Abstract
Background: Radiotherapy is one of the treatment methods for cancers using ionizing radiations. About 70% of cancer patients undergo radiotherapy. Radiation effect on the skin is one of the main complications of radiotherapy and dose limiting factor. To ameliorate this complication, we used melatonin as a radioprotective agent due to its antioxidant and anti-inflammatory effects, free radical scavenging, improving overall survival after irradiation as well as minimizing the degree of DNA damage and frequency of chromosomal abrasions.
Methods: Sixty male Wistar rats were randomly assigned to 4 groups: control (C), melatonin (M), radiation (R) and melatonin + radiation (MR). A single dose of 30 Gy gamma radiation was exposed to the right hind legs of the rats while 40 mg/ml of melatonin was administered 30 minutes before irradiation and 2 mg/ml once daily in the afternoon for one month till the date of rat’s sacrifice. Five rats from each group were sacrificed 4, 12 and 20 weeks after irradiation. Afterwards, their exposed skin tissues were examined histologically and biochemically.
Results: In biochemical analysis, we found that malondialdehyde (MDA) levels significantly increased in R group and decreased significantly in M and MR groups after 4, 12, and 20 weeks, whereas catalase (CAT) and superoxide dismutase (SOD) activities decreased in the R group and increased in M and MR groups during the same time periods compared with the C group (p<0.05). Histopathological examination found there were statistically significant differences between R group compared with the C and M groups for the three different time periods (p<0.005, p<0.004 and p<0.004) respectively, while R group differed significantly with MR group (p<0.013). No significant differences were observed between C and M compared with MR group (p>0.05) at 4 and 20 weeks except for inflammation and hair follicle atrophy, while there were significant effects at 12 weeks (p<0.05).
Conclusion: Melatonin can be successfully used for the prevention and treatment of radiation-induced skin injury. We recommend the use of melatonin in optimal and safe doses. These doses should be administered over a long period of time for effective radioprotection and amelioration of skin damages as well as improving the therapeutic ratio of radiotherapy.
Keywords: Radiation, melatonin, skin, oxidative stress, histopathology, biochemical.
Graphical Abstract
[1]
Ringborg, U.; Bergqvist, D.; Brorsson, B.; Cavallin-Ståhl, E.; Ceberg, J.; Einhorn, N.; Frödin, J-e.; Järhult, J.; Lamnevik, G.; Lindholm, C. The swedish council on technology assessment in health care (sbu) systematic overview of radiotherapy for cancer including a prospective survey of radiotherapy practice in sweden 2001--summary and conclusions. Acta Oncologica., 2003, 42(5-6), 357-365.
[2]
Bernstein, E.; Sullivan, F.; Mitchell, J.; Salomon, G.; Glatstein, E. Biology of chronic radiation effect on tissues and wound healing. Clin. Plast. Surg., 1993, 20(3), 435-453.
[3]
Murakami, R.; Baba, Y.; Nishimura, R.; Furusawa, M.; Yokoyama, T.; Yamashita, Y.; Takahashi, M.; Yamashita, N.; Ono, T. The effect of azelastine on acute radiation dermatitis in mice models. Int. J. Radiat. Oncol. Biol. Phys., 1997, 37(4), 907-911.
[4]
Hubenak, J.R.; Zhang, Q.; Branch, C.D.; Kronowitz, S.J. Mechanisms of injury to normal tissue after radiotherapy: A review. Plast. Reconstr. Surg., 2014, 133(1), 49e.
[5]
Birben, E.; Sahiner, U.M.; Sackesen, C.; Erzurum, S.; Kalayci, O. Oxidative stress and antioxidant defense. World Allergy Organ. J., 2012, 5(1), 9.
[6]
Chevion, S.; Or, R.; Berry, E.M. The antioxidant status of patients subjected to today body irradiation. IUBMB Life, 1999, 47(6), 1019-1027.
[7]
Taysi, S.; Uslu, C.; Akcay, F.; Sutbeyaz, M.Y. Malondialdehyde and nitric oxide levels in the plasma of patients with advanced laryngeal cancer. Surg. Today, 2003, 33(9), 651-654.
[9]
Victor, V.M.; McCreath, K.J.; Rocha, M. Recent progress in pharmacological research of antioxidants in pathological conditions: Cardiovascular health. Recent Pat. Antiinfect. Drug Discov., 2006, 1(1), 17-31.
