Application of whey protein in preparation of medicine for treating tic disorder

Abstract

The invention provides application of whey protein in preparation of a medicine for treating tic disorder, and belongs to the technical field of medicines. The invention provides a therapeutic preparation containing whey protein. The therapeutic preparation can effectively improve exercise symptoms of a patient suffering from tic disorder. The preparation can be independently used, can also be used as an auxiliary treatment means to be combined with a traditional anti-twitch medicine, has multiple effects of regulating neurotransmitter balance, improving intestinal microecology and relieving neuroinflammation, has no adverse reaction of the traditional medicine, and is particularly suitable for long-term use of children patients.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to the use of whey protein in the preparation of medicaments for treating tic disorders. Background Technology

[0002] Accurately assessing the severity of tic disorder symptoms is a crucial prerequisite for developing an appropriate treatment plan. Currently, the most commonly used assessment tool in clinical practice is the Yale Global Tic Severity Scale (YGTSS). This scale scores tic disorders on five dimensions: frequency, intensity, complexity, interference, and overall impairment, with a total score ranging from 0 to 100. Based on the YGTSS score, the severity of tic disorders can be categorized as: mild (<25 points), moderate (25-50 points), and severe (>50 points).

[0003] Based on the above classification, clinical treatment generally follows these principles:

[0004] 1. For mild tic disorders, non-pharmacological treatments are preferred, such as behavioral therapy (e.g., habit reversal training) or psychological interventions (e.g., cognitive behavioral therapy). If symptoms affect quality of life, low-dose dopamine receptor antagonists (e.g., aripiprazole) or α2-adrenergic receptor agonists (e.g., clonidine) may be considered.

[0005] 2. For moderate to severe tic disorders, dopamine receptor antagonists (such as haloperidol and risperidone) are the main treatment options, but they may cause adverse reactions such as extrapyramidal reactions, metabolic abnormalities and sedation, which may affect long-term medication adherence.

[0006] 3. For refractory tic disorders, combination therapy (such as topiramate to enhance the efficacy of dopamine antagonists) or neuromodulation techniques such as deep brain stimulation can be explored, but the latter still has surgical risks and high costs.

[0007] While traditional antitic medications are effective in controlling symptoms, their neuropsychiatric side effects and long-term safety remain a major concern. For example:

[0008] 1. Clinical research evidence: A long-term follow-up study of haloperidol showed that approximately 30% of patients discontinued the drug due to extrapyramidal reactions (such as dystonia and tardive dyskinesia); another retrospective analysis indicated that risperidone may lead to weight gain, glucose and lipid metabolism disorders, and increase the risk of metabolic syndrome in adolescent patients.

[0009] 2. Animal experimental studies: In animal models of tic disorders with striatal dopamine overactivation, long-term use of dopamine antagonists can lead to inhibition of γ-aminobutyric acid (GABA) neuronal function, which in turn aggravates tic-like behaviors; another study showed that haloperidol can exacerbate stereotyped behaviors in a rat model of 6-hydroxydopamine lesions. [4] .

[0010] In addition to neuropsychiatric side effects, traditional antitic drugs often cause gastrointestinal adverse reactions. For example, aripiprazole reported gastrointestinal discomfort such as nausea and abdominal pain in about 15% of patients in clinical trials, while clonidine may cause problems such as dry mouth and constipation, further reducing patient adherence to treatment.

[0011] In summary, current interventions for tic disorders primarily rely on a combination of medication and behavioral therapy based on the YGTSS score. However, existing medications may induce or worsen tics in some patients, or cause significant metabolic, psychological, and gastrointestinal adverse reactions, thus limiting their long-term use. Therefore, developing alternative treatment strategies with novel mechanisms and higher safety profiles has become a crucial issue urgently needing breakthroughs in the field of pediatric neuropsychiatry. Summary of the Invention

[0012] The purpose of this invention is to propose the use of whey protein in the preparation of drugs for treating tic disorders, which can effectively improve the motor symptoms of patients with tic disorders. This preparation can be used alone or as an adjunct therapy in combination with traditional antitic drugs. It has multiple effects, including regulating neurotransmitter balance, improving intestinal microecology, and reducing neuroinflammation, and has no adverse reactions of traditional drugs, making it particularly suitable for long-term use in pediatric patients.

