Topical Retinaldehyde Research Articles

Hyalurosome Gene Regulation and Dose-Dependent Restoration of Skin Atrophy by Retinaldehyde and Defined-Size Hyaluronate Fragments in Dermatoporosis

Background: Dermatoporosis is an emerging clinical condition caused by chronological skin aging, long-term sun exposure and chronic use of corticosteroids; however, genomic expression in dermatoporosis and the efficacy of different therapeutic approaches to prevent and treat dermatoporosis have not been investigated so far. Objective: We examined the possible effect of topical retinaldehyde (RAL) and defined-size hyaluronate fragments (HAFi) on the expression of hyalurosome genes potentially involved in the pathogenesis of dermatoporosis. We also explored the effect of different concentrations of HAFi on skin thickness. Methods: 13 persons were separated into a young control group (n = 8) and a dermatoporosis group (n = 5). Topical treatment of both groups with a combination of 0.05% RAL and 1 or 0.2% HAFi was applied on the forearm twice daily for 30 days. Forearm skin biopsies of both groups were performed before and after application. Hyalurosome genes CD44, heparin-binding epidermal growth factor (HB-EGF), ErbB1, hyaluronate synthase 3 (HAS3) and Hyal2 were chosen as potential markers of dermatoporosis. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed for quantification of mRNA expression of the target hyalurosome genes. Measurement of forearm skin thickness before and after treatment was performed by ultrasonography. Analysis of the results was done by Student's t test. A p value <0.05 was considered statistically significant. Results: In qRT-PCR analysis the relative expression of hyalurosome (CD44, HAS3, HB-EGF) genes was found to be reduced in patients prior to topical treatment and to be notably increased following treatment. The reduced expression of CD44 and HAS3 in patients was specifically restored in dermatoporotic patients after treatment. No difference in skin thickness was observed in controls after treatment. The treatment caused a significant increase in skin thickness in dermatoporotic patients. This increase was more significant with 1% HAFi when compared to 0.2% HAFi. RAL and HAFi also caused a significant reduction in purpuric lesions in patients with dermatoporosis. Conclusion: Our results indicate that topically applied RAL and HAFi regulate hyalurosome gene expression in dermatoporosis and that they show a dose-dependent effect on the correction of skin atrophy in dermatoporotic patients. However, the small number of patients analyzed in both groups somehow limits the statistical power of this study.

New therapeutic targets in dermatoporosis.

Dermatoporosis is a novel term proposed to describe the chronic cutaneous insufficiency/fragility syndrome characterized by an extreme skin atrophy. Dermatoporosis is principally due to chronological aging and long-term and unprotected sun exposure, but it may also result from the chronic use of topical and systemic corticosteroids. We have recently proposed a membrane organelle, hyalurosome, composed of molecules involved in hyaluronate (HA) metabolism and cell signaling in the keratinocytes, such as principal HA receptor CD44, heparin-binding epidermal growth factor (HB-EGF), HB-EGF receptor erbB1 and HA synthase 3 (HAS3), which is functionally defective in dermatoporosis and may be a target for intervention. Several lines of evidence suggest that hyalurosome is located in keratinocyte filopodia, thin, actin-rich plasma membrane protrusions implicated in cell motility. We have recently shown that keratinocyte filopodia are downregulated by corticosteroids in vitro. Intermediate size HA fragments (HAFi) inhibited the downregulation of filopodia induced by corticosteroids. Topical HAFi prevented the skin atrophy induced by topical corticosteroids in mice without interfering with their anti-inflammatory effect. Topical treatment with HAFi 1% of atrophic forearm skin of dermatoporosis patients for 1 month resulted in a significant clinical improvement and induced the expression of hyalurosome molecules. Topical retinaldehyde (RAL) and HAFi showed a synergy in HA production and pro-HB-EGF expression in mouse skin and in the correction of skin atrophy in dermatoporosis patients. Uncovering the molecular mechanisms implicating hyalurosome seems to be crucial to better understand the pathogenesis of dermatoporosis and to develop new therapeutic strategies.

