Pharmacological Properties of Myrtacine® and Its Potential Value in Acne Treatment

Abstract

This study aimed at evaluating the antiproliferative, antibacterial, and anti-inflammatory properties of an ethanolic myrtle extract (Myrtacine®) in vitro, characterising its potential active compounds (myrtucommulones A and B’) by structural analysis, and evaluating their biological activity. Antiproliferative activity was assessed by the BrdU incorporation assay in HaCat keratinocytes and inhibitory and bactericidal activities against P. acnes strains by measuring the minimal inhibitory concentration (MIC) and D value. Anti-inflammatory effect was evaluated by measuring 6-keto-prostaglandin F1α and [³H]‐arachidonic acid metabolite production in keratinocytes stimulated for inflammation. Myrtacine® inhibited keratinocyte proliferation by 27 % and 76 % at 1 and 3 µg/mL, respectively (p < 0.001). A comparable effect, though less marked, was observed with 5 µg/mL myrtucommulones A and B’ (−36 % and −28 %, respectively). Myrtacine® inhibited erythromycin-sensible and ‐resistant P. acnes strains growth with MICs of 4.9 µg/mL and 2.4 µg/mL, respectively. Myrtucommulone B’ and myrtucommulone A displayed a similar inhibitory activity against both strains (for both strains, MIC = 1.2 µg/mL and about 0.5 µg/mL, respectively). At 3 and 10 µg/mL, Myrtacine® significantly decreased all metabolite production from cyclooxygenase (81 % and 107 %, p < 0.0001) and lipoxygenase (52 % and 95 %, p < 0.001) pathways. Finally, Myrtacine® exhibited a concentration-dependent anti-lipase activity at 100 µg/mL and 1 mg/mL, as it decreased lipase activity by respectively 53 % and 100 % (p < 0.01 for both). In conclusion, in vitro, Myrtacine® demonstrated antiproliferative, antibacterial, and anti-inflammatory properties that may be of value to exert a global action in the treatment of acne lesions.

Key words

Myrtus communis - Myrtaceae - acne - inflammation - antibacterial activity - myrtucommulones - keratinocyte proliferation

