantly in the ABA+Prazosin group, indicating that prazosin could reduce abnormal hyperactivity. The total 24-hour activity volume ( Figure 3 E) was lower in the Prazosin group than in the Saline group, suggesting that prazosin helped reduce anxiety-like hyperactive behavior in ABA mice. Prazosin treatment did not significantly increase the food intake of mice ( Figure 3 F). The trend of weight loss was slower in the Prazosin group than in the Saline group ( Figure 3 G), indicating that prazosin had a certain protective effect in maintaining body weight. The body temperature of ABA mice decreased significantly after food restriction. The degree of body temperature decrease in the Prazosin group was smaller (P < 0.001), suggesting that prazosin could relieve hypothermia symptoms ( Figure 3 H).

[0083] Conclusion

[0084] Low-dose (1 mg / kg) prazosin could improve the survival rate of ABA mice, reduce abnormal high-level movement, and relieve hypothermia, but had little direct effect on food intake.

[0085] Example 4 - Effects of 2 mg / kg Prazosin Treatment on ABA Mice

[0086] On the basis of Example 3, the dose of prazosin was increased to 2 mg / kg in this experiment to observe its effects on ABA mice ( Figure 4 A).

[0087] Results analysis:

[0088] The survival rate of the ABA+Saline group decreased to approximately 50% on the 5th day of fasting. The survival rate of the mice in the ABA+Prazosin group increased, but did not fully recover to the normal level. The daytime activity level was significantly lower in the Prazosin group than in the Saline group ( Figure 4 C). The nocturnal activity level ( Figure 4 D) decreased in the Prazosin group, but the change range was less than that of the 1 mg / kg group. The total 24-hour activity level ( Figure 4 E) decreased, but the statistical difference was weak, indicating that a higher dose of Prazosin may have a weaker inhibitory effect on movement. The food intake in the Prazosin group was significantly higher than that in the Saline group (P<0.01, Figure 4 G), suggesting that a high dose of Prazosin may improve appetite.

[0089] The trend of weight loss was slower than that of the 1 mg / kg group ( Figure 4 F), indicating that the 2 mg / kg dose was more effective in maintaining body weight. Prazosin treatment reduced the body temperature drop (P<0.05), but the effect was not as significant as that of the 1 mg / kg group.

[0090] Conclusion:

[0091] A higher dose (2 mg / kg) of prazosin can further promote food intake and slow down weight loss in ABA mice, but has a slightly weaker effect on reducing excessive movement.

[0092] Summary of the results in Table 1

[0093] Parameter 1 mg / kg Prazosin 2 mg / kg Prazosin Survival rate Improved (P < 0.01) Improved (P < 0.05) Wheel running activity Significantly reduced (P<0.001) Slight reduction Food intake No significant improvement Increase (P < 0.01) Body weight maintenance Slight slowdown of body weight loss Significant slowdown of body weight loss Core body temperature Significantly increased (P < 0.001) Slightly elevated (P < 0.05)

[0094] Conclusion and technical advantages:

[0095] The research of this application shows that by antagonizing the NE receptor Adra1a (using prazosin), the core symptoms of the ABA mouse model can be effectively alleviated: reducing abnormally high levels of movement, and possibly improving anxiety-like behaviors;

[0096] Increasing the survival rate and reducing the physiological damage caused by fasting; improving appetite and weight maintenance at a 2 mg / kg dose; alleviating hypothermia, especially with a significant effect at a 1 mg / kg dose.

[0097] The technical advantages of this application are as follows: providing a treatment strategy based on α1-adrenergic receptor antagonism, and different doses can be optimized for different symptoms; the experimental results systematically verify the multi-faceted improvement effect of the drug on ABA mice; providing important experimental evidence for the anorexia-related neural mechanism and potential targets for future clinical applications.

[0098] Future applications

[0099] This study can provide new ideas for drug intervention in anorexia nervosa (AN) and other anxiety-related eating disorders. Future research can combine: neural circuit analysis to explore the specific effects of prazosin on the locus coeruleus pathway; long-term behavioral experiments to evaluate the long-term safety and efficacy of prazosin; and human trial data to further promote clinical translational applications.

[0100] The basic concepts have been described above. Obviously, for those skilled in the art, the above detailed disclosure is only an example and does not constitute a limitation to this specification. Although not explicitly stated here, those skilled in the art may make various modifications, improvements, and corrections to this specification. Such modifications, improvements, and corrections are suggested in this specification, so such modifications, improvements, and corrections still fall within the spirit and scope of the exemplary embodiments of this specification.