[0013] The technical solution of this invention is implemented as follows:

[0014] This invention provides the use of whey protein in the preparation of products for treating tic disorders.

[0015] As a further improvement of the present invention, the product is a tablet, capsule, liquid preparation, powder, or chewable tablet.

[0016] As a further improvement of the present invention, the liquid preparation is a solution, suspension, or injection.

[0017] As a further improvement of the present invention, the product is a medicine or a medical food.

[0018] As a further improvement of the present invention, the whey protein is used alone.

[0019] As a further improvement of the present invention, the whey protein is used in combination with drugs for treating tic disorders as an adjunctive treatment.

[0020] Technical principle:

[0021] 1. The regulatory effect of amino acids in whey protein on neurotransmitters.

[0022] Whey protein is rich in branched-chain amino acids and tryptophan, key amino acids that play important roles in neurotransmitter metabolism. Tryptophan is a precursor to serotonin (5-HT), while branched-chain amino acids competitively inhibit aromatic amino acids from crossing the blood-brain barrier, regulating the balance between dopamine and 5-HT. Furthermore, cysteine ​​in whey protein is a key substrate for glutathione synthesis, effectively scavenging free radicals and reducing oxidative stress damage in the basal ganglia.

[0023] 2. Neuroprotective effects of active components in whey protein

[0024] Lactoferrin, a component of whey protein, possesses significant neurotropic properties. It can cross the blood-brain barrier via a transport mechanism mediated by specific receptors on cerebral vascular endothelial cells, accumulating in key brain regions regulating motor function, such as the striatum and thalamus. Studies have shown that lactoferrin not only inhibits microglia activation and reduces neuroinflammatory responses but also promotes the expression of brain-derived neurotrophic factor (BDNF), enhancing neuronal plasticity. In animal models of tic disorders, lactoferrin intervention significantly reduced the frequency and intensity of abnormal motor behaviors.

[0025] 3. Regulating nervous system function through the gut-brain axis

[0026] Whey protein can regulate the balance of the gut microbiota through multiple mechanisms: (1) its rich lactoperoxidase system can selectively inhibit the growth of pathogenic bacteria; (2) as a prebiotic, it promotes the proliferation of beneficial bacteria such as Bifidobacteria; (3) it enhances the intestinal mucosal barrier function and reduces the entry of endotoxins into the blood. These effects collectively regulate the gut-brain axis function: on the one hand, short-chain fatty acids (such as butyrate) produced by gut microbiota metabolism can affect central motor regulation through vagal nerve afferent signals; on the other hand, it reduces the release of pro-inflammatory cytokines (such as IL-6 and TNF-α) and reduces the impact of systemic inflammation on the basal ganglia circuit.

[0027] The present invention has the following beneficial effects: whey protein preparations can safely and effectively improve tic symptoms, avoid the adverse reactions of traditional drugs, and significantly improve treatment compliance by regulating neurotransmitters and gut-brain axis function. While improving tic symptoms, it avoids the adverse reactions such as extrapyramidal reactions and metabolic abnormalities caused by traditional anti-tic drugs (such as dopamine receptor antagonists). Attached Figure Description

[0028] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0029] Figure 1 A technical roadmap for animal experiments;

[0030] Figure 2 The graphs show the scores for stereotyped behavior (left) and motor behavior (right) in mice. Compared with the control group, ***P<0.001; compared with the model group, #P<0.05, ##P<0.01; ns indicates P>0.05.

[0031] Figure 3 The results of the open field experiment are shown in the comparison figure. Compared with the blank group, ***P<0.001; compared with the model group, #P<0.05, ##P<0.01.