Synergistic Effect of Hyaluronate Fragments in Retinaldehyde-Induced Skin Hyperplasia Which Is a Cd44-Dependent Phenomenon

BackgroundCD44 is a polymorphic proteoglycan and functions as the principal cell-surface receptor for hyaluronate (HA). Heparin-binding epidermal growth factor (HB-EGF) activation of keratinocyte erbB receptors has been proposed to mediate retinoid-induced epidermal hyperplasia. We have recently shown that intermediate size HA fragments (HAFi) reverse skin atrophy by a CD44-dependent mechanism.Methodology and Principal FindingsTreatment of primary mouse keratinocyte cultures with retinaldehyde (RAL) resulted in the most significant increase in keratinocyte proliferation when compared with other retinoids, retinoic acid, retinol or retinoyl palmitate. RAL and HAFi showed a more significant increase in keratinocyte proliferation than RAL or HAFi alone. No proliferation with RAL was observed in CD44−/− keratinocytes. HA synthesis inhibitor, 4-methylumbelliferone inhibited the proliferative effect of RAL. HB-EGF, erbB1, and tissue inhibitor of MMP-3 blocking antibodies abrogated the RAL- or RAL- and HAFi-induced keratinocyte proliferation. Topical application of RAL or RAL and HAFi for 3 days caused a significant epidermal hyperplasia in the back skin of wild-type mice but not in CD44−/− mice. Topical RAL and HAFi increased epidermal CD44 expression, and the epidermal and dermal HA. RAL induced the expression of active HB-EGF and erbB1. However, treatment with RAL and HAFi showed a more significant increase in pro-HB-EGF when compared to RAL or HAFi treatments alone. We then topically applied RAL and HAFi twice a day to the forearm skin of elderly dermatoporosis patients. After 1 month of treatment, we observed a significant clinical improvement.Conclusions and SignificanceOur results indicate that (i) RAL-induced in vitro and in vivo keratinocyte proliferation is a CD44-dependent phenomenon and requires the presence of HA, HB-EGF, erbB1 and MMPs, (ii) RAL and HAFi show a synergy in vitro and in vivo in mouse skin, and (iii) the combination of RAL and HAFi seems to have an important therapeutic effect in dermatoporosis.

UVA and UVB Decrease the Expression of CD44 and Hyaluronate in Mouse Epidermis, which is Counteracted by Topical Retinoids

The transmembrane glycoprotein CD44 is currently thought to be the main cell surface receptor for the glycosaminoglycan hyaluronate. We previously showed that (1) CD44 regulate keratinocyte proliferation; (2) topical retinoids dramatically increase the expression of CD44, hyaluronate and hyaluronate synthase (HAS)s in mouse epidermis; (3) topical retinaldehyde restores the epidermal thickness and CD44 expression which are correlated with clinical improvement in lichen sclerosus et atrophicus lesions; and (4) retinaldehyde-induced proliferative response of keratinocytes is a CD44-dependent phenomenon and requires the presence of HB-EGF, erbB1 and matrix metalloproteinases. In this study, we analyzed the effect of UV irradiation on the levels of epidermal hyaluronate and CD44 in mice, as well as its potential prevention by topical retinoids. UVA (10 J/cm(2)) or UVB (1 J/cm(2)) irradiation significantly decreased the expression of CD44 and hyaluronate in the epidermis of hairless mice after 2 h. Expression of both epidermal CD44 and hyaluronate was reconstituted within 24 h. Topical application of retinaldehyde for 3 days prior to UVA or UVB irradiation prevented the decrease of CD44 and hyaluronate expression. Topical retinol and retinoic acid also increased the basal levels of epidermal CD44 and hyaluronate, although their preventive effect on UV-induced decrease of these molecules was less pronounced as compared to topical retinaldehyde. These data confirm the relationships between retinoid and CD44 pathways, although the primary target(s) of UV leading to CD44 and hyaluronate degradation remain to be elucidated.

