473M. Lodén, H.I. Maibach (eds.), Treatment of Dry Skin Syndrome, DOI 10.1007/978-3-642-27606-4_32, © Springer-Verlag Berlin Heidelberg 2012

Glycerol, also named glycerin, is found in many industries as nitroglycerin production in explo-sives manufacture, as food preservative, sweet-ening agent, and solvent in food industries. Due to its high hygroscopic and hyperosmotic pro-perties, glycerol is widely used in cosmetic and pharmaceutical formulations (e.g., as laxative in suppositories, as brain edema treatment in infusion, and mainly as humectant in topical preparations).

The glycerol physicochemical properties will be defi ned as its synthesis, metabolism, and medicinal uses.

In the skin, endogenous glycerol has been identifi ed. The understanding of its effects, into the skin, is important to promote the glycerol cutaneous application. The properties of gly cerol will be defi ned to explain the role of glycerol in the skin.

32.1 Fundamentals About Glycerol

Glycerol, etymologically from Greek word “sweet,” also called glycerin (propane-1,2,3-triol), is a natural compound found in living organisms and extensively used in pharmaceuti-cal and cosmetic formulations. Main physico-chemical properties of glycerol are reported in Table 32.1 . Glycerol has three hydrophilic hydroxyl groups that are responsible for its hygroscopicity and excellent water solubility. Glycerol can be dissolved easily into alcohols (e.g., ethanol and methanol) and water but not into oils. Glycerol is widely used as antimicrobial preservative, emollient (i.e., having the power of softening or relaxing the skin), and humectant (i.e., water absorption tendency of a substance from the surroundings) (Table 32.2 ). Furthermore, glycerol might be handled with many other sub-stances. It is a product which is viscous, odorless, and sweet-tasting fl uid.

Glycerin is nontoxic to the environment and to human health; it presents few side effects. It has nonirritating effect when applied externally. It is biocompatible and considered as a safe chemical agent by the Food and Drug Administration.

32.2 Glycerol Production and Metabolism

Glycerin is produced either by hydrolysis or saponifi cation of oils or fats (Fig. 32.1 ). Alternatively, alcoholic fermentation of sugar

L. Roussel • N. Atrux-Tallau • F. Pirot (�) Laboratoire de Recherche de Développement de Pharmacie Galénique Industrielle , EA 4169 Lyon , France

Université Lyon 1 , 8 Avenue Rockefeller , 69373 Lyon Cedex 08 , France

Université Claude Bernard Lyon , Lyon , France e-mail: laurene.roussel@univ-lyon1.fr ; nicolas.atrux@gmail.com ; fabrice.pirot@univ-lyon1.fr

Glycerol as a Skin Barrier Infl uencing Humectant

Laurène Roussel , Nicolas Atrux-Tallau , and Fabrice Pirot

32

L. Roussel et al.474

gives glycerol, especially when the reaction is done in presence of sodium sulphite (Na

2 SO

3 ).

Industrial production is based essentially on dif-ferent reactions from propylene (chlorination and saponifi cation) [ 16 ] .

In living organisms, glycerol results from fat hydrolysis [ 27 ] . Lipolysis in adipocytes is acti-vated during fasting or exercise for giving energy. A phosphorylated hormone-sensitive lipase hydrolyzes triglycerides to free fatty acid and glycerol, and both are released into the

bloodstream. Serum glycerol concentrations approximate 0.05 mmol·L −1 at rest and can increase up to 0.30 mmol·L −1 during increased lipolysis [ 44 ] . Then, glycerol could be used for gluconeogenesis in the liver.

32.3 Glycerol Therapeutic Uses

Glycerol can be useful for the treatment of some diseases. In fact, glycerol, as hyperosmolar agent, has been used in research settings in the short-term treatment of cerebral edema resulting from ischemic stroke [ 42, 43 ] . Glycerol’s infusion has become a standard practice for the management of head-injured patients with suspected or actual intracranial hypertension [ 10 ] .