[0032] Figure 4 This is a diagram showing the movement trajectory of mice in an open field test. Detailed Implementation

[0033] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0034] Example 1

[0035] 1. Structural composition of whey protein:

[0036] ① Material composition: Whey protein consists of approximately 70.2% β-lactoglobulin, 14.3% α-lactalbumin, 8.6% bovine serum albumin and approximately 6.9% immunoglobulins.

[0037] ② Nutritional Composition: Typical whey protein components include 93% protein (dry basis), 0.1% lactose, 1.3% fat, approximately 4.7% moisture, and 2.7% ash. Furthermore, each 100g WPI provides approximately 375 kcal of energy and 23 mg of cholesterol. In terms of minerals, WPI is rich in sodium (805mg / 100g), calcium (120mg / 100g), potassium (120mg / 100g), phosphorus (180mg / 100g), magnesium (15mg / 100g), and trace amounts of iron and chlorine, demonstrating its superiority as a low-fat, high-protein nutritional supplement.

[0038] ③ Amino Acid Composition: WPI contains abundant essential and functional amino acids. Among branched-chain amino acids, the content is as follows: leucine 10.6g / 100g, isoleucine 6.2g / 100g, and valine 5.2g / 100g. Among essential amino acids, tryptophan content is 1.7g / 100g, lysine 9.7g / 100g, methionine 2.4g / 100g, phenylalanine 2.7g / 100g, serine 4.1g / 100g, and threonine 6.4g / 100g. In addition, WPI is also rich in glutamic acid (17.1g / 100g), aspartic acid (9.4g / 100g), and lysine (9.7g / 100g).

[0039] 2. Application method:

[0040] ① Take 10-20g of oral powder, chewable tablet or liquid preparation 1-2 times a day for 4-8 weeks.

[0041] ② It can be used as a standalone nutritional intervention or adjunctive treatment for patients with tic disorders (especially children);

[0042] ③ It can be used in combination with other antitic drugs to reduce the dosage and side effects.

[0043] 3. Implementation Case (Animal Experiment)

[0044] In a mouse model of tic disorder induced by iminodiapropionitrile (IDPN), WPI intervention for 4 weeks resulted in the following:

[0045] ① Significant improvement in behavioral performance (including motor behavior, stereotyped behavior, and open field test);

[0046] ② No worsening of movement disorders or other adverse reactions were observed, indicating good safety.

[0047] Example 2

[0048] (1) Implementation plan Figure 1 )

[0049] 1. Animal grouping: 48 healthy male ICR mice were randomly divided into a control group (Con), a model group (Mod), a sulpiride treatment group (Tia), and a whey protein intervention group (WPI), with 12 mice in each group. The Mod, Tia, and WPI groups will use a tic disorder mouse model.

[0050] 2. Construction of a mouse model of tic disorder: A mouse model of tic disorder was established by intraperitoneal injection of IDPN once a day for 7 consecutive days.

[0051] 3. Administration of therapeutic drugs: Gavage administration began from the date of model establishment. The whey protein intervention group was given whey protein 2g / kg by gavage, the sulphide drug treatment group was given sulphide suspension 25mg / kg by gavage, and the control group and model group were given 10ml / kg of normal saline by gavage once a day for 4 consecutive weeks.

[0052] 4. Behavioral Testing: Four weeks after drug intervention, mice underwent behavioral testing and scoring. In a dimly lit, quiet indoor environment, mice were removed from their cages and placed in an observation box for 5 minutes to allow them to acclimatize before observation began, with each mouse observed for 5 minutes. Stereotyped behaviors and motor behaviors were scored using the Diamond Scoring Method. After behavioral scoring, mice were placed in an open field test chamber measuring 50cm (length) × 50cm (width) × 40cm (height) for 5 minutes to acclimatize. A video tracking system was then used to record the mice's activity over those 5 minutes. Animal behavior analysis software was used to analyze the mice's total distance traveled, average speed, dwell time in the central area, number of entries, and movement trajectory to assess motor activity and anxiety-like behaviors.

