Use of alpha1-adrenergic receptor antagonists in treatment of alopecia
By combining α1-adrenergic receptor antagonists with hair follicle cells, the targeted treatment problem of quiescent hair loss is solved, significantly improving hair follicle regeneration, and its effect is better than existing drugs.
Patent Information
- Application Number
- CN202510691461.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-27
- Publication Date
- 2025-08-01
AI Technical Summary
In the prior art, quiescent hair loss lacks targeted treatment methods, especially because the hair loss caused by abnormal activation of the α1-adrenergic receptor in hair follicles is not significant, and common treatment methods such as finasteride and minoxidil have limited therapeutic effects.
The α1-adrenergic receptor antagonist is used to bind to the α1-adrenergic receptor in hair follicle cells to reduce its activation degree, block the effect of norepinephrine, and reverse the prolongation of the quiescent period of hair follicles.
Targeted treatment of hair loss caused by abnormal activation of α1-adrenergic receptors is achieved, with significantly better results than minoxidil and is highly effective and practical.
Smart Images
Figure CN120393017A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the application of α1 - adrenergic receptor antagonists, specifically to the application of α1 - adrenergic receptor antagonists in the prevention and treatment of hair loss. Background Art
[0002] Hair loss is a common hair disease that affects the quality of life of a large number of people globally. According to statistics from the World Health Organization (WHO), the incidence of hair loss is relatively high among both men and women. Especially in modern society, due to factors such as life stress, environmental pollution, and bad living habits, the problem of hair loss is becoming increasingly common.
[0003] One of the reasons affecting hair loss is the change in the hair follicle cycle. All hairs and hair follicles go through a life cycle consisting of three stages, namely the anagen stage, the catagen stage, and the telogen stage. The anagen phase is the period when hair growth is active. For scalp hair, this usually lasts for 3 - 5 years. The catagen phase is a short transitional period between the anagen and telogen phases. In the case of scalp hair, it only lasts for 1 - 2 weeks. The last stage is the telogen phase, where all growth stops and the hair eventually falls out, preparing the hair follicle to grow new hair. The scalp hair in the telogen phase is also relatively short, and after about 3 - 4 months, the hair falls out and new hair begins to grow. Under normal hair growth conditions, approximately 88% of the hair is in the anagen phase, 1% is in the catagen phase, and the rest are in the telogen phase. However, under the influence of certain factors, if the duration of the follicle in the resting phase increases or the duration in the growth phase shortens, it will lead to symptoms of hair loss.
[0004] Telogen effluvium is an important type of hair loss, manifested as an extended resting phase of the hair follicle, which causes hair loss. Patients with telogen effluvium are very common. Telogen effluvium can occur at any age, but it is more common in young and middle - aged people. Moreover, in modern society, due to reasons such as the accelerating pace of life and increasing work pressure, its incidence is on the rise. In addition, people who are under high pressure for a long time, such as those engaged in high - intensity mental work, are more likely to develop telogen effluvium.
[0005] The main cause of telogen effluvium is neuroendocrine disorder. Mental stress can lead to the disorder of the neuroendocrine system, the excitement of the sympathetic nerve, and the promotion of the adrenal gland to secrete more hormones such as cortisol. These hormones will affect the hair follicle cycle and thus lead to telogen effluvium.
[0006] The applicant's research found that telogen effluvium is positively correlated with the activation level of α1 receptors in hair follicle cells. For example, an abnormal increase in the level of norepinephrine in the body will activate the α1 receptors of dermal papilla cells in hair follicles. Whether it is exogenous injection of norepinephrine or an endogenous increase in norepinephrine level caused by chronic stress, it will prolong the time of hair follicles in the telogen phase, thereby leading to hair loss. Currently, the treatment methods for telogen effluvium caused by mental stress (also known as psychogenic alopecia or stress-induced alopecia) mainly improve hair loss indirectly by improving the mental state, or taking other non-specific drugs for treating hair loss, such as finasteride (for androgenetic alopecia) or minoxidil. However, the therapeutic effects of these non-specific drugs are often extremely limited. There are also physical methods such as microneedle treatment and laser treatment, but they are also not targeted, with high costs, and their effectiveness cannot be guaranteed. Similarly, due to the high cost of hair follicle transplantation and the need for multiple surgeries, its audience is extremely limited.
