New Target for Minoxidil in the Treatment of Androgenetic Alopecia.

Objective: To investigate the mechanism of minoxidil in treating androgenetic alopecia (AGA). Methods: The mechanism of action of minoxidil on AGA was first systematically investigated from the viewpoint of network pharmacology, including minoxidil-AGA target prediction, protein-protein interaction (PPI) network analysis, molecular docking and enrichment analysis of targets related to minoxidil and AGA, and dermal papilla cell assays to confirm the viability of prediction. Results: The combined analysis revealed that minoxidil treatment of AGA not only acts on androgenic receptors (AR) but also on 2 new targets, steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1) and aromatase (CYP19A1). The biological processes linked to these targets were concentrated on several pathways, including enzymes and hormones. Further experiments have revealed that minoxidil suppresses the expression of AR and CYP17A1, boosts the activity of CYP19A1, decreases the formation and binding of dihydrotestosterone, and enhances the production of estradiol. Through these changes, minoxidil acts as a treatment for AGA. Conclusion: Minoxidil may act by altering hormonal and enzymatic pathways. Our study finds two new targets (CYP17A1, CYP19A1) of minoxidil and demonstrates that minoxidil inhibits AR. These targets may provide new ideas for drug research.

Natural Compounds Used for Treating Hair Loss.

Hair loss or alopecia is a common dermatological condition affecting up to 2% of the world population. It is often caused by hereditary factors, such as male or female pattern baldness, but it can also result from various environmental factors, an unbalanced diet, or chronic illness. While hair loss is not life-threatening, it can cause significant anxiety, depression, and other psychological problems, ultimately impacting an individual's quality of life. Various treatments for hair loss, including both synthetic drugs, such as minoxidil and finasteride, or medicinal herbs, have been approved by the Food and Drug Administration. Despite synthetic drugs' effectiveness, they may come with potential side effects. Natural remedies have been proposed as a viable option for treating hair loss because many chronic disorders can cause alopecia. As such, this review focuses on identifying alternative, efficient treatment agents with limited side effects. Specifically, it looks into medicinal plants as potential healing agents for treating hair loss. To gather relevant information for the study, multiple databases were searched, including Scopus, PubMed, and Google Scholar. A comprehensive search was conducted using a range of search terms, such as "hair loss", "alopecia", "natural remedies for hair loss", "herbal treatments for hair loss", and others to extract relevant scientific articles. Many medicinal plants and natural compounds have shown potential in reducing hair loss, thanks to their anti-inflammatory and antioxidant properties and the ability to improve local metabolism when applied externally. According to existing literature, herbal extracts and formulations derived from plants, such as Urtica dioica, Humulus lupulus, Serenoa repens, Vitis vinifera, Pygeum africanum, Cucurbita pepo, etc., as well as certain individual herbal compounds, micronutrients, bee products, and keratin, may be effective in reducing hair loss directly or indirectly. Research suggests that medicinal plants and a variety of natural compounds hold promise in promoting hair growth and preventing alopecia.

The medicinal activity of lyophilized aqueous seed extract of Lepidium sativum L. in an androgenic alopecia model.

This study evaluated the topical effect of Lepidium sativum lyophilized seed extract (LSLE) towards Sustanon-induced alopecia in male adult Wistar albino rats in vivo, compared to minoxidil topical reference standard drug (MRD). LC-MS/MS together with molecular networking was used to profile the metabolites of LSLE. LSLE treated group revealed significant changes in alopecia related biomarkers, perturbation of androgenic markers; decline in testosterone level and elevation in 5α-reductase (5-AR); decline in the cholesterol level. On the other hand, LSLE treated group showed improvement in vascular markers; CTGF, FGF and VEGF. Groups treated topically with minoxidil and LSLE showed significant improvement in hair length. LC-MS/MS profile of LSLE tentatively identified 17 constituents: mainly glucosinolates, flavonoid glycosides, alkaloids and phenolic acids. The results point to the potential role of LSLE in the treatment of alopecia through decreasing 5(alpha)-dihydrotestosterone levels. Molecular docking was attempted to evaluate the probable binding mode of identified compounds to androgen receptor (PDB code: 4K7A).

Boosting hair growth through follicular delivery of Melatonin through lecithin-enhanced Pickering emulsion stabilized by chitosan-dextran nanoparticles in testosterone induced androgenic alopecia rat model.