Glycerol ingestion with added fl uid has been used to create an osmotic gradient in the circula-tion favoring fl uid retention, thereby facilitating hyperhydration. Thus, glycerol provides benefi ts during endurance exercise or exposure to warm environments by inducing hyperhydration and rehydration [ 22 ] .

Glycerol-preserved skin allografts (GPA) are mainly used in the management of severe burn injuries, chronic ulcers, and complex, traumatic wounds. The selective and strategic use of the GPA in major burn patients ensures optimal benefi ts in the management of burns [ 28 ] .

50% Glycerol has been used for a long time as a viral preservation medium in tissue samples [ 53 ] . Preservation in 85% glycerol allowed to GPA to maintain its suppleness mandatory during surgery.

32.4 Endogenous Glycerol Content into the Skin

Endogenous glycerol is actually known to be an essential component to maintain stratum corneum (SC) hydration. In humans, glycerol skin content differs as a function of the body site. Onto the cheek, concentration is around 0.7 m g·cm −2 while in the forearm, glycerol content reaches 0.2 m g·cm −2 . Glycerol content seems dependent on the sebaceous gland density [ 54 ] .

Table 32.1 Physicochemical properties of glycerol

Physicochemical propertie Value

Chemical formula

HO OHOH

Molecular weight 92.09 g·mol −1 Density 1.26 g·cm −3 at 25°C Boiling point 290°C Melting point 17.8°C Surface tension 63.4 mN·m −1 at 20°C Dynamic viscosity at 20°C

5% aqueous solution (w/w): 1.14 mPa·s 83% aqueous solution (w/w): 111 mPa·s

Water solubility 1,000 g·L −1 at 20°C Acetone solubility Slightly soluble at 20°C Oil solubility Practically insoluble at 20°C Ethanol (95°) and methanol solubility

Soluble at 20°C

Osmolarity 2.6% (v/v) aqueous solution is isosmotic with serum

p K a 14.4

Log K (octanol/water) −1.98 Log K

p −8.27

Adapted from [ 40 ] Log K (octanol/water) is octanol/water partition, deter-mined by using ProLog ® software (ChemCAD, Obernai, France) Permeability coeffi cient of glycerol within the SC calculated as [ 39 ] : log K

p (cm·s −1 ) = −6.3 + 0.71 log K −0.0061 MW

Table 32.2 Uses of glycerol

Use Concentration (%)

Humectant £ 30 Emollient £ 30 Antimicrobial preservative <20

Adapted from [ 40 ]

32 Glycerol as a Skin Barrier Infl uencing Humectant 475

Glycerol is a byproduct of the triglycerides lipolysis within pilosebaceous gland [ 33 ] . The lipolysis of triglycerides is more effi cient within the pilosebaceous apparatus than within the SC [ 52 ] . In the SC, the level of triglycerides avail-able for lipolysis is low [ 47 ] .

It is also possible that there are sources of gly-cerol in SC other than those derived from seba-ceous glands. Indeed, SC phospholipid catabolism generates a family of nonessential free fatty acids required for the barrier function which might simultaneously generate glycerol in the SC inter-stices. The glycerol is formed by the breakdown of phospholipids by phospholipases [ 15 ] .

Glycerol diffuses from the dermis and is trans-ported into basal cells of the epidermis through aquaporin 3 (AQP3), a transmembrane water/glycerol transporting protein. Indeed, in AQP3 knockout mice [ 25 ] , deletion produced a signifi -cant reduction in glycerol content in SC and epi-dermis but not in dermis or blood. Therefore, glycerol transport via AQP3 occurs solely across the relatively glycerol-impermeable basal layer of epidermis in response to a steady-state dermal-to-epidermal glycerol gradient.

AQP3 is expressed in the innermost layer of keratinocytes in mammalian epidermis. By indi-rect immunofl uorescence and electron micros-copy gold labeling on human epidermis sections, AQP3 was primarily and abundantly localized in plasma membrane of the keratinocytes in epider-mal human skin [ 49, 50 ] .

AQP3 synthesis appears to occur early in basal cells with a predominant cytoplasmic dis-tribution, and the differentiation process could induce AQP3 translocation to the plasma mem-brane [ 49 ] .