[0007] Therefore, providing a drug that can relieve the influence of stress-related hormones on hair follicles for targeted treatment has stronger therapeutic efficacy. Summary of the Invention
[0008] Aiming at the problems mentioned in the background art, the purpose of the present invention is to provide the application of α1-adrenergic receptor antagonists in the prevention and treatment of hair loss, which can solve the problem that telogen effluvium cannot be treated specifically.
[0009] The present invention provides the application of α1-adrenergic receptor antagonists in the preparation of drugs or preparations for treating hair loss, wherein the hair loss is caused by abnormal activation of α1-adrenergic receptors. The α1-adrenergic receptor antagonists play a therapeutic role in hair loss by binding to the α1-adrenergic receptors of hair follicle cells and reducing the activation level of α1-adrenergic receptors.
[0010] Further, the hair follicle cells are dermal papilla cells.
[0011] Further, the abnormal activation of α1-adrenergic receptors includes activation caused by abnormal levels of norepinephrine in the body.
[0012] α1 - adrenergic receptor antagonists include a core structure and a side chain structure. The core structure of α1 - adrenergic receptor antagonists contains an aromatic ring, such as a benzene ring or its derivatives. This aromatic ring is a key part for the drug to bind to the receptor and can interact with the hydrophobic region of the receptor. For example: ① Benzene ring: Many antagonists use the benzene ring as the core structure, such as Prazosin; ② Heterocyclic ring: Some antagonists contain heterocyclic ring structures, such as quinazoline ring, indole ring, etc. For example, the structure of Prazosin contains a quinazoline ring, and this structure increases the rigidity of the molecule and helps the specific binding of the drug to the receptor. A side chain is connected to the ortho - or para - position of the core structure, and the length, functional group, and stereoconfiguration of the side chain have important effects on the activity and selectivity of the drug. Common side chain structures include: ① Piperazine ring: The side chain of prazosin - type antagonists is a piperazine ring, and the nitrogen atom on the piperazine ring can form a hydrogen bond with the receptor, enhancing the binding affinity between the drug and the receptor. ② Alkyl chain: The side chain of some antagonists is a simple alkyl chain, such as the side chain of Doxazosin is methylpiperazine.
[0013] Since the abnormal increase in the level of norepinephrine in the body can activate the α1 receptor of dermal papilla cells in hair follicles, prolong the resting phase of hair follicles and thus lead to hair loss. While α1 - adrenergic receptor antagonists can bind to the α1 - adrenergic receptor of dermal papilla cells, reduce the activation degree of α1 - adrenergic receptor, directly block the action of norepinephrine on the α1 receptor of dermal papilla cells, thereby reversing the ultra - long resting phase caused by high - level norepinephrine due to mental stress and treating hair loss caused by abnormal activation of α1 - adrenergic receptor.
[0014] Furthermore, the α1 - adrenergic receptor antagonist includes one or more of prazosin, terazosin, doxazosin, alfuzosin, trimazosin, A55453.
[0015] Furthermore, the dosage form of the drug includes oral dosage form, injection dosage form, and topical dosage form.
