Evaluating Radioprotection of Rat’s Jejunum by a Combination of Melatonin and Metformin

Author(s): Nasim Ahmadi Azar, Abdolreza Javadi, Masoud Najafi*, Alireza Shirazi*, Elham Tajabadi, Dheyauldeen Shabeeb, Ahmed Eleojo Musa

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 4 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: Jejunum is one of the most radiosensitive parts of the gastrointestinal system. This is the main issue, leading to several side effects to patients with abdominal cancers, in addition to affecting their quality of life. Epithelial layer and clonogenic cells in the jejunum are the most sensitive parts of the intestine, while damage to vascular may lead to chronic inflammation and bleeding. Both melatonin and metformin have shown abilities to attenuate radiation toxicities through the modulation of DNA damage responses, neutralization of free radicals and alleviation of inflammation. In this study, we aimed to evaluate the possible radioprotective effects of melatonin and metformin when administered either alone or as a combination, in rat’s jejunum against a high dose of radiation.

Methods: 40 male rats were divided into 8 groups as G1: control; G2: metformin; G3: melatonin; G4: melatonin + metformin; G5: radiation; G6: radiation + melatonin; G7: radiation + metformin; G8: metformin + melatonin + radiation. Rats were irradiated with 10 Gy gamma rays, while treatments were administered at 100 mg/kg. The ratio for melatonin and metformin was 1:1. 3.5 days after irradiation, all rats were sacrificed, followed by histopathological evaluation of the jejunum.

Results: This study showed that whole body irradiation of rats led to severe injuries to the epithelial and vascular of jejunum. A single administration of either melatonin or metformin was unable to mitigate radiation toxicity. However, administering the combination of melatonin and metformin could mildly mitigate radiation-induced jejunum injury.

Conclusion: From the results of this study, we suggest that the combination of melatonin and metformin has superior radioprotective effect for jejunum compared with the single administration of these drugs.

Keywords: Radiation, jejunum, melatonin, metformin, radioprotection, histopathological evaluation.