The importance of endogenous glycerol is now established in the SC hydration. Glycerol belongs to the natural moisturizing factor (NMF).

The decrease of the endogenous glycerol in SC is correlated to a decrease in SC hydration [ 16, 18, 26 ] . Choi [ 13 ] confi rmed that variation in SC hydration is correlated with variations in both blood and sebaceous gland glycerol content.

In asebia mice [ 18 ] , with a large depletion of sebaceous gland, the SC hydration was also decreased. As well, the glycerol content in SC decreased by 83%. The addition of sebum-like lipids (triglycerides) did not restore the normal SC hydra-tion while topical addition of glycerol did.

In AQP3 defi cient mice, the glycerol content decreased by 50% in the SC as compared to wild-type mice and by 37% in the epidermis. Additional skin phenotype analysis highlighted a delayed barrier recovery after SC removal by tape strip-ping in AQP3 null mice, as well as delayed wound healing [ 25 ] .

Reduction in skin conductance in AQP3 null mice was not corrected by occlusion or exposure to a humidifi ed atmosphere, suggesting an intrin-sic defect in SC water-holding capacity (WHC). Thus, the water transporting function of AQP3 did not appear to be responsible for the reduced

O

OO

+

+ +

+HOHydrolysis

Saponification

OH

OH

HO OH

OH

O

O

OH

OH

O

O

O

O

OH

ONa

ONa

ONa

O

O

OO

R1

R3

R2

R1

R3

3H2O

3 NaOH (or KOH)

R2 R1

R3

R2

R1

R3

R2O

OO

O

O

Fig. 32.1 Synthesis of glycerol

L. Roussel et al.476

superfi cial skin conductance. However, when glycerol is topically added, the hydration defect is corrected in AQP3 knockout mice [ 26 ] . Glycerol improvement by topical routes increased SC water content, with excellent correlation between SC water and glycerol content in AQP3 null mice.

The relationship between AQP3 and skin di sorders associated with abnormal water homo-eostasis (atopic dermatitis, psoriasis, xeroderma, and ichthyosis) needs to be investigated.

Modulation of AQP3 functions by different compounds could be interesting in activating the water/glycerol transport from the dermis to the basal layers of epidermis. An AQP3 upregulation may increase SC water content and improve the barrier function.

Hara-Chikuma and Verkman [ 24 ] provided evidence for involvement of AQP3-facilitated water transport in epidermal cell migration and for AQP3-facilitated glycerol transport in epider-mal cell proliferation during repair of skin wounds. Pharmacological modulation of AQP3 could be also therapy to accelerate wound hea-ling in traumas, burns, and other forms of injury.

32.5 Effects of Cutaneous Exposure to Glycerol

Glycerol is widely used in different dermatologi-cal and cosmetic preparations. It acts as natural moisturizer and preserves the SC barrier func-tion. It also infl uences the skin surface mechani-cal properties by plasticizing SC and inducing smoothing effect [ 9, 36 ] (by cell shrinking of the superfi cial corneocytes). It can also increase skin elasticity [ 36 ] .

It is actually known that the skin care benefi ts of glycerol are due to different properties of the compounds: attraction of moisture, maintenance of crystallinity/fl uidity of cell membranes and intracellular lipids [ 31 ] , keratolytic effect, and its ability to diffuse and penetrate into the SC [ 6 ] .

Glycerol is a hygroscopic compound, limiting thus water evaporation and improving SC hydra-tion. Glycerol effi ciency is also due to its capacity to diffuse and accumulate in the entire thickness

of the SC in a high proportion [ 35 ] . Indeed, in vivo determination of skin water content with a confo-cal Raman optical microprobe, revealed an increase of the water content after glycerol appli-cation with no dependence on the SC depth [ 14 ] .

Nevertheless, in guinea pig model, diglycerol and triglycerol, with a higher humectant activity in vitro than glycerol, showed less effective action on skin dryness improvement as compared to glycerol [ 46 ] . The chemical properties deter-mined in vitro could not be suffi cient to predict the molecule effect on SC hydration.