[0016] The beneficial effects of the present invention are as follows: Using α1 - adrenergic receptor antagonists as therapeutic drugs can specifically prevent and treat hair loss caused by abnormal activation of α1 - adrenergic receptor, with the characteristics of high efficiency and practicality, providing a new target for the treatment of telogen effluvium. BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Figure 1 It is a diagram showing the expression of adrenergic receptors in various cells of mouse hair follicles presented by GSE77256 data in Example 1;
[0018] Figure 2It is a diagram showing the expression of adrenergic receptors in DP cells for the GSE77256 data in Example 1;
[0019] Figure 3 It is a diagram showing the expression of adrenergic receptors in DP cells (dermal papilla cells) at different stages of mouse hair follicles for the GSE235480 data in Example 1;
[0020] Figure 4 It is a comparison diagram of mice in the NE group and the PBS group in Example 2;
[0021] Figure 5 It is a comparison diagram of mice in the NE group and the NE + α1 receptor antagonist group in Example 3;
[0022] Figure 6 It is a comparison diagram of the levels of NE and CORT in the body of mice in the CRS group and the non-stress control group in Example 4;
[0023] Figure 7 It is a comparison diagram of mice in the non-stress control group, the CRS group, and the CRS + α1 receptor antagonist group in Example 5;
[0024] Figure 8 It is a comparison diagram of mice in the NE group, the NE + α1 receptor antagonist group, and the NE + minoxidil group in Example 6;
[0025] Figure 9 It is a comparison diagram of mice in the CRS group, the CRS + α1 receptor antagonist group, and the CRS + minoxidil group in Example 7.
[0026] Figure 10 It is a comparison diagram of mice in the PBS group and the α1 receptor antagonist group in Example 8. Detailed implementation manners
[0027] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art belong to the protection scope of the present invention.
[0028] Example 1
[0029] Experiment on norepinephrine activating the adrenergic α1a receptor in quiescent hair follicle DP (dermal papilla) cells Experimental object: GEO database
[0030] Experimental treatment: Collect the expression of adrenergic receptors in various cells related to hair follicles during the growth period and the quiescent period.
[0031] Experimental results: As Figure 1 、Figure 2 As shown, in the GSE77256 data, it is shown that among the cells related to hair follicles in the growth phase and the resting phase, only DP (dermal papilla cells) highly express Adra1a (adrenergic alpha-1a receptor), and the expression level is high in the resting phase and significantly decreased in the growth phase. As Figure 3 shown, in another GSE235480 data, it is also shown that the Adra1a receptor in DP cells shows a periodic expression pattern, with a low expression level in the resting phase and a high expression level in the growth phase.
[0032] Experimental conclusion: DP (dermal papilla cells) are the target cells of NE (norepinephrine); the adrenergic alpha-1a receptor subtype is the receptor subtype of NE (norepinephrine) action.
[0033] Example 2
[0034] An increase in exogenous NE (norepinephrine) levels inhibits hair regeneration and causes hair loss
[0035] Experimental subjects: 8-week-old female C57 mice, divided into two groups, the NE group and the PBS control group.
[0036] Experimental treatment: The NE group was injected with NE (5 mg / kg) every day from Day 0 to Day 14, and hair was plucked immediately after injecting NE on Day 0; the PBS control group was injected with an equal amount of PBS every day from Day 0 to Day 14, and hair was plucked immediately after injecting PBS on Day 0.
[0037] Experimental results: As Figure 4 shown, the skin of the mice in the NE group was still pink on Day 14 and no hair grew; the skin of the PBS control group turned gray on Day 8 and the hair was basically fully grown on Day 14.
[0038] Experimental conclusion: Exogenous NE prolongs the resting phase of hair follicles and inhibits hair follicle regeneration; an abnormal increase in norepinephrine levels is a major cause of telogen effluvium.
[0039] Example 3
[0040] α1-Adrenergic receptor antagonists reverse the inhibitory effect of exogenous NE
[0041] Experimental subjects: 8-week-old female C57 mice, divided into 6 groups, the NE group, the NE + α1 receptor antagonist group, the NE + α2 receptor antagonist group, the NE + β1 receptor antagonist group, the NE + β2 receptor antagonist group, and the NE + β3 receptor antagonist group.
[0042] Experimental treatment: Mice in the NE group were injected with NE (5 mg / kg) daily from Day 0 to Day 14, and hair was plucked immediately after the injection of NE on Day 0; mice in the NE + corresponding antagonist group were injected with the antagonist and NE daily from Day 0 to Day 14, hair was plucked immediately after the injection of the antagonist on Day 0, and NE was injected 20 min after the injection of the antagonist.