[11]
Balter, S.; Hopewell, J.W.; Miller, D.L.; Wagner, L.K.; Zelefsky, M.J. Fluoroscopically guided interventional procedures: A review of radiation effects on patients’ skin and hair. Radiology, 2010, 254(2), 326-341.
[12]
Ryan, J.L. Ionizing radiation: The good, the bad, and the ugly. J. Invest. Dermatol., 2012, 132(3), 985-993.
[13]
Porock, D.; Nikoletti, S.; Kristjanson, L. Management of radiation skin reactions: Literature review and clinical application. Plast. Surg. Nurs., 1999, 19(4), 185-192.
[14]
Najafi, M.; Motevaseli, E.; Shirazi, A.; Graily, G.; Rezaeyan, A.; Norouzi, F.; Rezapoor, S.; Abdollahi, H. Mechanisms of inflammatory responses to radiation and normal tissues toxicity; Clinical implications. Int. J. Radiat. Biol., 2018, 1-62.
[15]
Allison, R.; Dicker, A. Minimizing morbidity in radiation oncology: A special issue from Future Oncology. Future Oncology., 2014, 10(15), 2303-2305.
[16]
Baydas, G.; Gursu, M.F.; Yilmaz, S.; Canpolat, S.; Yasar, A.; Cikim, G.; Canatan, H. Daily rhythm of glutathione peroxidase activity, lipid peroxidation and glutathione levels in tissues of pinealectomized rats. Neurosci. Lett., 2002, 323(3), 195-198.
[17]
Allegra, M.; Reiter, R.; Tan, D.X.; Gentile, C.; Tesoriere, L.; Livrea, M. The chemistry of melatonin’s interaction with reactive species. J. Pineal Res., 2003, 34(1), 1-10.
[18]
Yahyapour, R.; Shabeeb, D.; Cheki, M.; Musa, A.; Farhood, B.; Rezaeyan, A.; Amini, P.; Fallah, H.; Najafi, M. Radiation protection and mitigation by natural antioxidants and flavonoids; Implications to radiotherapy and radiation disasters. Curr. Mol. Pharmacol., 2018.
[19]
Reiter, R. Interactions of the pineal hormone melatonin with oxygen-centered free radicals: A brief review. Braz. J. Med. Biol. Res., 1993, 26(11), 1141-1155.
[20]
Reiter, R.J.; Herman, T.S.; Meltz, M.L. Melatonin reduces gamma radiation-induced primary DNA damage in human blood lymphocytes. Mutat. Res., 1998, 397(2), 203-208.
[21]
Anwar, M.M.; Mahfouz, H.A.; Sayed, A.S. Potential protective effects of melatonin on bone marrow of rats exposed to cytotoxic drugs. Comp. Biochem. Physiol. A Mol. Integr. Physiol., 1998, 119(2), 493-501.
[22]
Yu, H.; Dickson, E.J.; Jung, S-R.; Koh, D-S.; Hille, B. High membrane permeability for melatonin. J. Gen. Physiol., 2016, 147(1), 63-76.
[23]
Meltz, M.L.; Reiter, R.J.; Herman, T.S. Melatonin and protection from genetic damage in blood and bone marrow: Whole‐body irradiation studies in mice. J. Pineal Res., 1999, 27(4), 221-225.
[24]
Pablos, M.I.; Reiter, R.J.; Ortiz, G.G.; Guerrero, J.M.; Agapito, M.T.; Chuang, J-I.; Sewerynek, E. Rhythms of glutathione peroxidase and glutathione reductase in brain of chick and their inhibition by light. Neurochem. Int., 1998, 32(1), 69-75.
[25]
Bettahi, I.; Pozo, D.; Osuna, C.; Reiter, R.J.; Acuña‐Castroviejo, D.; Guerrero, J.M. Melatonin reduces nitric oxide synthase activity in rat hypothalamus. J. Pineal Res., 1996, 20(4), 205-210.
[26]
Fischer, T.W.; Slominski, A.; Zmijewski, M.A.; Reiter, R.J.; Paus, R. Melatonin as a major skin protectant: From free radical scavenging to DNA damage repair. J. Invest. Dermatol., 2008, 17(9), 713-730.