The strategy in this work was loading Melatonin (MEL), the powerful antioxidant photosensitive molecule, in novel Pickering emulsions (PEs) stabilized by chitosan-dextran sulphate nanoparticles (CS-DS NPs) and enhanced by lecithin, for treatment of androgenic alopecia (AGA). Biodegradable CS-DS NPs dispersion was prepared by polyelectrolyte complexation and optimized for PEs stabilization. PEs were characterized for droplet size, zeta potential, morphology, photostability and antioxidant activity. Ex-vivo permeation study through rat full thickness skin was conducted with optimized formula. Differential tape stripping trailed by cyanoacrylate skin surface biopsy was executed, for quantifying MEL in skin compartments and hair follicles. In-vivo evaluation of MEL PE hair growth activity was performed on testosterone induced AGA rat model. Visual inspection followed by anagen to telogen phase ratio (A/T) and histopathological examinations were conducted and compared with marketed 5% minoxidil spray "Rogaine ®". Data showed that PE improved MEL antioxidant activity and photostability. Ex-vivo results displayed MEL PE high follicular deposition. In-vivo study demonstrated that MEL PE treated testosterone induced AGA rat group, restored hair loss and produced maximum hair regeneration along with prolonged anagen phase amongst tested groups. The histopathological examination revealed that MEL PE prolonged anagen stage, increased follicular density and A/T ratio by 1.5-fold. The results suggested that lecithin-enhanced PE stabilized by CS-DS NPs was found to be an effective approach to enhance photostability, antioxidant activity and follicular delivery of MEL. Thus, MEL-loaded PE could be a promising competitor to commercially marketed Minoxidil for treatment of AGA.

Can we teach old drugs new tricks?-Repurposing of neuropharmacological drugs for inflammatory skin diseases.

Despite the "hype" for monoclonal antibodies, the so-called biologics, which added significant value to the therapeutic armamentarium of dermatologists and improved the life of many patients, but may exhibit significant adverse effects, the vast majority of dermatological patients suffering from atopic dermatitis or psoriasis is still treated topically. Thus, there is a huge need for locally applied, locally acting drugs for inflammatory skin diseases with better risk-benefit profiles compared to topical corticosteroids or calcineurin inhibitors. Drug repositioning is a complex process, but offers advantages, in particular for indications with lower revenues. In this viewpoint, the neuroendocrine system of the skin is described as an attractive drug target because it contributes significantly to neutralizing external noxious agents prior to inducing immune or vascular changes leading to the clinical signs of skin inflammation, for example, itch and erythema. In addition, epidermis and dermis are accessible for topically applied products which may act locally without pharmacodynamically relevant systemic exposure limiting adverse events. Moreover, since numerous drugs have been evaluated for various CNS diseases, some failed and some approved, this resource should be exploited for repurposing as anti-inflammatory drugs for topical application, for example, cannabidiol, fingolimod or asimadoline. Finally, a screening algorithm is shared which gives direct evidence of links between drug and inflammatory skin diseases.

Eclipta prostrata promotes the induction of anagen, sustains the anagen phase through regulation of FGF-7 and FGF-5.

CONTEXT: Eclipta prostrata L. (Asteraceae) (EP) has been widely used for the treatment of skin disease in Asian traditional medicine. OBJECTIVE: This study investigates the potency of EP in promoting hair growth in vivo and in vitro. MATERIALS AND METHODS: C57BL/6N mice were divided into four groups (n = 4) as follows: control (topical treatment of normal saline), topical 3% minoxidil to the dorsal skin of mice for 14 days, and low (1 mg/day) and high (10 mg/day) doses of EP orally administered once a day for 14 days. Dorsal hairs of C57BL/6N mice were depilated to synchronize anagen induction. Hair growth activity was evaluated by gross and microscopic observations. Sections of dorsal skin were stained with haematoxylin and eosin. We also treated the various concentrations of EP (5, 10 and 50 µg/mL) for 24 h on the human dermal papilla cells (HDPs) and examined the effects of EP on the expression of FGF-7 and mTOR signalling. RESULTS: EP enhanced the induction of anagen in the dorsal skin of mice, characterized by the appearance of inner root sheath along with hair shaft, the emergence of hair shaft through the epidermis. EP increased the expression of FGF-7, while decreased the level of FGF-5 in C57/BL6 mice. EP also increased the expression of FGF-7, activated the mTOR signalling in HDPs. DISCUSSION AND CONCLUSIONS: These results suggest that EP has a potency to enhance the growth of hair follicle, promoting hair growth through regulation of FGF-7 and FGF-5.

