Original ArticleTranexamic acid inhibits the plasma and non-irradiated skin markers of photoaging induced by long-term UVA eye irradiation in female mice
Graphical abstract
Introduction
Humans are exposed to ultraviolet rays (UV) on a daily basis, which can cause sunburn, suntan, and photoimmunosuppression of the skin with short-term exposure [1], and photoaging and skin cancer with long-term exposure [2]. Unlike natural aging, photoaging can induce various symptoms, such as skin dryness, pigmentation maculation (spot), tylosis, and elasticity depression (wrinkles) [2]. Active oxygen species induction is one of the causes of deep wrinkles that occur due to photoaging. If keratinocytes and fibroblasts are irradiated with UV, reactive oxygen species (ROS) are generated, which can damage the DNA. Furthermore, the activity of enzymes, such as tyrosine phosphatase, which can be oxidized and inactivated by UV irradiation, causes changes in the metabolic and cellular functions [3]. In addition, matrix metalloproteinase (MMP) is activated [4], resulting in the secretion of MMP-1, MMP-3, and MMP-9 and degradation of collagen and elastin in the dermis. It is known that the secretion of the transcription factor AP-1 is induced by tyrosine phosphatase, inhibiting the expression of the procollagen gene in fibroblasts [5,6]. Furthermore, UV causes DNA damage directly and indirectly through the genesis of active oxygen species; thus, the cells that have damaged DNA produce vascular endothelial growth factors (VEGFs) and inflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α, that can accumulate and degrade collagen in cells [5].
Another unique characteristic of photoaging is the induction of skin spots. Skin spots that occur due to photoaging are also called as senile pigment spots, which usually start off brown and gradually turn black over time. The skin spots can develop when the skin is exposed to UV because it induces a signal to keratinocytes, which then promotes melanocytes to generate melanin. However, if the spot is continued to be exposed to UV for a long period, excessive melanin will be synthesized and the spot turns darker in color [6,7]. Furthermore, UV irradiation can induce the metabolic failure of the stratum corneum; in other words, the outer layer of the skin cannot slough off and melanin accumulates in these skin layers [8].
Although long-term UV skin exposure can cause photoaging, it can also be caused by long-term local UV exposure to the eye [9,10]. We have reported the use of tranexamic acid as an anti-inflammatory agent against wrinkles of dry skin [11] and for the suppression of pigmentation caused by UV irradiation [12]. Tranexamic acid functions as a regulator of the α-melanocyte-stimulating hormone (α-MSH), adrenocorticotropic hormone (ACTH), and β-endorphin, which are secreted from pro-opiomelanocortin (POMC) [13]. Generally, UVA irradiation increases the occurrence of wrinkles, spots, and skin cancer through the POMC system, thus, causing photoaging [14]. Our previous study on photoaging induced by UVA eye irradiation indicated that the brain hormones ACTH, α-MSH, corticotropin-releasing hormone (CRH), and urocortin 2 are affected by UVA eye irradiation [15]. Therefore, tranexamic acid may regulate the expression of these additional peptide hormones that are induced during photoaging. In this milieu, we examined the effect of tranexamic acid on photoaging induced by long-term UVA eye irradiation in mice and analyzed the mechanism.
Section snippets
Animals
Specific-pathogen-free 8-week-old female C57BL/6 j mice (SLC, Hamamatsu, Shizuoka, Japan) were used in all the experiments. The mice were maintained individually in cages in an air-conditioned room at 23 ± 1°C. There were six mice per treatment group. UVA irradiation was performed as previously described [16]. Briefly, under light pentobarbital anesthesia, UVA (wavelength of 320–400 nm) was applied to the eye at a dose of 110 kJ/m2 (irradiation time: 30 min. d) using an FL20SBLB-A lamp
Effect of tranexamic acid treatment on photoaging induced by long-term UVA eye irradiation
The eyes of test mice were topically irradiated with UVA three times a week for 1 h per day over a period of one year, and then ear skin specimens were collected after the last UVA irradiation session. The chronic UVA exposure resulted in an increase in the dopa-positive cells in the skin of test mice compared with that in the skin of control mice (Fig. 1A). Furthermore, it increased the thickness of dorsal skin of test mice compared with that of the dorsal skin of control mice (Fig. 1B). These
Discussion
In the present study, photoaging due to long-term UVA eye irradiation in female mice was reduced by the administration of tranexamic acid. The plasma levels of urocortin 2, β-endorphin and methionine-enkephalin, which are peptide hormones, were increased by long-term UVA eye irradiation. In addition, the expression of CRHR type 2, μ-opioid, and OGFR receptors also increased. By the administration of tranexamic acid, the levels of urocortin 2 and methionine-enkephalin were decreased, whereas,
Conclusions
Our findings show that photoaging is induced by UVA eye irradiation, which can be ameliorated by tranexamic acid treatment. The results suggest the possible involvement of the pituitary-gland hormones ACTH, β-endorphin, and methionine-enkephalin in photoaging protection. In addition, although the UVA eye irradiation increased the presence of mast cells in the skin, the expression of estrogen receptor-β also increased in these mast cells of mice that received tranexamic acid treatment. This
Disclosure of interest
The authors declare no conflicts of interest in association with this study.
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