[27]
Yahyapour, R.; Amini, P.; Rezapour, S.; Cheki, M.; Rezaeyan, A.; Farhood, B.; Shabeeb, D.; Musa, A.E.; Fallah, H.; Najafi, M. Radiation-induced inflammation and autoimmune diseases. Mil. Med. Res., 2018, 5(1), 9.
[28]
Shirazi, A.; Ghobadi, G.; Ghazi-Khansari, M. A radiobiological review on melatonin: A novel radioprotector. J. Radiat. Res., 2007, 48(4), 263-272.
[29]
Zetner, D.; Andersen, L.; Rosenberg, J. Melatonin as protection against radiation injury: A systematic review. Drug Res., 2016, 66(06), 281-296.
[30]
Ghobadi, A.; Shirazi, A.; Najafi, M.; Kahkesh, M.H.; Rezapoor, S. Melatonin ameliorates radiation-induced oxidative stress at targeted and nontargeted lung tissue. J. Med. Phys., 2017, 42(4), 241.
[31]
Rezapoor, S.; Shirazi, A.; Abbasi, S.; Bazzaz, J.T.; Izadi, P.; Rezaeejam, H.; Valizadeh, M.; Soleimani-Mohammadi, F.; Najafi, M. Modulation of radiation-induced base excision repair pathway gene expression by melatonin. J. Med. Phys., 2017, 42(4), 245.
[32]
M., Najafi A.S., E. Motevaseli, Gh. Geraily, F. Norouzi, M. Heidari, S. Rezapoor. The melatonin immunomodulatory actions in radiotherapy. Biophys. Rev., 2017, 9(2), 139-148.
[33]
Aghazadeh, S.; Azarnia, M.; Shirazi, A.; Mahdavi, S.R.; Zangii, B.M. Melatonin as a protective agent in spinal cord damage after gamma irradiation. J. Med. Radiat. Sci., 2007, 12(2), 95-99.
[34]
Haddadi, G.; Shirazi, A.; Sepehrizadeh, Z.; Mahdavi, S.R.; Haddadi, M. Radioprotective effect of melatonin on the cervical spinal cord in irradiated rats. Cell J.(Yakhteh), 2013, 14(4), 246.
[35]
Karbownik, M.; Reiter, R.J. Antioxidative effects of melatonin in protection against cellular damage caused by ionizing radiation. Proc. Soc. Exp. Biol. Med., 2000, 225(1), 9-22.
[36]
Jourdan, M.; Lopez, A.; Olasz, E.; Duncan, N.; Demara, M.; Kittipongdaja, W.; Fish, B.; Mäder, M.; Schock, A.; Morrow, N. Laminin 332 deposition is diminished in irradiated skin in an animal model of combined radiation and wound skin injury. Radiat. Res., 2011, 176(5), 636-648.
[37]
Jang, W.H.; Shim, S.; Wang, T.; Yoon, Y.; Jang, W-S.; Myung, J.K.; Park, S.; Kim, K.H. In vivo characterization of early-stage radiation skin injury in a mouse model by two-photon microscopy. Sci. Rep., 2016, 6, 19216.
[38]
öhrnel, L.-O.; Brånemark, R.; Nyman, J.; Nilsso, P.; Thomsen, P. Effects of irradiation on the biomechanics of osseointegration: An experimental in vivo study in rats. Scand. J. Plast. Reconstr. Surg. Hand Surg., 1997, 31(4), 281-293.
[39]
Daglioglu, E.; Dike, M.S.; Kilinc, K.; Erdogan, D.; Take, G.; Ergungor, F.; Okay, O.; Biyikli, Z. Neuroprotective effect of melatonin on experimental peripheral nerve injury: An electron microscopic and biochemical study. J. Neurol. Surg. A. Cent. Eur. Neurosurg.
2018 Oct 31. doi: 10.1055/s-0038-1673400. [Epub ahead
of print] , 2009, 70(03), 109-114.
[40]
Atik, B.; Erkutlu, I.; Tercan, M.; Buyukhatipoglu, H.; Bekerecioglu, M.; Pence, S. The effects of exogenous melatonin on peripheral nerve regeneration and collagen formation in rats. J. Surg. Res., 2011, 166(2), 330-336.
[41]
Shirazi, A.; Haddadi, G.; Minaee, B.; Sepehrizadeh, Z.; Mahdavi, S.; Jaberi, E.; Haddadi, M. Evaluation of melatonin for modulation of apoptosis-related genes in irradiated cervical spinal cord. Int. J. Low Radiat., 2010, 7(6), 436-445.