[0053] (2) Experimental Results

[0054] 1. General situation

[0055] The animals used in this experiment were healthy male ICR mice, 4 weeks old, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. The mice were housed at the Experimental Animal Center of Tsinghua University under strictly controlled conditions, simulating natural diurnal rhythms with regular light-dark cycles, and provided with free access to standard feed and water. All experimental procedures followed the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals and were approved by the Laboratory Animal Ethics Committee of Tsinghua University School of Medicine (Approval No.: 23-GXH1.G23-2).

[0056] 2. Mouse behavioral scoring results

[0057] Four weeks after gavage, the stereotyped behaviors and motor behaviors of the mice were scored using the Diamond Score. Stereotyped behaviors: 0 points for no stereotyped behavior; 1 point for rotational behavior; 2 points for excessive up-and-down head and neck movements; 3 points for excessive up-and-down head and neck movements plus rotational behavior; 4 points for head turning to the side combined with excessive up-and-down head and neck movements. Motor behaviors: 0 points for quiet or normal activity; 1 point for hyperexcitability; 2 points for increased exploratory behavior; 3 points for constant running; 4 points for constant running with startle reflexes. The results showed that compared with the control group, the stereotyped behavior and motor behavior scores of mice in the model group were significantly increased; compared with the model group, the stereotyped behavior and motor behavior scores of mice in the whey protein intervention group and the sulphide treatment group were significantly decreased, and the differences were statistically significant, suggesting that both whey protein and sulphide can improve the behavioral performance of mice with tic disorders to varying degrees; compared with the sulphide treatment group, there was no statistically significant difference in stereotyped behavior and motor behavior in the whey protein intervention group, suggesting that both are equally effective in improving stereotyped and motor behaviors in mice with tic disorders. Figure 2 ).

[0058] 3. Comparison of open field test indicators among different groups of mice

[0059] Compared with the control group, the total distance traveled and the speed of movement in the model group mice were significantly increased, indicating that IDPN-induced tic disorder model mice had increased excitability and spontaneous movement; and the number of times they entered the central area was significantly increased, indicating increased exploratory behavior. In addition, the tic disorder model mice exhibited more spontaneous movement behaviors (such as circling, dashing, head shaking, etc.), which may increase their activity in the central area. Compared with the model group, the total distance traveled and the speed of movement in the whey protein intervention group and the sulphide treatment group were significantly decreased, with statistically significant differences (P<0.05); the number of times they entered the central area decreased, and the time spent in the central area showed a decreasing trend, but the differences were not statistically significant. Figure 3 This indicates that sulphide and whey protein may have a certain regulatory effect on excitability, spontaneous movement and exploratory behavior in mice with tic disorder.

[0060] Open field test mouse movement trajectory diagrams: The control group mice exhibited shorter, peripherally distributed movement trajectories within the open field test chamber, with fewer central trajectories, consistent with mouse avoidance behavior. The model group mice displayed significantly longer and more disordered movement trajectories with unclear distribution characteristics, involving both the central and peripheral areas, and exhibiting repetitive rotational movements, consistent with stereotyped behavioral trajectory characteristics of mice with tic disorders. The whey protein intervention group and the sulphide treatment group showed significantly reduced movement trajectories compared to the model group, closely resembling the movement trajectories of the control group. Figure 4 .

[0061] In conclusion, whey protein intervention demonstrated a significant anti-ticking effect in behavioral experiments, suggesting its potential neuromodulatory role in the treatment of tic disorders.

[0062] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. Use of a whey protein in the preparation of a product for treating tic disorders.

2. The use according to claim 1, characterized in that, The products are tablets, capsules, liquid preparations, powders, and chewable tablets.

3. The oral use according to claim 2, characterized in that, The liquid preparation is a solution, suspension, or injection.

4. The use according to claim 1, characterized in that, The product is a drug or a medical food.

5. The use according to claim 1, characterized in that, The whey protein is used alone.

6. The use according to claim 1, characterized in that, The whey protein is used as an adjunct therapy in combination with drugs for treating tic disorders.

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