Journal of Clinical and Aesthetic Dermatology

APR 2018

An evidence-based, peer-reviewed journal for practicing clinicians in the field of dermatology

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31 JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY April 2018 • Volume 11 • Number 4 O R I G I N A L R E S E A R C H LED wavelengths (via PBM) effectively inhibit melanin biosynthesis and its molecular mechanisms, underlying its effects on tyrosinase, tyrosinase-related protein 1, and microphthalmia-associated transcription factor expression with an intracellular signaling pathway. These investigators showed that LED irradiation at wavelengths of 830nm, 850nm, and 940nm (96mW/cm 2 , 5J/cm 2 , 10J/cm 2 , and 20J/cm 2 ; 114mW/cm 2 and 1J/cm 2 ; and 55.5mW/cm 2 , 5J/cm 2 , and 10J/cm 2 , respectively) effectively decreases melanin synthesis without cytotoxic effects in a normal human melanocyte monoculture and three-dimensional multiple cell type co-culture model. Based on this in-vitro study, we decided to use 940nm (to penetrate deeper in the dermis) with comparable energy parameters (fluence: 13.5J/cm 2 ). Another possible mechanism of action is PBM photons (at 940nm) would target p53 gene expression by downregulating hyperactive melanocytes via the p53 cell signaling pathway. The p53 cell signaling pathway plays a key role as a tumor suppressor to prevent the emergence of cancer cells. It is a transcriptional regulator and might increase deoxyribonucleic acid repair or promote apoptosis. In other words, it commands the cells to live or to die. However, it can also regulate the suntan response by p53-regulated pigmentation mechanisms, since the p53 gene is located close to the proopiomelanocortin complex. 25 Since NIR PBM photons can modulate p53 gene expression, 26 one can assume it could be beneficial (i.e., reduces hyperpigmentation) for an acquired pigmentary disorder like melasma. Another p53-mediated effect, however, might have played a role in the positive response to the treatment. The effectiveness of PBM (visible and NIR) as a prophylactic measure has recently become clear. 27 If nonwounded skin cells or tissues are exposed to certain wavelengths of visible and NIR light before the actual trauma, a preconditioning takes place. 27 A cutaneous application of PBM, termed photoprevention, uses visible and mostly IR radiation to ready the skin for impending trauma such as UV-induced sunburn. 19 Many in-vitro studies demonstrated that fibroblasts exposed to NIR light beforehand have incurred protection against future UVB damage by way of p53 cell signaling induced anti-apoptotic effects. 28,29 In this study, our therapeutic goal was to use MCD and PBM to eradicate melasma. Simultaneously, we might also have preconditioned the skin with a p53 anti- apoptotic effect to better resist UV damage. In other words, we likely induced UV resistance in the skin of our subjects as we were treating them over two months. Thus, photoprevention presumably had an impact on our study, which took place in the summer months, since sun exposure is the main triggering factor of melasma. A comparative histological study by Kang et al 30 on lesional and perilesional normal skin showed the histological nature of melasma. Melanocyte numbers were comparable between lesional and perilesional skin. A total of 279 genes were found to be differentially expressed in lesional and perilesional melasma skin. They reported that vascular endothelial growth factor (VEGF) 2 was downregulated in melasma skin. PBM has been shown to promote VEGF expression. An increase in expression was observed in the PBM-irradiated groups (904nm) in comparison within the control group in mice fibroblasts. 31 Furthermore, PBM irradiation with 635nm was shown to reduce intracellular reactive oxygen species production and increase angiogenesis (enhanced VEGF expression) in human umbilical vein endothelial cells in an in-vitro oxalyl chloride-induced severe hypoxia model. 32 Kang et al 30 also reported that the prostaglandin metabolic process was increased in melasma. They found that prostaglandin I2 synthase and prostaglandin-endoperoxide synthase 1 were upregulated in melasma. Conversely, PBM can downregulate protein targeting to glycogen gene expression. Mizutani et al 33 showed that serum prostaglandin E2 is lowered by PBM at 830nm. Additionally, Lim et al 34 showed that direct PBM exposure at 635nm can inhibit the activation of pro-inflammatory mediators like prostaglandin E2 in in-vitro gingival fibroblasts. Figure 4 describes our two- step approach. Pulsing. PBM acceptance has been slowed by the complexity of needing to choose specifics for a number of parameters, such as wavelength, dose, intensity, pulse structure, and timing of the applied light. The challenge is to gather the best combination of parameters à la carte for the condition treated. Among these, pulse structure or pulsing code seems to be an important factor to achieve optimal results. 35 A review by Hashmi et al 36 concluded that there is some evidence that pulsed light yields effects different from continuous wave light. In our own experience, tissue response was favorable when using sequential pulsing mode (i.e., repeated sequences of short pulse trains followed by longer intervals) rather than the continuous wave mode. 37 An understanding of mitochondrial ion channels elucidates the effectiveness of the pulsing light mode as compared with the simple continuous wave in providing successful treatment. Using a transcranially positioned 810nm laser, a 10Hz pulsed mode better improved neurobehavioral recovery in patients with traumatic brain injury as compared to a continuous wave or a 100Hz pulsed mode. 40 The authors of the study hypothesized that the pulse FIGURE 3. The photobiomodulation-treated side showed a 25% reduction in melanin index at Week 12 (p<0.05)

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