Topical Retinaldehyde with Glycolic Acid: Study of Tolerance and Acceptability in Association with Anti-Acne Treatments in 1,709 Patients

Background: Retinaldehyde (RAL), a key metabolite between vitamin A and retinoic acid, acts by modulating differentiation and proliferation of keratinocytes, which is of interest in acne lesions, mainly retentional lesions. Glycolic acid increases the exfoliation of corneocytes explaining its mild activity on retentional lesions. Thus, RAL and glycolic acid combined in the same product (Diacnéal^®) have complementary activities which can be of interest for acne patients. The aim of this study was to evaluate the tolerance of Diacnéal used by 1,709 acne patients in combination with their usual acne products except retinoids. Results: This study demonstrated a very good tolerance of Diacnéal when used with other acne treatments for 90 days. Complaints about side-effects were rare. Moreover, the significant decrease in both inflammatory and retentional lesions between day 0 and day 90 indicates that Diacnéal could amplify the efficiency of other anti-acne products used at the same time by the patients. The subjective evaluation of the preparation’s efficacy by investigators and patients was strongly favourable. Conclusion: These data show that a combination of RAL 0.1% and glycolic acid 6% may be used in association with other topical anti-acne treatments (benzoyl peroxide and topical antibiotics) with an excellent tolerance.

Biological Activities of Topical Retinaldehyde

Background: We had hypothesised that retinaldehyde (RAL) should be an interesting precursor for topical use. Aim: We review our observations about its biological activities. Methods: We performed pilot studies to explore its biological effects and tolerability in human skin and compared the effects of topical RAL to that of all-trans-retinoic acid (RA) in the mouse tail test. Results: The biological activities of RAL were found to be qualitatively identical to that of RA: (i) induction of cellular RA-binding protein type 2 mRNA and protein, (ii) increase in epidermal proliferation (increase in DNA synthesis, epidermal thickness, induction of 50-kD keratin mRNA and reduction in 70-kD keratin mRNA), and (iii) metaplastic effects (induction of orthokeratosis, reduction of 65-kD keratin mRNA, increase in filaggrin and loricrin mRNAs). When associated with RAL, citral (known for its capacity to inhibit the oxidation of retinol to RA in epidermis) counteracted the effects induced by RAL indicating that RAL exerts biological activities through transformation to RA. Hypothesising that keratinocytes would metabolize 9-cis-RAL to 9-cis-RA, we compared the biological effects induced by topical 9-cis-RAL and found that hyperplastic and metaplastic responses were lower than those induced by all-trans-RAL or all-trans-RA at similar concentrations. This suggests that 9-cis-RAL has no advantage over all-trans-RAL for specific delivery of natural retinoids into the skin. As in clinical studies conducted in human skin, we also found topical RAL less irritant than RA. Conclusion: These studies indicate that topical RAL has biological activity and is well tolerated.

Metabolism of Topical Retinaldehyde

Objective: In order to circumvent the tolerance problems encountered with topical application of retinoic acid – a biologically active metabolite of vitamin A – we performed in various models a series of experiments aimed at assessing the bio-availability of topical retinaldehyde and its conversion into either retinoid stores or biologically active metabolites. Methods: (i) ³H-retinaldehyde was used as a precursor of either ³H-retinol or ³H-retinoic acid in human skin extracts and human cultured keratinocytes; (ii) the concentration of various retinoids resulting from the metabolism of topical retinaldehyde was determined in mouse skin and in human plasma. Retinoids were quantified by reverse-phase HPLC with UV detection. Results: Human keratinocytes were shown to take up retinaldehyde and to convert it into retinoic acid in a differentiation-dependent manner, differentiating cells oxidising retinaldehyde more efficiently. In vivo models allowed us to demonstrate that retinaldehyde is taken up by the skin and is then predominantly converted into retinyl esters – a storage form of vitamin A – while delivering relatively low amounts of retinoic acid from a large reservoir. Conclusion: Topical retinaldehyde can be used as a precursor of endogenous retinoids, since it is converted into both storage and bio-active forms of vitamin A.