Preparation and in vivo evaluation of lecithin-based microparticles for topical delivery of minoxidil.

Minoxidil is widely used for treatment of androgenic alopecia. Commercial products containing minoxidil are usually in solution form. Repeated applications of minoxidil solution can lead to adverse effects such as skin irritation and horniness. The aims of this study were to prepare lecithin-based microparticle in minoxidil solution for enhancement of minoxidil topical delivery and skin protection and evaluate the ability of lecithin on in vitro delivery, in vivo hair growth, and skin trouble improvement compared to commercial minoxidil solution. In in vitro skin permeation study, minoxidil solution containing lecithin microparticle showed higher skin penetration rate and higher retention of drug inside the skin compared to minoxidil solution without lecithin. After topical application of minoxidil solutions with or without lecithin to C57BL/6 mice, minoxidil 5% solution containing lecithin microparticle showed hair re-growth as efficient as commercial product of minoxidil 5% solution. It also significantly improved skin troubles while commercial product presented horny substance and crust formation. Therefore, the lecithin-based microparticle in minoxidil 5% solution has good ability to promote hair growth without adverse effects.

Panax ginseng extract antagonizes the effect of DKK­1-induced catagen-like changes of hair follicles.

It is well known that Panax ginseng (PG) has various pharmacological effects such as anti-aging and anti-inflammation. In a previous study, the authors identified that PG extract induced hair growth by means of a mechanism similar to that of minoxidil. In the present study, the inhibitory effect of PG extract on Dickkopf-1 (DKK-1)-induced catagen-like changes in hair follicles (HFs) was investigated in addition to the underlying mechanism of action. The effects of PG extract on cell proliferation, anti-apoptotic effect, and hair growth were observed using cultured outer root sheath (ORS) keratinocytes and human HFs with or without DKK-1 treatment. The PG extract significantly stimulated proliferation and inhibited apoptosis, respectively, in ORS keratinocytes. PG extract treatment affected the expression of apoptosis-related genes Bcl-2 and Bax. DKK-1 inhibited hair growth, and PG extract dramatically reversed the effect of DKK-1 on ex vivo human hair organ culture. PG extract antagonizes DKK-1-induced catagen-like changes, in part, through the regulation of apoptosis-related gene expression in HFs. These findings suggested that PG extract may reduce hair loss despite the presence of DKK-1, a strong catagen inducer via apoptosis.

Nitric oxide synthase/K+ channel cascade triggers the adenosine A(2B) receptor-sensitive renal vasodilation in female rats.

Adenosine A2B-receptors mediate the adenosine-evoked renal vasodilations in male rats. Here, we tested whether this finding could be replicated in female renal vasculature and whether K(+) hyperpolarization induced by nitric oxide synthase (NOS) and/or heme oxygenase (HO) accounts for adenosine A2B receptor-sensitive renal vasodilations. In phenylephrine-preconstricted perfused kidneys, vasodilations caused by the adenosine analog 5'-N-ethylcarboxamidoadenosine (NECA, 1.6-50 nmol) were attenuated after blockade of adenosine A2B (alloxazine) but not A2A [8-(3-Chlorostyryl) caffeine, CSC] or A3 receptors (N-(2-methoxyphenyl)-N'-[2-(3-pyridinyl)-4-quinazolinyl]-urea, VUF 5574), confirming the preferential involvement of A2B receptors in NECA responses. NOS activation mediated the A2B receptor-mediated NECA response because: (i) NOS inhibition (N(ω)-nitro-L-arginine-methyl ester, L-NAME) attenuated NECA vasodilations, (ii) concurrent L-NAME/alloxazine exposure caused more inhibition of NECA responses, and (iii) inhibition of NECA responses by alloxazine disappeared in L-arginine-supplemented preparations. Although HO inhibition (zinc protoporphyrin) failed to modify NECA responses, the attenuation of these responses by alloxazine disappeared in hemin (HO inducer)-treated preparations. NECA vasodilations were also attenuated after exposure to BaCl2, glibenclamide but not tetraethylammonium (blockers of inward rectifier, ATP-sensitive, and Ca(2+)-dependent K(+)-channels, respectively). The combined alloxazine/BaCl2/glibenclamide infusion caused no additional attenuation of NECA vasodilations. Vasodilations caused by minoxidil (K(+)-channel opener) were reduced by L-NAME or BaCl2/glibenclamide, supporting the importance of NOS signaling in K(+) hyperpolarization. NECA or minoxidil vasodilations were attenuated by ouabain, Na(+)/K(+)-ATPase inhibitor, and in KCl-preconstricted preparations. Overall, facilitation of adenosine A2B receptor/NOS/K(+) channel/Na(+)/K(+)-ATPase cascade underlies NECA vasodilations in female rats. Enhancing HO activity, albeit not causally related to NECA vasodilations, improves the pharmacologically compromised (alloxazine) NECA response.