The SC water content in a healthy skin is around 20–30% by weight [ 48 ] . The SC needs to be hydrated to maintain its integrity. SC hydration varia tions can infl uence the SC barrier function [ 16 ] .

Glycerol prevents damaging effect on the SC. Glycerol pretreatment decreases irritancy caused by alkali solution (e.g., sodium hydroxide), dimethyl sulfoxide, and sodium lauryl sulphate (SLS) [ 16 ] .

Glycerol leads to a more rapid reconstitution of the protective skin barrier following mechani-cal (tape stripping) or chemical (repeated SLS application, acetone) damage. It can absorb water and thus creating water fl ux in the SC which may lead to a stimulus for barrier repair [ 17 ] . In Andersen et al. studies [ 1– 3 ] , only glycerol treat-ment improved skin barrier recovery after acute and cumulative irritations induced by SLS or nonanoic acid applications in hairless guinea pig model and in human volunteers. The high hygro-scopicity of glycerol can be involved in this action, supporting transepidermal water loss (TEWL) and ion movement (especially calcium) [ 8 ] .

In the case of aqueous solution, after SLS-induced irritation on skin, it appears that glycerol effi cacy on hydration (evaluated by capacitance measurement) and TEWL reached a plateau phase when enhancing glycerol concentration, resulting in a maximal WHC value [ 5 ] . The recovery of the water barrier function with gly-cerol by skin rehydration is thus saturable. The WHC of stratum corneum is related to hygro-scopic compounds and to SC osmotic pressure. The WHC and skin hydration were found to be correlated with SC osmolality, varied as a func-tion of the osmolality of solutions (Fig. 32.2 ), and the SC permeability of osmolytes [ 37, 38 ] .

32 Glycerol as a Skin Barrier Infl uencing Humectant 477

A low-dose topical application of glycerol was shown to restore the water barrier func-tion of SLS-damaged skin. The beneficial effect of glycerol on skin barrier function, dis-rupted by acute chemical, acts throughout the increase of WHC [ 5 ] . WHC reflects an equi-librium between bound and free water deter-mined, respectively, by hydration measurement and TEWL.

In normal SC, it is thought that the ratio of lipids in ordered and disordered (liquid crystal-line) phases modulates the SC barrier function properties [ 11 ] .

The entity of the skin barrier is ensured by the optimal organization and the interactions of the SC components, i.e., corneocytes and the intercel-lular lipids bilayers. The lipid bilayers disorgani-zation, rather than lipid extraction, is responsible for barrier impairment.

A pure liquid crystal system, produced by an all-unsaturated fatty acid mixture, allows a rapid water loss through the bilayers with a moderate barrier action. The solid system produced with an all-saturated fatty acid mixture causes an extreme water loss due to breaks in the solid crystal phase [ 16 ] . Maintaining the balance between the two phases is required for optimal barrier function in preventing water loss [ 51 ] .

Thus, the proportion of lipophilic components in solid state was noted in skin exhibiting SC bar-rier damage [ 19 ] .

Froebe et al. [ 19 ] showed, from an in vitro experiment, that by glycerol adding to the SC lipids, the transition of the lipophilic components from the liquid crystalline phase to the solid crystalline phase can be prevented at low relative humidity. It has been hypothesized that glycerol can interact with polar head groups of the lipid bilayers rather than by penetrating the alkyl chains. Consequently, maintaining the fl uidity of the lipid membrane improves skin conditions in dry climates. Thus, glycerol decreases SC permeability to water but enhances SC barrier function.

Batt and Fairhurst [ 7 ] postulated that a depot formation of glycerol in the depth of the horny layer lipids occurs because of glycerol persistent effects after discontinuation of the therapy over 24 h. This would suggest that the effect on the SC lipids is present not only to the upper layers, but also to the SC lipids deeper layers.

Glycerol-containing moisturizers continue to improve barrier function for at least a week after cessation of treatment [ 4 ] .