Comedolytic Effect of Topical Retinaldehyde in the Rhino Mouse Model

Background: Retinaldehyde is a key molecule in the metabolism of vitamin A by keratinocytes. In order to evaluate its range of topical activity in acne, its comedolytic effect was compared to that of retinoic acid in the same vehicle, in the rhino mouse model. Methods: The animals were treated on the back daily for 5 consecutive days per week for 3 weeks. At the end of this period, histological slides were analyzed in order to quantify the features of comedones and epidermal thickness. Results: Topical treatment with a retinaldehyde (0.05% w/w) and a retinoic acid formulation (0.025% w/w) induced comedolysis and increased the epidermal thickness with the same intensity. Conclusion: These data indicate that retinaldehyde exerts a significant comedolytic activity.

Clinical Use of Topical Retinaldehyde on Photoaged Skin

Background: Retinaldehyde, the natural precursor of retinoic acid, should exert similar effects on photoaged skin. Objective: To establish the efficacy and safety of topical retinaldehyde on photoaged skin. Methods: Open and controlled clinical studies using image analysis of silicone skin replicas. Results: Retinaldehyde proved efficient and safe. Conclusion: Retinaldehyde is efficient and well tolerated for the improvement of the signs of photoaging.

Efficacy of Topical 0.05% Retinaldehyde in Skin Aging by Ultrasound and Rheological Techniques

Background: The natural precursor of retinoic acid, i.e. retinaldehyde, has been proven to exert retinoid activities. Aim and Methods: The aim of this prospective instrument study was to determine the effect of topical retinaldehyde 0.05% on the physical properties of aging skin. This was performed using two devices, namely a high-resolution (70–80 µm) ultrasound scanner, which visualizes the thickness of both the epidermis and the dermis, and an echorheometer, which assesses the stiffness and elasticity of the skin by suction. In a 1-year study, 21 patients applied retinaldehyde cream 0.05% on the face, while another group of 19 volunteers were only treated with an emollient (control group). Epidermal and dermal thicknesses were measured on the forehead and temple, and stiffness and elasticity were measured on the forehead only. All the instrumental parameters were assessed at baseline and at the end of treatment. Results: Compared to the control group, retinaldehyde treatment induced a significant increase in epidermal thickness of the temple, as well as in cutaneous elasticity (p < 0.01). Similarly, retinaldehyde treatment tended to increase dermal thickness and reduce cutaneous stiffness, but no statistical difference could be observed between the two groups. Conclusion: Taken together, the results further suggest that retinaldehyde has counteracting effects on skin aging

Profilometric evaluation of photodamage after topical retinaldehyde and retinoic acid treatment

Objective: We compared the activity and tolerance profile of a 0.05% retinaldehyde cream with a 0.05% retinoic acid cream and the retinaldehyde vehicle in patients with photodamaged skin of the face. Methods: A silicone replica of the left crow’s feet area was taken at baseline and at weeks 18 and 44. Skin replicas were then analyzed by means of an optical profilometry technique. Standard wrinkle and roughness features were then calculated and statistically analyzed. The tolerance profile of the test products was also clinically evaluated during the entire study. Results: A total of 125 patients (40 in the retinoic acid group, 40 in the retinaldehyde group, and 45 in the vehicle group) were studied. At week 18, a significant reduction of the wrinkle and roughness features was observed with both retinaldehyde and retinoic acid. At week 44, a less pronounced reduction was demonstrated in both active groups. No statistically significant changes were observed with the retinaldehyde vehicle at any assessment point. A total of 135 patients constituted the safety population. Retinaldehyde was well tolerated during the entire study. In contrast, retinoic acid caused more local irritation, and affected compliance of the patients. Conclusion: Retinaldehyde was efficacious and well tolerated in patients with photodamage. (J Am Acad Dermatol 1998;39:960-5.)

