Role of Beta-Endorphin in the Skin COSMETICS BETA-ENDORPHIN

International Journal for Applied Science ■ Personal Care ■ Detergents ■ Specialities

Reprint from D. Schmid, F. Zülli: 4-2005 Role of Beta-Endorphin in the Skin COSMETICS BETA-ENDORPHIN

D. Schmid, F. Zülli* Role of Beta-Endorphin in the Skin

Keywords: beta-endorphin, happiness, Vitex agnus-castus, chaste tree, monk’s pepper casticin, wrinkle depth

Endorphins: hormone cortisol, the melanocyte-stimu- Abstract Structure and Function lating hormone (MSH) that is involved in skin pigmentation and beta-endorphin Morphin, a substance found in Papaver that comprises the 31 C-terminal amino eta-endorphin is a peptide somniferum, has an analgesic effect. Our acids. POMC and its cleavage products are neurotransmitter that is body produces compounds with a similar produced mainly in the hypothalamus and Bmainly produced in the cen- effect and this is why they are called en- in the anterior lobe of the pituitary gland. tral nerve system where it causes dogenous opioids. This is a group of pep- There are several functions for beta-en- an analgesic effect and a feeling tide hormones comprising beta-endor- dorphin described. Binding with its N-ter- of euphoria after binding to opiate phin, enkephalin and dynorphin. They minus to the three opioid receptors mu, share the N-terminal amino acid sequence kappa and delta (preference for mu) leads receptors. During the last years Tyr-Gly-Gly-Phe-X (X = Met or Leu). This to morphine-like effects. Beta-endorphin several research groups confirmed is the binding sequence to the opioid re- produces analgesia by acting on both, the presence of a fully functional ceptor. Each of these peptide hormones is central and peripheral opioid receptors beta-endorphin/mu-opiate recep- produced out of a separate precursor pep- which inhibits the transmission of the sig- tor system in a variety of cuta- tide. Beta-endorphin is a cleavage prod- nal along nerve cells from the source of neous cell types. The beta-endor- uct of proopiomelanocortin (POMC), a the pain (nociceptor) to the spinal cord. protein with 267 amino acid residues. Pro- Beta-endorphin was also found to bind to phin/mu-opiate receptor system cessing of POMC leads to several peptide receptors on cells of the immune system. was shown to modulate migration hormones with different functions It seems to be involved in the fine tuning of keratinocytes and to be in- (Fig. 1): the adrenocorticotropic hormone of the immune response. Finally there is volved in wound healing. Chaste (ACTH), also known as corticotrophin, that strong evidence that endorphins are con- tree, a medicinal plant indigenous stimulates the adrenal cortex to secrete nected with »pleasure centres« in the to the Mediterranean region and the anti-inflammatory and anti-allergic brain. Asia, was shown to produce lipophilic substances that bind to the mu-opiate receptor and to stimulate beta-endorphin production in vivo. Topical application of a preparation of the lipophilic fraction of chaste tree berries was found to exert a positive effect on skin hydration, firmness and wrinkle depth.