Visible-to-near IR quantum dot-based hypermulticolor high-content screening of herbal medicines for the efficacy monitoring of hair growth promotion and hair loss inhibition.

There is a growing interest in alopecia prevention strategies, as the number of alopecia patients is increasing. We examine the efficacy of herbal medicine for hair growth promotion/hair loss inhibition in two cell lines via Western blot and high-content screening (HCS). Nine herbal extracts were obtained from three different herbal medicine mixtures using 3 different extraction methods. Five target proteins-IGF-1 (insulin-like growth factor-1), TGF-ß2 (transforming growth factor-ß2), VEGF (vascular endothelial growth factor), DKK-1 (Dickkopf-1), and Wnt5α-were observed for the assessment of hair growth promotion/hair loss inhibition efficacy. The efficacies of nine extracts were compared with minoxidil as control. Efficacy was defined as a rise in the expression levels of IGF-1, VEGF, and Wnt5α but a decrease in DKK-1 and TGF-ß2. Intracellular concurrent imaging of these proteins was successfully achieved using HCS, employing visible-to-near infrared probing based on quantum-antibody conjugates and hypermulticolor imaging.

Effects of Lycopersicon esculentum extract on hair growth and alopecia prevention.

To evaluate the potential hair growth-promoting activity and the expression of cell growth factors of Lycopersicon esculentum extracts, each 3% (w/w) of ethyl acetate extract (EAE), and supercritical CO2 extract (SCE) of L. esculentum and isolated lycopene Tween 80 solution (LTS) and test hair tonic (THT) containing LTS were applied on the dorsal skin of C57BL/6 mice, once a day for 4 weeks. At week 4, LTS and THT exhibited hair growth-promoting potential similar to that of 3% minoxidil as a positive control (PC). Further, in the LTS group, a significant increase of mRNA expression of vascular endothelial growth factor (VEGF), keratinocyte growth factor, and insulin-like growth factor-1 (IGF-1) was observed than PC, as well as the negative control (NC). In the THT group, increases in IGF-1 and decrease in VEGF and transforming growth factor-ß expression were significant over the NC. In a histological examination in the THT group, the induction of anagen stage of hair follicles was faster than that of NC. In the Draize skin irritation study for THT, no observable edema or erythema was observed on all four sectors in the back skin after exposure for 24 or 72 h for any rabbit. Therefore, this study provides reasonable evidence that L. esculentum extracts promote hair growth and suggests that applications could be found in hair loss treatments without skin irritation at moderate doses.

Transcutol containing vesicles for topical delivery of minoxidil.

The aim of this work was to evaluate the ability of Transcutol (Trc) to produce elastic vesicles with soy lecithin (SL) and study the influence of the obtained vesicles on in vitro (trans)dermal delivery of minoxidil. To this purpose, so-called penetration enhancer-containing vesicles (PEVs) were prepared using Trc aqueous solutions (5-10-20-30% v/v) as hydrophilic phase. SL liposomes, without Trc, were used as control. Prepared formulations were characterized in terms of size distribution, morphology, zeta potential, deformability, and rheological behavior. The influence of the obtained PEVs on (trans)dermal delivery of minoxidil was studied by in vitro diffusion experiments through pig skin. Results showed that all prepared PEVs were able to give good entrapment efficiency (E%≈67) similar to that of conventional liposomes. Trc-containing PEVs showed to be more deformable than liposomes only when minoxidil was loaded in 5 and 10% Trc-containing vesicles. Rheological studies showed that PEVs have higher fluidity than conventional liposomes. All PEVs showed a higher stability than liposomes as shown by studying zeta potential and size distribution during three months. Results of in vitro diffusion experiments showed that Trc-containing PEVs are able to deliver minoxidil to deep skin layers without any transdermal permeation.