Furthermore, 10% glycerol addition in an aqueous solution of SLS prevents the skin barrier perturbation induced by the surfactant in vitro by reducing the skin aqueous pore radius and the aqueous pore number density [ 20 ] . Glycerol pre-sent in the SC is able to bind water in the SC and thus reduce the mobility of water. In hydrated skin, aqueous pores are constituted by lacunar domains within water is mobile. The limited mobility of water may result in lacunar domains structural continuity loss within the SC extracel-lular lipid bilayers [ 34 ] . Ghosh et al. [ 20 ] sug-gested that it may involve the reduction of the radius of the aqueous pore if the loss of continuity is partial and the reduction of the aqueous pore number density if the loss is complete. Moreover, the glycerol property to maintain the intercellular lipid mortar in liquid phase can also lead to mini-mize the lacunar domains and thus reduce the continuity of it.

The glycerol-hydrating property occurs not only on healthy skin but also on skin affected by xerosis.

300y = 3.99x – 13.68, r = 0.975, p < 0.01

250

200

150

ΔSC

osm

olal

ity (

%)

100

50

00 10 20 30

Urea

Formamide

Glycerol

Mannitol

Osmotic pressure (atm)

Glucose

40 50 60

Fig. 32.2 Linear relationship between D SC osmolality (%) and the osmotic pressure (atm) of donor solutions. Each data point is the mean ± standard deviation of 3 or 5 experi-mental determinations [ 38 ] . ■ = Mannitol, ● = Glucose, ▲ = Glycerol, ▼ = Urea, ♦ = Formamide

L. Roussel et al.478

The understanding of skin moisturization distur-bances is of major importance for new treatment of pathologies such as atopic dermatitis, eczema.

Glycerol seems to be a relevant treatment in atopic dermatitis (AD). However, Lodén et al. [ 30 ] were not able to detect differences in the bio-physical assessment of epidermal functions in a placebo-controlled AD study. Thirty days gly-cerin treatment versus placebo in atopic dermati-tis patient showed no differences in TEWL.

Breternitz et al. [ 12 ] investigated lesional skin of atopic patients and detected a positive (but not signifi cant) effect of glycerol for recovery of altered epidermal barrier function. Concerning hydration, glycerol cream has signifi cant advan-tages as compared to the glycerol-free formula-tion. The erythema values as a marker of skin irritation or infl ammation were slightly lower in the group of patients treated with glycerol. However, any signifi cant differences were distin-guished between the glycerol-based formulation and glycerol-free formulation regarding improve-ment of epidermal barrier function, irritation parameters, surface pH, and clinical scores.

The recent observation that xerotic skin is associated with incomplete desmosome digestion suggests that moisturizers improve the desqua-mation process in such conditions.

Glycerol seems to have keratolytic properties. After fi rst week of glycerol treatment, an activa-tion of SC protease activity occurs (simply by ele-vated water activity). This protease is responsible of the regulation of corneocytes desquamation, resulting in more effi cient reduction in SC thick-ness. The desmosome degradation is essential to maintain a healthy skin which requires an equilib-rium between degradation and synthesis of desmo-some. Furthermore, glycerol desmolytic effect, demonstrated by Rawlings et al. [ 41 ] , causes a decrease in intraepidermal pressure on the bila-mellar intercellular lipids and, therefore, indirectly causes an increase in the liquid crystalline state lipids. The dry skin scaliness is thus reduced, and the SC barrier is maintained in xerotic skin.

Investigations on the infl uence of the vehicle used showed that the benefi cial effect of glycerol on skin was more pronounced in using oil in water emulsion compared with water in oil

emulsion [ 21, 23 ] . The quantity of absorbed humectant in the SC infl uences the glycerol mois-turization effect [ 35 ] . Furthermore, glycerol moisturizing effi ciency depends on solvents in which it is dissolved. Therefore, glycerol acts as an effective humectant only when it is dissolved in water [ 45 ] .

Gloor [ 21 ] showed that the pretreatment with oil in water emulsions containing glycerol pre-vents dehydration, barrier perturbation, and irri-tation caused by washing with SLS. In the case of oil in water emulsions, the proportion of glycerol should not be less than 8.5%. However, glycerol high concentration application results in dehy-dration of the skin because of the osmotic water extraction from the SC caused by glycerol.