Fig. 1 Processing of proopiomelanocortin

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Existence of the Beta-Endorphin / to acute wounds (4). The group of Bi- (PMS). The term refers to symptoms such mu-Opiate Receptor System gliardi showed also a possible role of skin as irritability, tension, anxiety and physi- in the Skin beta-endorphin in the communication cal changes that some women experi- with peripheral nerve endings (5). They ence in the two weeks before the period Our skin is a target for the POMC-derived found that keratinocytes positive for starts. High levels of the hormone pro- hormone MSH, which regulates skin pig- beta-endorphin staining are clustered lactin are thought to play a role in PMS. mentation. Recently the in situ produc- around the terminal ends of afferent C- Chaste tree was found to reduce the re- tion of POMC and its products ACTH, fibres, which signal the sensations of lease of prolactin, probably through its MSH and beta-endorphin and their cor- warmth, cold or pain to the central ner- dopaminergic action. Binding of lipophilic responding receptors in skin cells has vous system. Further, they showed that compounds of chaste tree to the dopamine been demonstrated (1). It has been pro- the mu-opiate receptor was expressed receptor is well documented (6). Meier et posed that a cutaneous POMC system on these nerve fibres in the dermis and al. showed also binding to the opiate re- acts in an autocrine manner in response epidermis. It was hypothesized that ker- ceptors, especially to the mu and kappa to external or internal stresses. POMC atinocytes can communicate directly type (7). Since anxiety, depression and processing in melanocytes and a MSH / with the nervous system through the sleeping problems are important symp- melanocortin 1 receptor / cAMP cascade opiate receptor system and that this toms of PMS and beta-endorphins are in control of pigmentation is well docu- might open potential therapies of skin known to induce feelings of pleasure and mented. Recent data have demonstrated diseases like atopic dermatitis and psori- euphoria, the beta-endorphin-like activi- the existence of a functionally active be- asis. ty might be also involved in the benefi- ta-endorphin / mu-opiate receptor system cial effect of chaste tree in the treatment in melanocytes, keratinocytes and fibrob- of PMS. Binding to the mu and kappa lasts. Regarding epidermal and hair fol- Monk’s Pepper Produces opiate receptor was more pronounced in licle melanocytes, it was shown that be- Substances with Beta-Endoprhin the lipohhilic fraction of an ethanol ex- ta-endorphin can regulate melanogenesis, Activity tract, but the exact molecular nature of dendricity and proliferation (2). Bigliardi the active compounds is not known jet. et al. 2002 observed for beta-endorphin a Chaste tree (Vitex agnus-castus), also Samochowiec et al. also showed a possi- stimulation of the migration of cultured known as monk's pepper, is a large shrub ble role of beta-endorphin in the thera- human keratinocytes (3). They proposed native to the Mediterranean area that peutic effect of chaste tree against PMS for beta-endorphin a key role in the fi- produces aromatic berries with a bitter (8). When they fed rats over 4 days with nal reepithelialization and tissue regen- taste. Dried chaste tree berries have been a chaste tree extract, they found an in- eration in wound healing. Supporting used as a pepper substitute and as herbal crease in the beta-endorphin level in the this theory is the fact that expression of medicine until now to treat disorders of blood of 105%. It implies that chaste tree mu-opiate receptors on keratinocytes the female reproductive system. Nowa- contains substances that stimulate the close to the wound margin of chronic days it is especially recommended for body's own production of beta-endor- wounds was indeed reduced compared the treatment of premenstrual syndrome phin.

Topical Application of a Monk’s Peper Berries Extract

Dried monk's pepper berries were ex- tracted in ethanol, glycerine and beta cyclodextrin. For standardisation the lipophilic flavonoid casticin was measured by HPLC-analysis. Casticin is a chemotaxonomic marker of the genus Vitex and the most dominant substance in the fingerprint chromatogram of the monk's pepper berries (9). Extraction of 5% dried berries yielded in a solution of 15 mg / l casticin. The final cosmetic ingredient (Happybelle-PE) consisted of monk's pepper berries extract, lecithin, tocopherol, ascorbyl tetraisopalmitate Fig. 2 Liposomes and nanoparticles as skin carrier systems. The lipophilic compo- and beta cyclodextrin. Combination of nents of monk's pepper berries extract are concentrated in beta cyclodextrin cap- beta cyclodextrin and lecithin resulted in sules that are incorporated into liposomes a double vector system (Fig. 2). Casticin

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and other lipophilic monk's pepper com- 250 pounds are enriched in the hydrophobic pocket of beta cyclodextrin and these 200 complexes are enclosed in the lecithin liposomes. The lipophilic vitamins were en- 150 capsulated in a nanoemulsion, stabilized 100 with lecithin. The double vector system in- creases the stability of the monk's pepper Mitochondrial 250 compounds and enhances their penetra- tion into the skin. In an in vitro assay with