Promotion effect of norgalanthamine, a component of Crinum asiaticum, on hair growth.

This study was conducted to evaluate the effect of Crinum asiaticum, a plant native to Jeju Island, Korea, on the promotion of hair growth. When rat vibrissa follicles were treated with a 95% ethanol (EtOH) extract of C. asiaticum, the hair-fiber lengths of the vibrissa follicles increased significantly. In addition, after daily topical application of the EtOH extract of C. asiaticum onto the back of C57BL/6 mice, anagen progression of the hair shaft was induced. Moreover, the extract increased the proliferation of immortalized vibrissa dermal papilla cells. When the vibrissa follicles in the anagen phase were treated with the extract, immunohistochemical analysis revealed that the extract was found to increase the expression of proliferating cell nuclear antigen (PCNA) in the bulb region of the 7-day cultured follicles. In particular, norgalanthamine, a principal of the extract, showed activity that increased the hair-fiber lengths of vibrissa follicles and the proliferation of dermal papilla cells. These results suggest that norgalanthamine, a principal of C. asiaticum, has the potential to promote hair growth via the proliferation of dermal papilla.

Eclipta alba extract with potential for hair growth promoting activity.

ETHNOPHARMACOLOGICAL RELEVANCE: Eclipta alba is traditionally known to potentiate hair growth promotion. AIM OF THE STUDY: The study was aimed to investigate the efficacy of methanol extract of Eclipta alba as hair growth promoter. MATERIALS AND METHODS: Pigmented C57/BL6 mice, preselected for their telogen phase of hair growth were used. In these species, the truncal epidermis lacks melanin-producing melanocytes and melanin production is strictly coupled to anagen phase of hair growth. The extract was applied topically to assess telogen to anagen transition. Immunohistochemical investigation was performed to analyze antigen specificity. Animals in anagen phase of hair growth were positive for FGF-7 and Shh and negative for BMP4, whereas the animals in telogen phase were positive only for BMP4 antigen. RESULTS: The methanol extract of whole plant when tested for hair growth promoting potential, exhibited dose dependent activity in C57BL6 mice. The activity was assessed by studying the melanogenesis in resected skin, follicle count in the subcutis, skin thickness and surrogate markers in vehicle control and extract treated animals. CONCLUSION: These findings suggest that methanol extract of Eclipta alba may have potential as a hair growth promoter.

Promotion effect of Schisandra nigra on the growth of hair.

This study was conducted to evaluate the effect of Schisandra nigra, a plant native to Jeju Island, South Korea, on the promotion of hair growth. When rat vibrissa follicles were treated with 85% ethanol (EtOH) extract of S. nigra, the hair-fiber lengths of the vibrissa follicles increased significantly. In addition, after topical application of the EtOH extract of S. nigra onto the back of C57BL/6 mice every other day, anagen progression of the hair shaft was induced. Moreover, the extract increased both the expression of proliferating cell nuclear antigen (PCNA) in the bulb matrix region and the proliferation of immortalized vibrissa dermal papilla cells. In order to determine the mechanism by which S. nigra promotes hair growth, we examined its relationship with the transforming growth factor-beta2 (TGF-beta2) signal pathway, which is known to be a regulator of catagen induction. When the vibrissa follicles in the anagen phase were treated with S. nigra extract for 7 days, the expression of TGF-beta2 in the bulb matrix region was found to be lower than that of the control follicles that were expected to be in the anagen-catagen transition phase. These results suggest that S. nigra extract has the potential to promote hair growth via down regulation of TGF-beta2 and the proliferation of dermal papilla.

Medical treatments for male and female pattern hair loss.