[42]
Gibbs, F.P.; Vriend, J. The half-life of melatonin elimination from rat plasma. Endocrinology, 1981, 109(5), 1796-1798.
[43]
Anwar, M.M.; Moustafa, M.A. The effect of melatonin on eye lens of rats exposed to ultraviolet radiation. Comp. Biochem. Physiol. Part C: Toxicol. Pharmacol., 2001, 129(1), 57-63.
[44]
Reiter, R.J.; Tan, D-X.; Herman, T.S.; Thomas, C.R. Melatonin as a radioprotective agent: A review. Int. J. Radiat. Oncol. Biol. Phys., 2004, 59(3), 639-653.
[45]
Slominski, A.; Tobin, D.J.; Zmijewski, M.A.; Wortsman, J.; Paus, R. Melatonin in the skin: Synthesis, metabolism and functions. Trends Endocrinol. Metabol., 2008, 19(1), 17-24.
[46]
Reiter, R.J.; Tan, D-x.; Manchester, L.C.; Qi, W. Biochemical reactivity of melatonin with reactive oxygen and nitrogen species. Cell Biochem. Biophys., 2001, 34(2), 237-256.
[47]
Shirazi, A.; Hadadi, G.H.; Ghazi, K.M.; Abou, A.F.; Mahdavi, S.R.; Eshraghian, M. Evaluation of melatonin for prevention of radiation myelopathy in irradiated cervical spinal cord., 2009, 11(1), 43-48.
[48]
Martin, M.T.; Vulin, A.; Hendry, J.H. Human epidermal stem cells: Role in adverse skin reactions and carcinogenesis from radiation. Mutat. Res. Rev. Mutat. Res., 2016, 770, 349-368.
[49]
Schaue, D.; Marples, B.; Trott, K. The effects of low-dose X-irradiation on the oxidative burst in stimulated macrophages. Int. J. Radiat. Biol., 2002, 78(7), 567-576.
[50]
Xu, H.; Yan, Y.; Li, L.; Peng, S.; Qu, T.; Wang, B. Ultraviolet B‐induced apoptosis of human skin fibroblasts involves activation of caspase-8 and-3 with increased expression of vimentin. Photodermatol. Photoimmunol. Photomed., 2010, 26(4), 198-204.
[51]
Shechmeister, I.L.; Fishman, M. The effect of ionizing radiation on phagocytosis and the bactericidal power of the blood: i. The effect of radiation on migration of leucocytes. J. Exp. Med., 1955, 101(3), 259-274.
[52]
Ran, X.; Cheng, T.; Shi, C.; Xu, H.; Qu, J.; Yan, G.; Su, Y.; Wang, W.; Xu, R. The effects of total-body irradiation on the survival and skin wound healing of rats with combined radiation-wound injury. J. Trauma Acute Care Surg., 2004, 57(5), 1087-1093.
[53]
Hebbar, S.; Mitra, A.; George, K.; Verma, N. Caffeine ameliorates radiation-induced skin reactions in mice but does not influence tumour radiation response. J. Radiol. Prot., 2002, 22(1), 63-69.
[54]
Chen, Y-J.; Dai, Y-S.; Chen, B-F. chang, A.; CHEN, H.-C.; Lin, Y.-C.; Chang, K.-H.; Lai, Y.-L.; Chung, C.-H.; Lai, Y.-J. The effect of tetrandrine and extracts of Centella asiatica on acute radiation dermatitis in rats. Biol. Pharm. Bull., 1999, 22(7), 703-706.
[55]
Prise, K.M.; Saran, A. Concise review: Stem cell effects in radiation risk. Stem Cells, 2011, 29(9), 1315-1321.
[56]
Schönmeyr, B.H.; Wong, A.K.; Soares, M.; Fernandez, J.; Clavin, N.; Mehrara, B.J. Ionizing radiation of mesenchymal stem cells results in diminution of the precursor pool and limits potential for multilineage differentiation. Plast. Reconstr. Surg., 2008, 122(1), 64-76.
[57]
Pandey, B.; Mishra, K. In vitro studies on radiation induced membrane oxidative damage in apoptotic death of mouse thymocytes. Int. J. Low Radiat., 2003, 1(1), 113-119.