[0043] Experimental results: As Figure 5 shown, the skin of mice in the NE group was still pink on Day 14 and no hair grew; the skin of mice in the NE + α1 receptor antagonist group turned gray on Day 8 and the hair was basically fully grown on Day 14; there was no significant difference between other NE + antagonist groups and the NE group.
[0044] Experimental conclusion: The α1 receptor antagonist significantly reversed the inhibitory effect of NE on hair follicles, suggesting that exogenous norepinephrine can inhibit hair follicle regeneration by activating α1 - adrenergic receptors.
[0045] Example 4
[0046] The norepinephrine level in the body of CRS (chronic restraint stress mice) model mice increased significantly
[0047] Experimental subjects: 8 - week - old female C57 mice were divided into two groups, one group was the non - stress control group and the other group was the CRS group.
[0048] Experimental treatment: Mice in the CRS group were placed in a 50 - ml centrifuge tube for 6 h daily from Day 0 to 14 (placed in the centrifuge tube from 13:00 to 19:00), and hair was plucked first and then placed in the centrifuge tube on Day 0; mice in the non - stress group were not placed in the centrifuge tube, but water and food were not provided during the CRS period. Blood was collected from the mice on the 15th day. The mouse blood was centrifuged at 3000 r / min at 4 °C for 10 min, and the plasma was collected and stored in a - 80 °C refrigerator for the detection of NE (norepinephrine) and CORT (corticosterone).
[0049] Experimental results: As Figure 6 shown, the corticosterone level in the body of CRS (chronic restraint stress) model mice increased significantly, indicating successful modeling. The norepinephrine level in CRS mice increased significantly, suggesting that the abnormal increase in the norepinephrine level in the body is an important hormone for telogen effluvium caused by mental stress.
[0050] Experimental conclusion: The abnormal increase in the norepinephrine level is an important cause of telogen effluvium.
[0051] Example 5
[0052] α1 - adrenergic receptor antagonist reverses the inhibition of hair regeneration in CRS (chronic restraint stress) model mice
[0053] Experimental subjects: Female C57 mice at 8 weeks of age, divided into 3 groups: a non-stress control group, a CRS group, and a CRS + α1 receptor antagonist group.
[0054] Experimental treatment: In the CRS group, from Day 0 to 14, the mice were placed in a 50-ml centrifuge tube for 6 hours every day (from 13:00 to 19:00). On Day 0, the hair was first plucked and then the mice were placed in the centrifuge tube. In the non-stress group, the mice were not placed in the centrifuge tube, but water and food were not provided during the CRS period. The treatment method of the CRS + α1 receptor antagonist group was the same as that of the CRS group, but the α1 receptor antagonist (prazosin) was injected every day from Day 0 to 14.
[0055] Experimental results: As Figure 7 shown, in the non-stress control group, the skin turned gray on Day 8 and the hair was basically fully grown on Day 14. In the CRS group, the hair was still not fully grown on Day 14. In the CRS + α1 receptor antagonist group, the skin turned gray on Day 8 and the hair was basically fully grown on Day 14.
[0056] Experimental conclusion: The α1-adrenergic receptor antagonist reversed the inhibition of chronic stress on hair follicle regeneration, suggesting that the α1-adrenergic receptor antagonist can treat telogen effluvium.
[0057] Example 6
[0058] The α1-adrenergic receptor antagonist has a stronger therapeutic effect on hair loss caused by an increase in exogenous NE levels than minoxidil
[0059] Experimental subjects: Female C57 mice at 8 weeks of age, divided into 3 groups: an NE group, an NE + α1 receptor antagonist group, and an NE + minoxidil group.
[0060] Experimental treatment: In the NE group, NE (5 mg / kg) was injected every day from Day 0 to Day 14, and the hair was plucked immediately after injecting NE on Day 0. In the NE + α1 receptor antagonist group, the antagonist and NE were injected every day from Day 0 to Day 14 (NE was injected 20 minutes after injecting the antagonist), and the hair was plucked immediately after injecting the antagonist on Day 0. In the NE + minoxidil group, minoxidil and NE were injected every day from Day 0 to Day 14 (NE was injected 20 minutes after injecting minoxidil), and the hair was plucked immediately after injecting minoxidil on Day 0.