UNLABELLED: Male and female pattern hair loss affects a large percentage of the population, and patients frequently present for treatment of this to their dermatologist. Here we review the many treatments available for hair loss. We review the evidence for each, and outline the most effective treatment strategies for both men and women. LEARNING OBJECTIVE: At the conclusion of this article, the reader should be able to describe the most effective treatments for hair loss, understand their mechanism(s) of action, and explain which treatments are the best in different settings.

Evaluation of blood flow parameters in addition to blood pressure and electrocardiogram in the conscious telemetered beagle dog.

INTRODUCTION: The objective of this study was to evaluate a model for measuring blood flow parameters in addition to blood pressure, heart rate and electrocardiogram (ECG) in conscious telemetered restrained and unrestrained beagle dogs. METHODS: Male beagle dogs were instrumented with fully implantable ITS radio telemetry devices for the measurement of blood pressure and ECG. In addition, the dogs were instrumented with a probe around the pulmonary artery for the measurement of blood flow by ultrasound. Dobutamine at 5, 10 and 20 mug/kg/min, given intravenously to sling restrained animals (n=4), and minoxidil at 2 mg/kg, given orally to unrestrained animals (n=4), were selected as test compounds known to cause changes in the cardiovascular parameters of interest in this work. RESULTS: Dobutamine produced a small increase in mean (9%) and systolic blood pressure (5%), and an increase in pulse pressure (37%) and heart rate (30%). The additional blood flow parameters showed that dobutamine also increased stroke volume (21%) and cardiac output (58%) and reduced total peripheral resistance (52%). Minoxidil treatment resulted in a prolonged reduction in mean, systolic and diastolic blood pressure (up to 24%). Additionally, a prolonged increase in heart rate (169%) and cardiac output (120%) were observed along with a reduction in total peripheral resistance (62%). The effects of both compounds were consistent with their known pharmacology. DISCUSSION: The results show that measurement of blood flow parameters can be successfully added to the standard telemetered cardiovascular dog model to provide valuable additional information on the effects of compounds on the cardiovascular system.

Development and evaluation of polyherbal formulation for hair growth-promoting activity.

BACKGROUND: Cuscuta reflexa (Roxb.), Citrullus colocynthis (Schrad.), and Eclipta alba (Hassk.) are traditionally acclaimed herbs for their hair growth-promoting potential. Aim In the present study, it was envisaged to prepare herbal formulations containing petroleum ether extracts of the three herbs in varying ratio and evaluating the formulations for the hair growth-promoting activity. METHODS: The formulations as well as minoxidil (2%) solution (positive control) were applied topically on shaved skin of rats, and the time required for initiation and completion of hair growth cycle was recorded. RESULTS AND CONCLUSIONS: Hair growth initiation time was markedly reduced to one third on treatment with the prepared formulation compared with control animals. The time required for complete hair growth was also reduced by 32%. Quantitative analysis of hair growth cycle after treatment with formulations and minoxidil (2%) exhibited greater number of hair follicles in anagenic phase compared with control. The results thus corroborate with the traditionally acclaimed hair growth-promoting capabilities of the plants. The prepared formulation also holds potential for treatment of alopecia.

Effect of potassium channel modulators on toxicity of Cleistanthus collinus.

The study was conducted to determine the effects of boiled extract of Cleistanthus collinus on rats by observing ECG changes and electrolyte levels in serum and urine. Influence of minoxidil and glibenclamide on Cleistanthus collinus induced toxicity was determined. ED50 for arrhythmia, changes in contractility and heart rate were recorded using the isolated frog heart. Cleistanthus at low doses caused transient tachycardia and increase in contractility and at high dose caused arrhythmia and cardiac arrest in rat. LD50 was found to be 1690 mg/kg. Minoxidil potentiated cardiac toxicity, whereas glibenclamide did not produce any significant change. High concentration of potassium in Cleistanthus extract hindered comparison of its levels. There was excretion of sodium even in the presence of hyponatraemia. Cleistanthus at low dose caused transient tachycardia and increase in contractility and at high dose caused arrhythmia and cardiac arrest in isolated frog heart. ED50 for arrhythmia was found to be 1406 mg/kg. Acute toxicity was mainly due to depressive cardiac activity of Cleistanthus. It also caused renal failure. Potassium channel modulators did not have important role in acute cardiac toxicity treatment. Probably in chronic toxicity, electrolyte level changes are involved and potassium channel modulators might have a role.