[58]
Tabarraei, Y.; Bakhshandeh, Z.; Behrouzkia, Z.; Peirouvi, T.; Pourissa, M.; Asghari, M.; Dehghan, M.; Refahi, S.; Ghamami, G. Short-term changes in histopathological markers of irradiated rat’s lung: Preliminary study. RJPBCS, 2014, 5(3), 307-315.
[59]
Shabeeb, D.; Najafi, M.; Kashavarz, M.; Hasanzadeh, G.; Hadian, M.; Shirazi, A. Recent finding in repair of the peripheral nerve lesions using pharmacological agents; Common methods for evaluating the repair process. Cent. Nerv. Syst. Agents Med. Chem., 2018.
[60]
Valko, M.; Rhodes, C.; Moncol, J.; Izakovic, M.; Mazur, M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem. Biol. Interact., 2006, 160(1), 1-40.
[61]
Riley, P. Free radicals in biology: Oxidative stress and the effects of ionizing radiation. Int. J. Radiat. Biol., 1994, 65(1), 27-33.
[62]
Kleinman, W.A.; Richie, Jr , J.P. Status of glutathione and other thiols and disulfides in human plasma. Biochem. Pharmacol., 2000, 60(1), 19-29.
[63]
Naveena, B.B. Selvasubramanian. Antitumor activity of Aloe vera against Ehrlich ascitis carcinoma (EAC) in Swiss albino mice. Int. J. Pharma Bio Sci., 2011, 2(2), 400-409.
[64]
Jeon, S-M.; Bok, S-H.; Jang, M-K.; Kim, Y-H.; Nam, K-T.; Jeong, T-S.; Park, Y.B.; Choi, M-S. Comparison of antioxidant effects of naringin and probucol in cholesterol-fed rabbits. Clinica Chimica . Acta, 2002, 317(1-2), 181-190.
[65]
Ohta, Y.; Kongo‐Nishimura, M.; Matsura, T.; Yamada, K.; Kitagawa, A.; Kishikawa, T. Melatonin prevents disruption of hepatic reactive oxygen species metabolism in rats treated with carbon tetrachloride. J. Pineal Res., 2004, 36(1), 10-17.
[66]
Kalpana, C.; Menon, V.P. Modulatory effects of curcumin on lipid peroxidation and antioxidant status during nicotine-induced toxicity. Pol. J. Pharmacol., 2004, 56(5), 581-586.
[67]
Saada, H.; Ussama, Z.; Mahdy, A. Effectiveness of Aloe vera on the antioxidant status of different tissues in irradiated rats. Die Pharmazie-. Int. J. Pharm., 2003, 58(12), 929-931.
[68]
Said, U.; Azab, K.; Soliman, A. Cardio protective role of garlic (Allium Sativum) against oxidative stress induced by gamma radiation exposure. Isotope Rad. Res., 2004, 36(3), 465-479.
[69]
Farhood, B.; Goradel, N.; Mortezaee, K.; Khanlarkhani, N.; Salehi, E.; Nashtaei, M.; Mirtavoos-Mahyari, H.; Motevaseli, E.; Shabeeb, D.; Musa, A. Melatonin as an adjuvant in radiotherapy for radioprotection and radiosensitization. Clin. Transl. Oncol., 2018, 1-12.
[70]
Ben-David, M.A.; Elkayam, R.; Gelernter, I.; Pfeffer, R.M. Melatonin for prevention of breast radiation dermatitis: A Phase II, prospective, double-blind randomized trial. Isr. Med. Assoc. J., 2016, 18(3-4), 188-192.
[71]
Ündeğer, Ü.; Giray, B.; Zorlu, A.F.; Öge, K.; Baçaran, N. Protective effects of melatonin on the ionizing radiation induced DNA damage in the rat brain. Exp. Toxicol. Pathol., 2004, 55(5), 379-384.
[72]
Tahamtan, R.; Monfared, A.S.; Tahamtani, Y.; Tavassoli, A.; Akmali, M.; Mosleh-Shirazi, M.A.; Naghizadeh, M.M.; Ghasemi, D.; Keshavarz, M.; Haddadi, G.H. Radioprotective effect of melatonin on radiation-induced lung injury and lipid peroxidation in rats. Cell J. (Yakhteh), 2015, 17(11), 111.
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