dehydrogenase activity (%) dehydrogenase 250 cell cultures of human keratinocytes the Control 0.0625% 0.25% 1.0% cosmetic ingredient Happybelle-PE was found to clearly stimulate the activity of Concentration of Happybelle-PE in the culture medium the mitochondrial succinate dehydrogenase indicating increased cell prolifera- Fig. 3 Happybelle-PE stimulates cell proliferation of keratinocytes. Mitochondrial tion. Already 0.0625% monk's pepper in- dehydrogenase activity was measured by the MTT assay. Keratinocytes (HaCaT) were gredient was significantly increasing the preincubated at 37°C for 24 hours. Then Happybelle-PE was added, diluted in cell enzyme activity (Fig. 3). For the in vivo culture medium. The cells were incubated for another 72 hours before the MTT as- efficacy a cream with 1% Happybelle-PE say was performed was tested in a study with 20 women (hydration and firmness) and 40 women (wrinkle depth) in the age of 30 to 61. 25 The cream was applied twice daily for 28 days. Skin hydration, skin firmness and 20 wrinkle depth were determined at the beginning of the study and 8 to 12 hours 15 following product application after 14 and after 28 days. Skin hydration was 10 improved by nearly 30% and skin firmness increased by 20%. A significant re- 255 duction in wrinkle depth could be ob- Decrease in wrinkle depth (%) Decrease served after the treatment (Fig. 4). 250 after two weeks after four weeks

References Fig. 4 Reduction of wrinkle depth compared to the beginning of the study and the untreated area. Wrinkle depth was measured by recording the crow feet area as a (1) Wintzen M. & Gilchrest B.A. (1996) Proopiome- 3D topography using the PRIMOS system. One skin side around the eye was treat- lanocortin, its derived peptides, and the skin. J ed with a cream containing 1% Happybelle-PE. The other side stayed untreated as Invest Dermatol 106: 3-10 control (2) Kauser S., Thody A. J., Schallreuter K. U., Gum- mer Ch. L. & Tobin D.J. (2004) β-Endorphin as a Regulator of Human Hair Follicle Melanocyte ceptor and Beta-Endorphin Expression in Nerve (9) Hoberg E., Meier B. & Sticher O. (2001) Quantita- Biology. J Invest Dermatol 123: 184-195 Endings and Keratinocytes in Human Skin. Der- tive High Performance Liquid Chromatographic matology 209: 183-189 Analysis of Casticin in the Fruits of Vitex ag- (3) Bigliardi P.L., Büchner S., Rufli T. & Bigliardi-Qi M. nus-castus. Pharmaceutical Biology 39: 57-61 (2002) Specific Stimulation of Migration of Hu- (6) Wuttke W., Jarry H., Christoffel V., Spengler B. man Keratinocytes by µ-Opiate Receptor Ago- & Seidlovai-Wuttke D. (2003) Chaste tree (Vi- nists. Journal of Receptors and Signal Transduc- tex agnus-castus) – pharmacology and clinical tion 22: 191-199 indications. Phytomedicine 10: 348-357 * Authors’ address: Daniel Schmid, Fred Zülli (4) Bigliardi P. L., Sumanovski L. T., Büchner S., Ru- (7) Meier B., Berger D., Hoberg E., Sticher O. & Schaff- Mibelle AG Cosmetics fli T. & Bigliardi-Qi M. (2003) Different Expres- ner W. (2000) Pharmacological activities of Vi- Bolimattstrasse 1 µ sion of -Opiate Receptor in Chronic and Acute tex agnus-castus extract in vitro. Phytomedi- 5033 Buchs Wounds and the Effect of β-Endorphin on cine 7: 373-381 Transforming Growth Factor β Type II Receptor Switzerland and Cytokeratin 16 Expression. J Invest Derma- (8) Samochowiec L., Glaesmer R. & Samochowiec Email: [email protected] tol 120: 145-152 J. (1998) Einfluss von Mönchspfeffer auf die Konzentration von beta-Endorphin im Serum (5) Bigliardi-Qi M., Sumanovski L.T., Büchner S., weiblicher Ratten. Aerztezeitschrift für Natur- Rufli T. & Bigliardi P.L. (2004) Mu-Opiate Re- heilverfahren 39: 213-215

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