Adenosine is a key molecule within the human body, contributing to energy metabolism, nucleic acid structure, cellular signaling, and neurotransmission, among others. It is composed of an adenine attached to ribose and is one of the four nucleotides found in RNA, while its deoxyadenosine form is found in DNA.
Adenosine binds to the adenosine receptors (ARs), also called P1 receptors, that are part of the G-protein-coupled receptor family. ARs are divided into four subtypes—A1, A2A, A2B, and A3—that can all be activated by extracellular adenosine [1]. However, differences in adenosine binding affinities, pattern of expression, and tissue distribution between subtypes give distinct signaling profiles [2,3]. ARs are broadly expressed in the central nervous system and peripheral tissues, more specifically in the cardiovascular, respiratory, renal, and immune systems [1,4]. Consequently, adenosine plays a role in a wide range of physiological processes, such as sleep regulation, angiogenesis, and immune system modulation, among others.
Adenosine is also a component of essential biomolecules, including adenosine monophosphate (AMP), adenosine diphosphate (ADP), and adenosine triphosphate (ATP), a source of energy for use and storage in cells. These molecules can be converted to adenosine by spontaneous hydrolysis or through the activity of enzymes such as 5′-ectonucleotidases, ecto-ADPases, or ecto-ATPases [5]. Adenosine can then be further converted to inosine after an irreversible deamination by adenosine deaminase [6]. Adenosine is produced by the rapid breakdown of ATP, and when externalized, it can mediate diverse physiological processes like proliferation, differentiation, migration, and cell death [5]. Adenosine shows interesting properties in humans as a local messenger in the skin.
Adenosine for skin anti-aging
The skin is composed of three layers. The epidermis, the outermost layer, is mainly composed of keratinocytes. These cells synthesize keratin, a protein constituting the skin barrier against water loss, pathogen agents, or environmental damage. The epidermis is bonded to the dermis, a deeper skin layer, which offers skin strength and elasticity thanks to collagen and elastin. It also contains blood vessels and nerve fibers. In the epidermis, adenosine through the A2A receptors (A2ARs) stimulates collagen production. The deepest skin layer, the hypodermis, contains a fat stratum that works as an energy reserve, an insulation medium, and a cushion for falls [7]. In the hypodermis, adenosine through the A1 receptors (A1Rs) stimulates adipogenesis and lipogenesis.With aging and exposure to environmental free radicals, skin collagen degrades. Adenosine, by stimulating the synthesis of new collagen, can improve skin elasticity and hydration, thereby reducing skin aging and wrinkles [7].
Adenosine has been tested as a topical application in a randomized, placebo-controlled, double-blind study in female volunteers. Its effects on the skin, measured after 3 and 8 weeks of the twice-daily application using fast optical in vivo topometry, resulted in a significant decrease in skin roughness [8]. Another clinical trial compared the use of adenosine-loaded dissolving microneedle patches and an adenosine cream. Skin wrinkling, dermal density, elasticity, and hydration were measured to test adenosine efficacy. Both groups of participants showed statistically significant improvement in almost all parameters, with no adverse effects observed in either group [9]. These findings highlight the potential of adenosine in skin care and as a beneficial ingredient in skin care products, such as for soothing the appearance of wrinkles and smoothing fine lines.
Adenosine for skin wound healing
Adenosine, released from injured skin tissue, plays an essential role in wound healing and tissue repair by modulating inflammation, promoting angiogenesis, and stimulating collagen production [9].
Adenosine and inflammation
After injury, the first phase of skin wound healing involves acute inflammation. Adenosine released by the injured skin shows anti-inflammatory properties by inhibiting neutrophil rolling and adhesion to vascular endothelium and limiting neutrophil production of free radicals via the A2A receptor. Additionally, adenosine, through the activation of A1R and A2AR receptors, influences endothelial cell permeability by reducing vascular leakage induced by bradykinin and histamine [10].
Adenosine and angiogenesis
In vivo, A2A receptors promote angiogenesis and vasculogenesis [11]. This angiogenic effect is mediated directly via increased endothelial cell migration and microvascular endothelial cell VEGF production [12,13], and indirectly via the promotion of VEGF production by macrophages [14]. Additionally, A2A receptors suppress thrombospondin I, a potent inhibitor of angiogenesis, which enhances vascular tube formation in vitro [15]. Thus, A2ARs play an essential role in skin neovascularization during wound healing [9].
Adenosine and collagen production for wound closing
After skin injury, once the debris and destroyed collagenous matrix are eliminated, dermal fibroblasts lay down a new matrix via A2A receptors. Adenosine, acting at A2AR, stimulates the production of collagen types I and III, while downregulating matrix metalloproteinase 9, an enzyme that degrades skin elastin fibers [16,17]. As this new collagenous matrix remodels over time, the skin develops the appearance of a scar [9]. Finally, A2AR agonists (like adenosine) increase the rate of wound closure [18].