However, in aqueous solution, glycerol con-centration must not exceed 5% to restore barrier function [ 5 ] .

In addition, it has been reported that glycerol facilitated skin penetration of topically applied drugs [ 17, 29 ] . After tape stripping, glycerol could have penetration-enhancing effect mainly by the glycerol action on SC lipid organization [ 8 ] , whereas protective and curative effect against irritants was reported [ 16 ] .

Recently, glycerol-derived compounds have been identifi ed and could be effi cient as moisturi-zer treatment: Glycerol quat ® (dihydroxypropyltri-monium chloride) is a combination of glycerin and a quat (i.e., a positively charged group of molecules attached to negatively charged skin proteins). Such compound is less lipophilic (allowing it to remain at the outermost layers) and binds four times more water molecules than glycerol. The objective is to compensate glycerol poor moisturizing effi ciency at skin surface outermost layers [ 32 ] .

Take Home Messages

Endogenous glycerol represents an • interesting compound in the epidermis. It maintains the hydration properties of the SC and thus the barrier function. The AQP3 functions modulation by dif-• ferent compounds could be interesting in order to activate the water/glycerol

32 Glycerol as a Skin Barrier Infl uencing Humectant 479

References

1. Andersen F, Hedegaard K, Fullerton A et al (2006) The hairless guinea-pig as a model for treatment of acute irritation in humans. Skin Res Technol 12:183–189

2. Andersen F, Hedegaard K, Petersen TK et al (2006) Anti-irritants I: dose–response in acute irritation. Contact Dermatitis 55:148–154

3. Andersen F, Hedegaard K, Petersen TK et al (2006) Anti-irritants II: effi cacy against cumulative irritation. Contact Dermatitis 55:155–159

4. Appa Y, Hemingway L, Orth D et al (1997) High glycerine therapeutic moisturizers. In: Poster pre-sented at the 55th annual meeting of the American Academy of Dermatology, San Francisco, CA

5. Atrux-Tallau N, Romagny C, Padois K et al (2010) Effects of glycerol on human skin damaged by acute sodium lauryl sulphate treatment. Arch Dermatol Res 302:435–441

6. Batt MD, Davis WB, Fairhurst E et al (1988) Changes in the physical-properties of the stratum-corneum fol-lowing treatment with glycerol. J Soc Cosmet Chem 39:367–381

7. Batt MD, Fairhust E (1986) Hydration of the stratum corneum. Int J Cosmet Sci 8:253–264

8. Bettinger J, Gloor M, Peter C et al (1998) Opposing effects of glycerol on the protective function of the horny layer against irritants and on the penetration of hexyl nicotinate. Dermatology 197:18–24

9. Bettinger J, Gloor M, Vollert A et al (1999) Comparison of different non-invasive test methods with respect to the different moisturizers on skin. Skin Res Technol 5:21–27

10. Biestro A, Alberti R, Galli R et al (1997) Osmotherapy for increased intracranial pressure: comparison between mannitol and glycerol. Acta Neurochir (Wien) 139:725–732; discussion 732–723

11. Boncheva M, Damien F, Normand V (2008) Molecular organization of the lipid matrix in intact Stratum cor-neum using ATR-FTIR spectroscopy. Biochim Biophys Acta 1778:1344–1355

12. Breternitz M, Kowatski D, Langenauer M et al (2008) Placebo controlled, double blind, randomized prospec-tive study of a glycerol-based emollient on eczematous skin in atopic dermatitis: biophysical and clinical eval-uation. Skin Pharmacol Physiol 21:39–45

13. Choi EH, Man MQ, Wang FS et al (2005) Is endoge-nous glycerol a determinant of stratum corneum hydration in humans? J Invest Dermatol 125:288–293

14. Chrit L, Bastien P, Sockalingum GD et al (2006) An in vivo randomized study of human skin moisturiza-tion by a new confocal Raman fi ber-optic microprobe: assessment of a glycerol-based hydration cream. Skin Pharmacol Physiol 19:207–215