References

• 1 Krautheim A, Gollnick H. Transdermal penetration of topical drugs used in the treatment of acne.  Clin Pharmacokinet. 2003;  42 1287-1304
• 2 Jappe U. Pathological mechanisms of acne with special emphasis on Propionibacterium acnes and related therapy.  Acta Dermatol Venereol. 2003;  83 241-248
• 3 AFSSAPS . [Recommendations of good clinical practice on the treatment of acne].  Ann Dermatol Venereol. 2008;  135 S137-S141
• 4 Strauss J S, Krowchuk D P, Leyden J J, Lucky A W, Shalita A R, Siegfried E C, Thiboutot D M, Van Voorhees A S, Beutner K A, Sieck C K, Bhushan R. American Academy of Dermatology/American Academy of Dermatology Association: guidelines of care for acne vulgaris management.  J Am Acad Dermatol. 2007;  56 651-663
• 5 Rotstein A, Lifshitz A, Kashman Y. Isolation and antibacterial activity of acylphloroglucinols from Myrtus communis.  Antimicrob Agents Chemother. 1974;  6 539-542
• 6 Deriu A, Branca G, Molicotti P, Pintore G, Chessa M, Tirillini B, Paglietti B, Mura A, Sechi L A, Fadda G, Zanetti S. In vitro activity of essential oil of Myrtus communis L. against Helicobacter pylori.  Int J Antimicrob Agents. 2007;  30 562-563
• 7 Appendino G, Maxia L, Bettoni P, Locatelli M, Valdivia C, Ballero M, Stavri M, Gibbons S, Sterner O. Antibacterial galloylated alkylphloroglucinol glucosides from myrtle (Myrtus communis).  J Nat Prod. 2006;  69 251-254
• 8 Sacchetti G, Muzzoli M, Statti G A, Conforti F, Bianchi A, Agrimonti C, Ballero M, Poli F. Intra-specific biodiversity of Italian myrtle (Myrtus communis) through chemical markers profile and biological activities of leaf methanolic extracts.  Nat Prod Res. 2007;  21 167-179
• 9 Rosa A, Deiana M, Casu V, Corona G, Appendino G, Bianchi F, Ballero M, Dessì M A. Antioxidant activity of oligomeric acylphloroglucinols from Myrtus communis L.  Free Radic Res. 2003;  37 1013-1019
• 10 Feisst C, Franke L, Appendino G, Werz O. Identification of molecular targets of the oligomeric nonprenylated acylphloroglucinols from Myrtus communis and their implication as anti-inflammatory compounds.  J Pharmacol Exp Ther. 2005;  315 389-396
• 11 Kashman Y, Rotstein A, Lifshitz A. The structure determination of two new acylphloroglucinols from Myrtus communis L.  Tetrahedron. 1974;  30 991-997
• 12 Puybaret C, David B, Charveron M, Mamatas S. Myrtle extract, preparation method and use. EU patent EP1112079. 2001
• 13 Chene G, Dubourdeau M, Balard P, Escoubet-Lozach L, Orfila C, Berry A, Bernad J, Aries M F, Charveron M, Pipy B. n-3 and n-6 Polyunsaturated fatty acids induce the expression of COX-2 via PPAR gamma activation in human keratinocyte HaCaT cells.  Biochim Biophys Acta. 2007;  1771 576-589
• 14 Pollaud C, Krause S, Lepert J C, Orfila C, Seguelas M, Festal D, Decerprit J, Pipy B. Acetylated low density lipoprotein inhibits the incorporation of arachidonic acid in phospholipids with a concomitant increase of cholesterol arachidonate in rat peritoneal macrophages.  Biochim Biophys Acta. 1995;  1259 211-219
• 15 Salmon J A, Flower R J. Extraction and thin layer chromatography of arachidonic acid metabolites.  Methods Enzymol. 1982;  86 478-493
• 16 Cunliffe W J, Holland D B, Clark S M, Stables G I. Comedogenesis: some new aetiological, clinical and therapeutic strategies.  Br J Dermatol. 2000;  142 1084-1091
• 17 Plewig G, Fulton J E, Kligman A M. Cellular dynamics of comedo formation in acne vulgaris.  Arch Dermatol Forsch. 1971;  242 12-29
• 18 Popadic S, Ramic Z, Medenica L, Mostarica Stojkovic M, Trajković V, Popadic D. Antiproliferative effect of vitamin A and D analogues on adult human keratinocytes in vitro.  Skin Pharmacol Physiol. 2008;  21 227-234
• 19 Schroeder M, Zouboulis C C. All-trans-retinoic acid and 13-cis-retinoic acid: pharmacokinetics and biological activity in different cell culture models of human keratinocytes.  Horm Metab Res. 2007;  39 136-140
• 20 Leyden J J, McGinley K J, Vowels B. Propionibacterium acnes colonization in acne and nonacne.  Dermatology. 1998;  196 55-58
• 21 Strauss J S, Stranieri A M. Acne treatment with topical erythromycin and zinc: effect of Propionibacterium acnes and free fatty acid composition.  J Am Acad Dermatol. 1984;  11 86-89
• 22 Jeremy A H, Holland D B, Roberts S G, Thomson K F, Cunliffe W J. Inflammatory events are involved in acne lesion initiation.  J Invest Dermatol. 2003;  121 20-27
• 23 Rossi A, Di Paola R, Mazzon E, Genovese T, Caminiti R, Bramanti P, Pergola C, Koeberle A, Werz O, Sautebin L, Cuzzocrea S. Myrtucommulone from Myrtus communis exhibits potent anti-inflammatory effectiveness in vivo.  J Pharmacol Exp Ther. 2009;  329 76-86
• 24 Decker L C, Deuel D M, Sedlock D M. Role of lipids in augmenting the antibacterial activity of benzoyl peroxide against Propionibacterium acnes.  Antimicrob Agents Chemother. 1989;  33 326-330