[0101] At the same time, this specification uses specific words to describe the embodiments of this specification. Such as "one embodiment", "an embodiment", and / or "some embodiments" mean a certain feature, structure, or characteristic related to at least one embodiment of this specification. Therefore, it should be emphasized and noted that the "one embodiment" or "an embodiment" or "an alternative embodiment" mentioned twice or more at different positions in this specification does not necessarily refer to the same embodiment. In addition, certain features, structures, or characteristics in one or more embodiments of this specification can be appropriately combined.

[0102] In some embodiments, numbers are used to describe the components and the quantity of attributes. It should be understood that such numbers used to describe the embodiments, in some examples, are modified by the modifiers "about", "approximate", or "substantially". Unless otherwise stated, "about", "approximate", or "substantially" indicate that the said numbers allow a variation of ±20%. Accordingly, in some embodiments, the numerical parameters used in the specification and claims are approximate values, and these approximate values can change according to the characteristics required by individual embodiments. In some embodiments, the numerical parameters should consider the specified significant digits and adopt the method of retaining the general number of digits. Although the numerical ranges and parameters used to confirm the breadth of the scope in some embodiments of this specification are approximate values, in specific embodiments, such numerical settings are made as precise as possible within the feasible range.

[0103] Finally, it should be understood that the embodiments described in this specification are only used to illustrate the principles of the embodiments of this specification. Other deformations may also fall within the scope of this specification. Therefore, by way of example and not limitation, alternative configurations of the embodiments of this specification can be considered to be consistent with the teachings of this specification. Accordingly, the embodiments of this specification are not limited to the embodiments explicitly introduced and described in this specification.

Claims

1. Use of prazosin in the preparation of a product having one or more of the following functions: Treating anorexia; Reducing the overactivation of locus coeruleus neurons; Reversing or inhibiting the overactivation of locus coeruleus noradrenergic neurons; Reducing locus coeruleus c-Fos positive cells and TH / c-Fos co-expressing cells; Promoting food intake and weight recovery; Reducing anxiety-like hyperactive behavior and decreasing total activity; Protecting brain nerves and reducing brain damage caused by chronic stress; Reducing anxiety and metabolic disorders; Increasing individual survival rate; Alleviating the degree of body temperature drop.

2. The use according to claim 1, characterized in that, The product reduces the overactivation of locus coeruleus neurons in anorexic individuals; And / or, the product reverses or inhibits the overactivation of locus coeruleus noradrenergic neurons in anorexic individuals; And / or, the product reduces locus coeruleus c-Fos positive cells and TH / c-Fos co-expressing cells in anorexic individuals; And / or, the product promotes food intake and weight recovery in anorexic individuals; And / or, the product reduces anxiety-like hyperactive behavior and decreases total activity in anorexic individuals; And / or, the product protects the brain nerves of anorexic individuals and reduces cognitive and emotional disorders caused by chronic stress in anorexic individuals; And / or, the product reduces anxiety and metabolic disorders in anorexic individuals; And / or, the product increases the survival rate of anorexic individuals; And / or, the product alleviates the degree of body temperature drop in anorexic individuals; And / or, the product does not affect cognitive function or cause drowsiness.

3. The use according to claim 1, characterized in that, The product does not affect the cognitive function of anorexic individuals or cause drowsiness.

4. The use according to claim 1, wherein The anorexia includes at least one of anorexia nervosa, emotional anorexia, physiological anorexia, anorexia related to depression, or anorexia related to anxiety.

5. The use according to claim 1, characterized in that, The anorexia is anorexia nervosa.

6. A method for treating anorexia, characterized in that, Administering a therapeutically effective amount of a pharmaceutical composition containing prazosin to an anorexic individual.

7. The method according to claim 6, wherein The pharmaceutical composition further includes a pharmaceutically acceptable carrier or excipient.

8. The method according to claim 6, characterized in that The administration mode of the pharmaceutical composition is selected from any one of oral administration, intraperitoneal injection, intravenous injection, subcutaneous injection, or intramuscular injection.

9. The method according to claim 6, wherein The anorexia includes at least one of anorexia nervosa, emotional anorexia, physiological anorexia, anorexia related to depression, or anorexia related to anxiety.

10. The method according to claim 6, characterized in that, The anorexia is anorexia nervosa.

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