Adenosine and skin diseases
Adenosine, via its receptors and their activity in tissue repair, also plays a role in pathologic fibrosis such as scarring [9].
Adenosine and dermal fibrosis
A study in a murine model of bleomycin-induced dermal fibrosis resembling scleroderma highlighted the implication of A2ARs in the pathologic process. Continuously activated A2ARs via adenosine binding promote collagen production in mice fibroblasts, leading to diffuse dermal fibrosis. Conversely, A2A knockout mice or those treated with a selective A2AR antagonist (inhibitor) never developed bleomycin-induced dermal fibrosis [17]. Thus, A2AR may represent an interesting therapeutic target for treating dermal fibrosis [19,20].
Adenosine and psoriasis
High levels of adenosine are detected in the blood of psoriasis patients, and adenosine has been found to increase cAMP levels in both affected and unaffected skin areas [21]. Psoriasis patients exhibit altered nucleotide metabolism, characterized by lower ATP incorporation and adenylyl cyclase activity in plaques [22]. Furthermore, elevated adenosine deaminase activity, a marker of T-cell activation, is observed in their serum and skin [23].
Adenosine and atopic dermatitis
Adenosine has been shown to up-regulate the production of IL-31 by CD4+ T cells, contributing to the pathogenesis of dermatitis and associated pruritus. This effect is mediated through A2A receptors. Administration of an A2AR agonist (activator) increases IL-31 production, while an A2AR antagonist inhibits it. In a mouse model, the use of an A2AR antagonist suppressed the symptoms of atopic dermatitis [24].
Adenosine and melanoma
Melanoma cells evade immune surveillance, partly through adenosine receptors. Specifically, the A2AR and A2BR receptors mediate adenosine-induced immune suppression, facilitating tumor growth. In contrast, stimulation of the A3 receptor enhances the anti-tumor immune response and inhibits cancer cell proliferation. Thus, targeting both A2AR and A3R presents potential for the development of novel melanoma treatments [25].
Conclusion
Adenosine, together with its receptors, plays important roles in skin, both in matrix production and neovascularization, which are critical processes for wound healing and tissue repair. They are also involved in skin diseases such as dermal fibrosis, psoriasis, or atopic dermatitis, among others.
Adenosine is one of the main ingredients in our complete sleep solution buccal troche, Tro Zzz. If you don't want to ruin your day with yet another sleepless night, check out Tro Zzz to give yourself the sleep you need, tonight.
References
[1] Fredholm, B.B., IJzerman, A.P., Jacobson, K.A., Klotz, K.N. and Linden, J. (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacological Reviews, United States. 53, 527–52.
[2] Cieślak, M., Komoszyński, M. and Wojtczak, A. (2008) Adenosine A2A receptors in Parkinson’s disease treatment. Purinergic Signalling, 4, 305. https://doi.org/10.1007/s11302-008-9100-8
[3] Fredholm, B.B. (2014) Adenosine—a physiological or pathophysiological agent? Journal of Molecular Medicine, 92, 201–6. https://doi.org/10.1007/s00109-013-1101-6
[4] Fredholm, B.B., IJzerman, A.P., Jacobson, K.A., Linden, J. and Müller, C.E. (2011) International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors—An Update. Pharmacological Reviews, 63, 1–34. https://doi.org/10.1124/pr.110.003285
[5] Burnstock, G., Knight, G.E. and Greig, A.V.H. (2012) Purinergic Signaling in Healthy and Diseased Skin. Journal of Investigative Dermatology, 132, 526–46. https://doi.org/10.1038/jid.2011.344
[6] Cristalli, G., Costanzi, S., Lambertucci, C., Lupidi, G., Vittori, S., Volpini, R. et al. (2001) Adenosine deaminase: functional implications and different classes of inhibitors. Medicinal Research Reviews, United States. 21, 105–28. https://doi.org/10.1002/1098-1128(200103)21:2<105::aid-med1002>3.0.co;2-u
[7] Marucci, G., Buccioni, M., Varlaro, V., Volpini, R. and Amenta, F. (2022) The possible role of the nucleoside adenosine in countering skin aging: A review. BioFactors, 48, 1027–35. https://doi.org/10.1002/biof.1881
[8] Legendre, J.Y., Schnitzler, I., Li, Q.-Y., Hausen, C., Huart, M., Luengo, G.S. et al. (2007) Formulation, characterization, and efficacy of an adenosine-containing dissolvable film for a localized anti-wrinkle effect. Journal of Cosmetic Science, United States. 58, 147–55.
