224 JOURNAL OF COSMETIC SCIENCE COSMECEUTICAL PROPERTIES OF FERMENTED SAGE COMPOUND Ven Subbiah, Ph.D. and David Peele, Ph.D. R. J Reynolds Background: Adipose cells in the hypodermis play two important roles in the maintenance of healthy sion (1, 2). The first role of adipose tissue is to protect the skin. Subcutaneous adipose is an energy storage site and insulating layer necessary for healthy skin. The second role of adipose tissue is to nurture the skin. Lipolysis is the process of breaking down stored triacylglycerol in the fat cell to release free fatty acids and glycerol. This occurs by triggering Hormone Sensitive Lipase (HSL) which is under acute hormonal and neural contr61. Catecholamines like adrenaline and nor-adrenaline activate HSL, the rate-limiting enzyme of lipolysis, through cAMP-dependent phosphorylation (3). Cellular communication involves the interaction of neurotransmitter, hormones, and hormonal factors with receptors expressed on the cell surface. Following interaction with receptors particularly those belonging to the metabotrophic super family, hormones are secreted from the pituitary gland and cellular transduction occurs through activation of second messenger pathways including the adenylyl cyclase system and the calcium-phospholipid pathways (3). The modulations of these second messengers result in changes in the phenotype and/or Renotype of the target cell resulting in the biological response. Significance: Fermented sage compound (FSC), a natural product (Molecular weight - 250) is a bicyclic terpenoid, white crystalline compound. FSC is an adenylyl cyclase activator like Forskolin, obtained from the mots of Coleus forskoli (2). cAMP assays indicate (3) that FSC has a similar activity profile and potency as that of forskolin, a well established adenylyl cyclase activator, in interaction with ligand Rated ion channels (Figure 1). It is believed that it may also act as a therapeutic agent by selectively activating secondary messenger pathways. Forskolin is known to promote lean body mass (4). Results: FSC elicits physiological effects consonant with its ability to stimulate adenylate eyclase and increase intracellular cyclic AMP. Other responses which are elicited by FSC and have been associated with increased intracellular cyclic AMP include lipolysis in adipocytes, inhibition of platelet aggregation, and relaxation of smooth muscle and stimulation of steroidogenesis. FSC increases sodium transport in cultured epithelia (Figure 2). The ability of FSC to induce lipolysis/lipogenesis is an integral component of anti-wrinkle, anti-aging, and cellulite creams and lotions. It is believed that FSC and analogs can selectively activate adenylyl eyeIasc system making analogs suitable as selective probes. The activities associated with increased cellular c-AMP include lipolysis in adipocytes and inhibition of platelet aggregation. FSC increases sodium tramport (89%). The exact site of action of FSC still remains unclear, and it is possible that FSC acts directly at the catalytic subunit of adenylate cyclase or at another subunit which has not yet been identified. Other cosmeceutical properties of FSC: FSC has very significant antimicrobial properties in in vitro assays against Propionibacterium acnes indicating that this compound could be very effective to treat ache (5, 6). Another study using FSC (0.1%) showed lipid barrier-enhancing properties by strengthening the natural lipid barrier of the skin as well as other methods of skin treatment that are made possible by the strengthening of the barrier (7). In addition, the report also mentions that FSC reduces the skin's response to irritants and sensitizers and could be used for tanning the skin without exposure to the sun. FSC is known to cure disorders characterized by excessive cell proliferation in patients with benign hyperplasia and psoriasis (8). Safety studies: The safety test show FSC with low irritancy potential (safe as saline) R/PT-no indication of irritation or sensitization at 1.0%. Orally it was non-toxic-acute oral LD50 5g/kg (in rat as per MSDS) no observed adverse effect level-50 mg/kg bw/day for 28 wks (FEMA GRAS no. 3794). Further, RTPCR studies showed no sensitization or irritation. Conclusion: Subcutaneous adipose forms the deepest layer of skin, or hypoderrnis, and is responsible for protecting and nourishing the outer layers. Subcutaneous adipose tissue helps to keep skin soft and supple by insulating it from the elements and providing vital moisture and nuta-ient supply. FSC has potential use in personal care products, primarily anti-wrinkle, "orange peel" and other signs of aging. These compounds work in harmony with the metabolism of adipose cells in that they stimulate lipolysis/lipogenesis, thereby altering the outward appearance of the skin. FSC has been shown to breakdown lipid (triglycerides) barrier which is unique and could have application in the

2002 ANNUAL SCIENTIFIC MEETING 225 cosmetics industry. In conclusion, FSC could become an alternate for Forskolin and could be used in creams and body lotions as well as in weight loss management. References: 1. Metzget, R. H. and Lindner, E. Drug Res. 31:1248-1250 (1981) 2. Kenneth, B. S. Ann. Reports in Med Chem. 19:293-302 (1984) 3. Yajima, H. Diabetes, 48:1006-1012 (1999) 4. Majeed, M Badmacy, V and Rajendran, R. Patent number US 5804596 (1998) 5. Subbiah, V. Patent number US 6,150,381 (2000) ß 6. Subblab, V. Patent number and US 6,331,551 BI (2001) 7. Maes, D Anderson, J Marenus, K. D Mammone, T and Ethenakis, C. G. Patent number WO 01/74327 AI (200•) 8. Braquet, P and Zigg, D. Patent number WO 96/20704 (1996) Figure 1. Effects of FSC on human nAChR functions % • Sclareolide ] i • I Forskolln i. ,4, \ (Diterpene), (uM) Figure 2. Other cosmeceutical properties of FSC