15. Feingold KR (2007) Thematic review series: skin lip-ids. The role of epidermal lipids in cutaneous permea-bility barrier homeostasis. J Lipid Res 48:2531–2546

16. Fluhr JW, Darlenski R, Surber C (2008) Glycerol and the skin: holistic approach to its origin and functions. Br J Dermatol 159:23–34

17. Fluhr JW, Gloor M, Lehmann L et al (1999) Glycerol accelerates recovery of barrier function in vivo. Acta Derm Venereol 79:418–421

18. Fluhr JW, Mao-Qiang M, Brown BE et al (2003) Glycerol regulates stratum corneum hydration in sebaceous gland defi cient (asebia) mice. J Invest Dermatol 120:728–737

19. Froebe CL, Simion AF, Ohlmeyer H et al (1990) Prevention of stratum corneum lipid phase transitions in vitro by glycerol ± an alternative mechanism for skin moisturization. J Soc Cosmet Chem 41:51–65

20. Ghosh S, Blankschtein D (2007) The role of sodium dodecyl sulfate (SDS) micelles in inducing skin bar-rier perturbation in the presence of glycerol. J Cosmet Sci 58:109–133

21. Gloor M (2004) How do dermatological vehicles infl uence the horny layer? Skin Pharmacol Physiol 17:267–273

22. Goulet ED, Robergs RA, Labrecque S et al (2006) Effect of glycerol-induced hyperhydration on thermo-regulatory and cardiovascular functions and endur-ance performance during prolonged cycling in a 25

transport from the dermis to the epider-mis basal layers. AQP3 expression pharmacological • modulation could be benefi t in a number of skin disorders, burn repair, and other wounds. Glycerol, by its high hygroscopic pro-• perties, acts as a humectant. Glycerol leads to maintain crystallinity/• fl uidity of cell membranes and intracel-lular lipids. Glycerol prevents damaging effect • induced by alkali, surfactant, and organic solvent on the SC. The recovery of the water barrier func-• tion induced by glycerol after chemical damage can be explained by the improvement of WHC and skin hydra-tion which are correlated with SC osmo-lality and the SC permeability of osmolytes. In xerotic skin, its keratolytic property • confers to glycerol the capacity to improve skin barrier function and decrease its scaliness.

L. Roussel et al.480

degrees C environment. Appl Physiol Nutr Metab 31:101–109

23. Grunewald AM, Lorenz J, Gloor M et al (1996) Lipophilic irritants. Protective values of urea and glycerol containing oil in water emulsions. Dermatosen 44:81–86

24. Hara-Chikuma M, Verkman AS (2008) Aquaporin-3 facilitates epidermal cell migration and proliferation during wound healing. J Mol Med 86:221–231

25. Hara M, Ma T, Verkman AS (2002) Selectively reduced glycerol in skin of aquaporin-3-defi cient mice may account for impaired skin hydration, elasticity, and barrier recovery. J Biol Chem 277:46616–46621

26. Hara M, Verkman AS (2003) Glycerol replacement corrects defective skin hydration, elasticity, and bar-rier function in aquaporin-3 defi cient mice. Proc Natl Acad Sci USA 100:7360–7365

27. Hibuse T, Maeda N, Nagasawa A et al (2006) Aquaporins and glycerol metabolism. Biochim Biophys Acta 1758:1004–1011

28. Khoo TL, Halim AS, Saad AZM et al (2010) The application of glycerol-preserved skin allograft in the treatment of burn injuries: an analysis based on indi-cations. Burns 36:897–904

29. Kiwada H, Barichello JM, Yamakawa N et al (2008) Combined effect of liposomalization and addition of glycerol on the transdermal delivery of isosorbide 5-nitrate in rat skin. Int J Pharm 357:199–205

30. Lodén M, Andersson AC, Andersson C et al (2001) Instrumental and dermatologist evaluation of the effect of glycerine and urea on dry skin in atopic der-matitis. Skin Res Technol 7:209–213