[0061] Experimental results: As Figure 8 shown, in the NE group, no hair grew on Day 14 and the skin was pink. In the NE + α1 receptor antagonist group, the skin turned gray on Day 8 and the hair was basically fully grown on Day 14. In the NE + minoxidil group, the skin began to turn gray on Day 14, but no hair grew.
[0062] Experimental conclusion: The α1-adrenergic receptor antagonist has a stronger therapeutic effect on hair loss caused by an increase in exogenous NE levels than minoxidil.
[0063] Example VII
[0064] The α1-adrenergic receptor antagonist has a stronger therapeutic effect on telogen effluvium than minoxidil
[0065] Experimental subjects: C57 female 8-week-old mice, divided into 3 groups, CRS group, CRS + minoxidil group, CRS + α1 receptor antagonist group.
[0066] Experimental treatment: The CRS group was placed in a 50 ml centrifuge tube for 6 h every day from Day 0 to 14 (placed in the centrifuge tube from 13:00 to 19:00), and hair was plucked on Day 0 before being placed in the centrifuge tube; the treatment method of the CRS + α1 receptor antagonist group was the same as that of the CRS group, but the α1 receptor antagonist (prazosin) was injected every day from Day 0 to 14; the treatment method of the CRS + minoxidil group was the same as that of the CRS group, but minoxidil was injected every day from Day 0 to 14.
[0067] Experimental results: As Figure 9 shown, the skin of the CRS + α1 receptor antagonist group turned gray on Day 8, and the hair grew almost fully on Day 14; the hair of the CRS group was not fully grown on Day 14. There was no significant difference between the CRS + minoxidil group and the CRS group.
[0068] Experimental conclusion: The α1-adrenergic receptor antagonist is more effective than minoxidil in treating telogen effluvium.
[0069] Example VIII
[0070] The α1-adrenergic receptor antagonist promotes hair regeneration in normal mice
[0071] Experimental subjects: C57 female 8-week-old mice, divided into 2 groups, PBS group, simple α1 receptor antagonist group
[0072] Experimental treatment: Prazosin was injected every day from Day 0 to Day 14 in the simple α1 receptor antagonist group, and PBS was injected every day from Day 0 to Day 14 in the PBS group.
[0073] Experimental results: As Figure 10 shown, the skin gray scale of the simple α1 receptor antagonist group was higher than that of the PBS group on Day 7 and Day 8; on Day 14, the hair on the neck of the PBS group was relatively sparse, while the hair of the simple α1 receptor antagonist group was denser.
[0074] Experimental conclusion: The α1-adrenergic receptor antagonist has a promoting effect on hair regeneration in normal mice.
[0075] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. within the spirit and principle of the present invention shall be included within the protection scope of the present invention.
Claims
1. Use of an α1 - adrenergic receptor antagonist in the preparation of a medicament or preparation for treating hair loss, wherein the hair loss is caused by abnormal activation of the α1 - adrenergic receptor, and the α1 - adrenergic receptor antagonist exerts a therapeutic effect on hair loss by binding to the α1 - adrenergic receptor of hair follicle cells, reducing the degree of activation of the α1 - adrenergic receptor or preventing the α1 - adrenergic receptor from being activated.
2. The application according to claim 1, wherein The hair follicle cells are dermal papilla cells.
3. The application according to claim 1, characterized in that The abnormal activation of the α1 - adrenergic receptor includes activation caused by abnormal levels of norepinephrine in the body.
4. The application according to claim 1, characterized in that The α1 - adrenergic receptor antagonist includes one or more of prazosin, terazosin, doxazosin, alfuzosin, trimazosin, and A55453.
5. The application according to claim 1, characterized in that, The dosage form of the medicament or preparation includes oral dosage form, injection dosage form, and topical dosage form.