Metabolism and biological activities of topical retinaldehyde

Metabolism and biological activities of topical retinaldehyde

Clinical uses of topical retinaldehyde

Clinical uses of topical retinaldehyde

Tolerance profile of the 3 topical retinoids retinol, retinaldehyde, and retinoic acid

Tolerance profile of the 3 topical retinoids retinol, retinaldehyde, and retinoic acid

Topical Retinaldehyde Increases Skin Content of Retinoic Acid and Exerts Biologic Activity in Mouse Skin

Retinaldehyde, a natural metabolite of beta-carotene and retinol, has been proposed recently for topical use in humans. Because retinaldehyde does not bind to retinoid nuclear receptors, its biologic activity should result from enzymatic transformation by epidermal keratinocytes into ligands for these receptors, such as all-trans retinoic acid and 9-cis-retinoic acid. In this study, we analyzed by high performance liquid chromatography the type and amounts of tissue retinoids as well as several biologic activities resulting from topical application of either retinaldehyde or all-trans retinoic acid on mouse tail skin. Biologic activities of all-trans retinoic acid and retinaldehyde were qualitatively identical in metaplastic parameters (induction of orthokeratosis, reduction of keratin 65-kDa mRNA, increase in filaggrin and loricrin mRNAs) and hyperplastic parameters (increase in epidermal thickness, increase in bromodeoxyuridine (BrdU)-positive cells, increase in keratin 50-kDa mRNA, and reduction in keratin 70-kDa mRNA). Some quantitative differences, not all in favor of all-trans retinoic acid, were found in several indices. Cellular retinoic acid-binding protein II and cellular retinol-binding protein I mRNAs were increased by both topical retinaldehyde and all-trans retinoic acid. Whereas all-trans retinoic acid, 9-cis-retinoic acid, and 13-cis-retinoic acid were not detectable (limit 5 ng/g) in vehicle-treated skin, 0.05% retinaldehyde-treated skin contained 13 +/- 6.9 ng/g wet tissue of all-trans retinoic acid (mean +/- SD), 12.6 +/- 5.9 ng/g 13-cis-retinoic acid, and no 9-cis-retinoic acid. In contrast, 9-cis-retinoic acid was detectable in 0.05% of all-trans retinoic acid-treated skin, which also contained 25-fold more all-trans retinoic acid and 5-fold more 13-cis-retinoic acid than retinaldehyde-treated skin. Our results show that topical retinaldehyde is transformed in vivo into all-trans retinoic acid by mouse epidermis. The small amounts of ligand for retinoic acid nuclear receptors thus produced are sufficient to induce biologic effects similar to those resulting from the topical application of the ligand itself in much higher concentration.

Topical Retinaldehyde on Human Skin: Biologic Effects and Tolerance

The present study was designed to explore if *etinaldehyde, a natural metabolite of vitamin A, has any biologic activity and is tolerated by human skin. Biologic activity was shown by the induction of cellular retinoic acid-binding protein type 2 (CRABP 2) mRNA and protein; the rank order for CRABP-2 increase was retinoic acid > retinaldehyde > 9 cis retinoic acid > retinol > beta carotene. In volunteers treated 1-3 months with 0.5, 0.1, and 0.05% retinaldehyde, there was a dose-dependent and significant increase in epidermal thickness, keratin 14 immunoreactivity, and Ki67-positive cells. The area of distribution of involucrin, transglutaminase, and filaggrin immunoreactivity was also increased in a dose-dependent manner, and keratin 4 immunoreactivity was induced in the upper epidermis. In pilot clinical tolerance studies, 229 patients received topical retinaldehyde at different concentrations; the 1% preparation was tolerated by up to 70% of the treated subjects; tolerance of the 0.5% preparation was slightly better, whereas both 0.1 and 0.05% preparations applied on facial skin were well tolerated and allowed prolonged use (up to 3 years) in patients with inflammatory dermatoses. These findings indicate that topical retinaldehyde has biologic activity and is well tolerated on human skin.