31. Lodén M, Maibach HI (2000) Dry skin and moistur-izers: chemistry and function. CRC Press, Boca Raton

32. Lu N, Chandar P, Nole G et al (2010) Development and clinical analysis of a novel humectant system of glycerol, hydroxyethylurea, and glycerol quat. Cosmet Dermatol 23:86–94

33. Marples RR, Kligman AM, Downing DT (1971) Control of free fatty acids in human surface lipids by corynebacterium-acnes. J Invest Dermatol 56:127–131

34. Menon GK, Elias PM (1997) Morphologic basis for a pore-pathway in mammalian stratum corneum. Skin Pharmacol 10:235–246

35. Okamoto T, Inoue H, Anzai S et al (1998) Skin-moisturizing effect of polyols and their absorption into human stratum corneum. J Cosmet Chem 49:57–58

36. Olsen OL, Jemec GBE (1993) The infl uence of water, glycerin, paraffi n oil and ethanol on skin mechanics. Acta Derm Venereol 73:404–406

37. Pirot F, Falson F, Pailler-Mattéi C et al (2004) Stratum corneum: an ideal osmometer? Exog Dermatol 3:339–349

38. Pirot F, Morel B, Peyrot G et al (2003) Effects of osmosis on water-holding capacity of stratum cor-neum and skin hydration. Exog Dermatol 2:252–257

39. Potts RO, Guy RH (1992) Predicting skin permeabil-ity. Pharm Res 9:663–669

40. Price J (2005) Glycerin. In: Rowe RC, Sheskey P, Owen SC (eds) Handbook of Pharmaceutical Exci-pients. Fifth edition, p 301–303

41. Rawlings A, Harding C, Watkinson A et al (1995) The effect of glycerol and humidity on desmosome degra-dation in stratum corneum. Arch Dermatol Res 287:457–464

42. Righetti E, Celani MG, Cantisani T et al (2004) Glycerol for acute stroke. Cochrane Database Syst Rev (2):CD000096

43. Righetti E, Celani MG, Cantisani TA et al (2002) Glycerol for acute stroke: a cochrane systematic review. J Neurol 249:445–451

44. Robergs RA, Griffi n SE (1998) Glycerol. Biochemistry, pharmacokinetics and clinical and practical applica-tions. Sports Med 26:145–167

45. Sagiv AE, Dikstein S, Ingber A (2001) The effi ciency of humectants as skin moisturizers in the presence of oil. Skin Res Technol 7:32–35

46. Sagiv AE, Marcus Y (2003) The connection between in vitro water uptake and in vivo skin moisturization. Skin Res Techol 9:306–311

47. Schurer NY, Plewig G, Elias PM (1991) Stratum-corneum lipid function. Dermatologica 183:77–94

48. Silva CL, Topgaard D, Kocherbitov V et al (2007) Stratum corneum hydration: phase transformations and mobility in stratum corneum, extracted lipids and isolated corneocytes. Biochim Biophys Acta 1768:2647–2659

49. Sougrat R, Morand M, Gondran C et al (2002) Functional expression of AQP3 in human skin epider-mis and reconstructed epidermis. J Invest Dermatol 118:678–685

50. Sugiyama Y, Ota Y, Hara M et al (2001) Gene expres-sion of the water channels, aquaporins, in human keratinocyte and skin-equivalent cultures, and osmotic stress induction of aquaporin-3 mRNA in cultured keratinocytes. J Invest Dermatol 117:410

51. Thau P (2002) Glycerin (glycerol): current insights into the functional properties of a classic cosmetic raw material. J Cosmet Sci 53:229–236

52. Thody AJ, Shuster S (1989) Control and function of sebaceous glands. Physiol Rev 69:383–416

53. Vanbaare J, Buitenwerf J, Hoekstra MJ et al (1994) Virucidal effect of glycerol as used in donor skin pres-ervation. Burns 20:S77–S80

54. Yoneya T, Nishijima Y (1979) Determination of free glycerol on human skin surface. Biol Mass Spectrom 6:191–193