Carballo, N.; González-Cortijo, L.; González-Martín, A.; Rojo, A.; Chiva, L. Indications for adjuvant radiotherapy treatment after surgery and novel modalities for treatment. Gynecol. Oncol., 2008, 110(3)(Suppl. 2), S41-S44.
[http://dx.doi.org/10.1016/j.ygyno.2008.07.009] [PMID: 18760712]
Duggan, F.J., Jr; Sanford, E.J.; Rohner, T.J., Jr Radiation enteritis following radiotherapy for prostatic carcinoma. Br. J. Urol., 1975, 47(4), 441-444.
[http://dx.doi.org/10.1111/j.1464-410X.1975.tb04003.x] [PMID: 810207]
Graziani, C.; Hegde, S.; Saif, M.W. Radiation recall gastritis secondary to erlotinib in a patient with pancreatic cancer. Anticancer Res., 2014, 34(12), 7339-7343.
[PMID: 25503169]
Boerma, M.; Wang, J.; Sridharan, V.; Herbert, J.M.; Hauer-Jensen, M. Pharmacological induction of transforming growth factor-beta1 in rat models enhances radiation injury in the intestine and the heart. PLoS One, 2013, 8(7) e70479
[http://dx.doi.org/10.1371/journal.pone.0070479] [PMID: 23936211]
Driak, D.; Osterreicher, J.; Vavrova, J.; Rehakova, Z.; Vilasova, Z. Morphological changes of rat jejunum after whole body gamma-irradiation and their impact in biodosimetry. Physiol. Res. Academia. Sci. Bohemoslov, 2008, 57(3), 475-479.
[PMID: 17465702]
Ong, Z.Y.; Gibson, R.J.; Bowen, J.M.; Stringer, A.M.; Darby, J.M.; Logan, R.M.; Yeoh, A.S.; Keefe, D.M. Pro-inflammatory cytokines play a key role in the development of radiotherapy-induced gastrointestinal mucositis. Radiat. Oncol., 2010, 5(1), 22.
[http://dx.doi.org/10.1186/1748-717X-5-22] [PMID: 20233440]
Barker, C.A.; Kim, S.K.; Budhu, S.; Matsoukas, K.; Daniyan, A.F.; D’Angelo, S.P. Cytokine release syndrome after radiation therapy: Case report and review of the literature. J. Immunother. Cancer, 2018, 6(1), 1.
[http://dx.doi.org/10.1186/s40425-017-0311-9] [PMID: 29298730]
Shadad, A.K.; Sullivan, F.J.; Martin, J.D.; Egan, L.J. Gastrointestinal radiation injury: Symptoms, risk factors and mechanisms. World J. Gastroenterol., 2013, 19(2), 185-198.
[http://dx.doi.org/10.3748/wjg.v19.i2.185] [PMID: 23345941]
Empey, L.R.; Papp, J.D.; Jewell, L.D.; Fedorak, R.N. Mucosal protective effects of vitamin E and misoprostol during acute radiation-induced enteritis in rats. Dig. Dis. Sci., 1992, 37(2), 205-214.
[http://dx.doi.org/10.1007/BF01308173] [PMID: 1735337]
Parihar, V.K.; Prabhakar, K.R.; Veerapur, V.P.; Kumar, M.S.; Reddy, Y.R.; Joshi, R.; Unnikrishnan, M.K.; Rao, C.M. Effect of sesamol on radiation-induced cytotoxicity in Swiss albino mice. Mutat. Res., 2006, 611(1-2), 9-16.
[http://dx.doi.org/10.1016/j.mrgentox.2006.06.037] [PMID: 17045515]
Goradel, N.H.; Asghari, M.H.; Moloudizargari, M.; Negahdari, B.; Haghi-Aminjan, H.; Abdollahi, M. Melatonin as an angiogenesis inhibitor to combat cancer: Mechanistic evidence. Toxicol. Appl. Pharmacol., 2017, 335, 56-63.
[http://dx.doi.org/10.1016/j.taap.2017.09.022] [PMID: 28974455]
de la Puerta, C.; Carrascosa-Salmoral, M.P.; García-Luna, P.P.; Lardone, P.J.; Herrera, J.L.; Fernández-Montesinos, R. Melatonin is a phytochemical in olive oil. Food Chem., 2007, 104(2), 609-612.
Setyaningsih, W.; Saputro, I.E.; Barbero, G.F.; Palma, M.; García Barroso, C. Determination of melatonin in rice (Oryza sativa) grains by pressurized liquid extraction. J. Agric. Food Chem., 2015, 63(4), 1107-1115.
[http://dx.doi.org/10.1021/jf505106m] [PMID: 25572452]
Haghi-Aminjan, H.; Farhood, B.; Rahimifard, M.; Didari, T.; Baeeri, M.; Hassani, S.; Hosseini, R.; Abdollahi, M. The protective role of melatonin in chemotherapy-induced nephrotoxicity: A systematic review of non-clinical studies. Expert Opin. Drug Metab. Toxicol., 2018, 14(9), 937-950.
[http://dx.doi.org/10.1080/17425255.2018.1513492] [PMID: 30118646]
Haghi-Aminjan, H.; Asghari, M.H.; Farhood, B.; Rahimifard, M.; Hashemi Goradel, N.; Abdollahi, M. The role of melatonin on chemotherapy-induced reproductive toxicity. J. Pharm. Pharmacol., 2018, 70(3), 291-306.
[http://dx.doi.org/10.1111/jphp.12855] [PMID: 29168173]