[9] Feoktistov, I., Biaggioni, I. and Cronstein, B.N. (2009) Adenosine receptors in wound healing, fibrosis and angiogenesis. Handbook of Experimental Pharmacology, Germany. 383–97. https://doi.org/10.1007/978-3-540-89615-9_13
[10] Williams, M. and Jarvis, M.F. (2000) Purinergic and pyrimidinergic receptors as potential drug targets. Biochemical Pharmacology, 59, 1173–85. https://doi.org/10.1016/S0006-2952(99)00341-X
[11] Montesinos, M.C., Desai, A., Chen, J.-F., Yee, H., Schwarzschild, M.A., Fink, J.S. et al. (2002) Adenosine Promotes Wound Healing and Mediates Angiogenesis in Response to Tissue Injury Via Occupancy of A2A Receptors. The American Journal of Pathology, 160, 2009–18. https://doi.org/10.1016/S0002-9440(10)61151-0
[12] Khoa, N.D., Montesinos, M.C., Williams, A.J., Kelly, M. and Cronstein, B.N. (2003) Th1 Cytokines Regulate Adenosine Receptors and Their Downstream Signaling Elements in Human Microvascular Endothelial Cells. The Journal of Immunology, 171, 3991–8. https://doi.org/10.4049/jimmunol.171.8.3991
[13] Montesinos, M.C., Gadangi, P., Longaker, M., Sung, J., Levine, J., Nilsen, D. et al. (1997) Wound Healing Is Accelerated by Agonists of Adenosine A2 (Gαs-linked) Receptors. The Journal of Experimental Medicine, 186, 1615–20. https://doi.org/10.1084/jem.186.9.1615
[14] Leibovich, S.J., Chen, J.-F., Pinhal-Enfield, G., Belem, P.C., Elson, G., Rosania, A. et al. (2002) Synergistic Up-Regulation of Vascular Endothelial Growth Factor Expression in Murine Macrophages by Adenosine A2A Receptor Agonists and Endotoxin. The American Journal of Pathology, 160, 2231–44. https://doi.org/10.1016/S0002-9440(10)61170-4
[15] Desai, A., Victor-Vega, C., Gadangi, S., Montesinos, M.C., Chu, C.C. and Cronstein, B.N. (2005) Adenosine A 2A Receptor Stimulation Increases Angiogenesis by Down-Regulating Production of the Antiangiogenic Matrix Protein Thrombospondin 1. Molecular Pharmacology, 67, 1406–13. https://doi.org/10.1124/mol.104.007807
[16] Philips, N., Auler, S., Hugo, R. and Gonzalez, S. (2011) Beneficial Regulation of Matrix Metalloproteinases for Skin Health. Enzyme Research, 2011, 1–4. https://doi.org/10.4061/2011/427285
[17] Chan, E.S.L., Fernandez, P., Merchant, A.A., Montesinos, M.C., Trzaska, S., Desai, A. et al. (2006) Adenosine A 2A receptors in diffuse dermal fibrosis: Pathogenic role in human dermal fibroblasts and in a murine model of scleroderma. Arthritis & Rheumatism, 54, 2632–42. https://doi.org/10.1002/art.21974
[18] Victor-Vega, C., Desai, A., Montesinos, M.C. and Cronstein, B.N. (2002) Adenosine A2A Receptor Agonists Promote More Rapid Wound Healing Than Recombinant Human Platelet–Derived Growth Factor (Becaplermin Gel). Inflammation, 26, 19–24. https://doi.org/10.1023/A:1014417728325
[19] Fernández, P., Trzaska, S., Wilder, T., Chiriboga, L., Blackburn, M.R., Cronstein, B.N. et al. (2008) Pharmacological Blockade of A2A Receptors Prevents Dermal Fibrosis in a Model of Elevated Tissue Adenosine. The American Journal of Pathology, 172, 1675–82. https://doi.org/10.2353/ajpath.2008.070952
[20] Chan, E.S.L. and Cronstein, B.N. (2010) Adenosine in fibrosis. Modern Rheumatology, 20, 114–22. https://doi.org/10.3109/s10165-009-0251-4
[21] Duell, E.A. (1980) Adenosine-Induced Alterations in the Adenosine 3’:5’-Monophosphate Levels in Mammalian Epidermis. Molecular Pharmacology, 18, 49.
[22] Kiehl, R. and Ionescu, G. (1992) A defective purine nucleotide synthesis pathway in psoriatic patients. Acta Dermato-Venereologica, Sweden. 72, 253–5.
[23] Bukulmez, G., Akan, T. and Ciliv, G. (2000) Serum adenosine deaminase levels in patients with psoriasis: a prospective case-control study. European Journal of Dermatology : EJD, France. 10, 274–6.
[24] Kawano, M., Takagi, R., Tokano, M. and Matsushita, S. (2023) Adenosine induces IL-31 secretion by T-helper 2 cells: Implication for the effect of adenosine on atopic dermatitis and its therapeutic strategy. Biochemical and Biophysical Research Communications, 645, 47–54. https://doi.org/10.1016/j.bbrc.2023.01.038
[25] Montinaro, A., Iannone, R., Pinto, A. and Morello, S. (2013) Adenosine receptors as potential targets in melanoma. Pharmacological Research, 76, 34–40. https://doi.org/10.1016/j.phrs.2013.07.002
Comments (0)
There are no comments for this article. Be the first one to leave a message!