Theophylline exerts complex anti‐ageing and anti‐cytotoxicity effects in human skin ex vivo

Abstract

OBJECTIVE: Theophylline is a phosphodiesterase inhibitor that is being used clinically for asthma therapy. In addition, it is recognized as a cosmetic agent with possible anti-ageing and anti-oxidative properties. Nevertheless, how it affects human skin is still poorly examined. METHODS: Theophylline (10 or 100 µM) was administered to the culture medium of full-thickness human skin ex vivo for 24 or 72 h. RESULTS: Theophylline stimulated protein expression of the antioxidant metallothionein-1 and mRNA levels of collagen I and III. Assessment of fibrillin-1 immunohistology revealed enhanced structural stability of dermal microfibrils. Theophylline also exerted extracellular matrix-protective effects by decreasing MMP-2 and MMP-9 mRNA levels, partially antagonizing the effects of menadione, the potent, toxic ROS donor. In addition, it decreased menadione-stimulated epidermal keratinocytes apoptosis. Interestingly, theophylline also increased the level of intracutaneously produced melatonin, that is the most potent ROS-protective and DNA damage repair neuromediator, and tendentially increased protein expression of MT1, the melatonin receptor. Theophylline also increased the expression of keratin 15, the stem cell marker, in the epidermal basal layer but did not change mitochondrial activity or epidermal pigmentation. CONCLUSION: This ex vivo pilot study in human skin shows that theophylline possesses several interesting complex skin-protective properties. It encourages further examination of theophylline as a topical candidate for anti-ageing treatment. R esum e OBJECTIF: la th eophylline est un inhibiteur de la phosphodiest erase actuellement utilis ee en clinique pour le traitement de l'asthme. En outre, elle est reconnue comme etant un agent cosm etique ayant des propri et es potentiellement anti-âge et antioxydantes. Cependant, la mani ere dont elle affecte la peau chez l'homme est encore tr es peu etudi ee. M ETHODES: de la th eophylline (10 ou 100 lM) a et e ajout ee dans le milieu de culture d'un echantillon de peau humaine d' epaisseur totale ex vivo pendant 24 ou 72 h. Theophylline effects in human skin ex vivo M. Bertolini et al. 84 Theophylline effects in human skin ex vivo M. Bertolini et al. Theophylline effects in human skin ex vivo M. Bertolini et al. Theophylline effects in human skin ex vivo M. Bertolini et al.

Revisiting the role of melatonin in human melanocyte physiology: A skin context perspective

“…Given that theophylline (which is licensed for topical application as a cosmetic agent) can increase melatonin levels released by organ‐cultured human skin into the medium 260 while noradrenaline stimulates melatonin synthesis within human scalp HFs ex vivo, 30 it is also possible that the intracutaneous synthesis of melatonin can be stimulated by topically applied agents that increase intracellular cAMP levels and thus intracutaneous production of endogenous melatonin.…”

Bioengineered Skin Intended as In Vitro Model for Pharmacosmetics, Skin Disease Study and Environmental Skin Impact Analysis

“…In this context, human skin and hair follicle ex vivo models are increasingly used in preclinical studies from various areas. For example, Bertolini et al performed cytotoxicity and aging analyses in human skin ex vivo [39]; Gheraldini et al validated caffeine as a treatment for hair follicles damaged by exposure to ultraviolet (UV) light in ex vivo skin models [40]. Fischer et al carry out studies on the action of caffeine on hormonal pathways involved in the development of the hair follicle in skin ex vivo models [41].…”

“…By adding this compound to the human skin culture medium, there was a decrease in the apoptosis levels of epidermal keratinocytes, an increase in melatonin, a potent ROS protector, and an increase in KRT15, marker for basal keratinocyte. Theophylline, therefore, has important antioxidant properties, and could be a good candidate for skin anti-aging [39].…”

The biology of human hair greying

“…With regard to maintaining melanogenesis within the HFPU itself, topically applied serotonin‐reuptake inhibitors like fluoxetine (Chéret et al ., 2020), which exploit the existing capacity of epidermal and HF melanocytes to synthesize and metabolize serotonin (Slominski et al ., 2002 a ; Slominski, Wortsman & Tobin, 2005), may be productive. Additionally, L‐thyroxine (Van Beek et al ., 2008), α‐MSH or afamelanotide/melanotan (Paus et al ., 2014), TRH (Gáspár et al ., 2011) or theophylline, which increase intracutaneous melatonin synthesis (Bertolini et al ., 2020), melatonin itself (Iyengar, 2000; Kobayashi et al ., 2005; Fischer et al ., 2008), and agents that stabilize ATM expression (Sikkink et al ., in press) all deserve preclinical testing in organ‐cultured greying human scalp skin.…”