Gürses, I.; Özeren, M.; Serin, M.; Yücel, N.; Erkal, H.S. Histopathological evaluation of melatonin as a protective agent in heart injury induced by radiation in a rat model. Pathol. Res. Pract., 2014, 210(12), 863-871.
[http://dx.doi.org/10.1016/j.prp.2014.08.006] [PMID: 25249491]
Hussein, M.R.; Abu-Dief, E.E.; Kamel, E.; Abou El-Ghait, A.T.; Abdulwahed, S.R.; Ahmad, M.H. Melatonin and roentgen irradiation-induced acute radiation enteritis in Albino rats: an animal model. Cell Biol. Int., 2008, 32(11), 1353-1361.
[http://dx.doi.org/10.1016/j.cellbi.2008.08.001] [PMID: 18762261]
Jang, S.S.; Kim, H.G.; Lee, J.S.; Han, J.M.; Park, H.J.; Huh, G.J.; Son, C.G. Melatonin reduces X-ray radiation-induced lung injury in mice by modulating oxidative stress and cytokine expression. Int. J. Radiat. Biol., 2013, 89(2), 97-105.
[http://dx.doi.org/10.3109/09553002.2013.734943] [PMID: 23046278]
Karslioglu, I.; Ertekin, M.V.; Taysi, S.; Koçer, I.; Sezen, O.; Gepdiremen, A.; Koç, M.; Bakan, N. Radioprotective effects of melatonin on radiation-induced cataract. J. Radiat. Res. (Tokyo), 2005, 46(2), 277-282.
[http://dx.doi.org/10.1269/jrr.46.277] [PMID: 15988147]
Xu, G.; Wu, H.; Zhang, J.; Li, D.; Wang, Y.; Wang, Y.; Zhang, H.; Lu, L.; Li, C.; Huang, S.; Xing, Y.; Zhou, D.; Meng, A. Metformin ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice. Free Radic. Biol. Med., 2015, 87, 15-25.
[http://dx.doi.org/10.1016/j.freeradbiomed.2015.05.045] [PMID: 26086617]
Wang, J.; Wang, Y.; Han, J.; Mei, H.; Yu, D.; Ding, Q.; Zhang, T.; Wu, G.; Peng, G.; Lin, Z. Metformin attenuates radiation-induced pulmonary fibrosis in a murine model. Radiat. Res., 2017, 188(1), 105-113.
[http://dx.doi.org/10.1667/RR14708.1] [PMID: 28437189]
Saisho, Y. Metformin and inflammation: Its potential beyond glucose-lowering effect. Endocr. Metab. Immune Disord. Drug Targets, 2015, 15(3), 196-205.
[http://dx.doi.org/10.2174/1871530315666150316124019] [PMID: 25772174]
Qing, L.; Fu, J.; Wu, P.; Zhou, Z.; Yu, F.; Tang, J. Metformin induces the M2 macrophage polarization to accelerate the wound healing via regulating AMPK/mTOR/NLRP3 inflammasome singling pathway. Am. J. Transl. Res., 2019, 11(2), 655-668.
[PMID: 30899369]
Onseng, K.; Johns, N.P.; Khuayjarernpanishk, T.; Subongkot, S.; Priprem, A.; Hurst, C.; Johns, J. Beneficial effects of adjuvant melatonin in minimizing oral mucositis Complications in head and neck cancer patients receiving concurrent chemoradiation. J. Altern. Complement. Med., 2017, 23(12), 957-963.
[http://dx.doi.org/10.1089/acm.2017.0081] [PMID: 28657801]
Fernandez-Gil, B.I.; Guerra-Librero, A.; Shen, Y.Q.; Florido, J.; Martínez-Ruiz, L.; García-López, S.; Adan, C.; Rodríguez-Santana, C.; Acuña-Castroviejo, D.; Quiñones-Hinojosa, A.; Fernández-Martínez, J.; Abdel Moneim, A.E.; López, L.C.; Rodríguez Ferrer, J.M.; Escames, G. melatonin enhances cisplatin and radiation cytotoxicity in head and neck squamous cell carcinoma by stimulating mitochondrial ROS generation, apoptosis, and autophagy. Oxid. Med. Cell. Longev., 2019, 2019 7187128
[http://dx.doi.org/10.1155/2019/7187128] [PMID: 30944696]
Dal Pra, A.; Zannella, V.; Glicksman, R.; Sykes, J.; Muaddi, H. joshua, a. metformin and prostate cancer radiation therapy: Improved outcomes due to enhanced tumor oxygenation. Int. J. Radiat. Oncol. Biol. Phys., 2013, 87(2), S170.
Murray, D.; Milas, L.; Meyn, R.E. Radioprotection of mouse jejunum by WR-2721 and WR-1065: Effects on DNA strand-break induction and rejoining. Radiat. Res., 1988, 114(2), 268-280.
[http://dx.doi.org/10.2307/3577224] [PMID: 2836883]
Singh, V.K.; Singh, P.K.; Wise, S.Y.; Posarac, A.; Fatanmi, O.O. Radioprotective properties of tocopherol succinate against ionizing radiation in mice. J. Radiat. Res. (Tokyo), 2013, 54(2), 210-220.
[http://dx.doi.org/10.1093/jrr/rrs088] [PMID: 23038797]
Jeong, B.K.; Song, J.H.; Jeong, H.; Choi, H.S.; Jung, J.H.; Hahm, J.R.; Woo, S.H.; Jung, M.H.; Choi, B.H.; Kim, J.H.; Kang, K.M. Effect of alpha-lipoic acid on radiation-induced small intestine injury in mice. Oncotarget, 2016, 7(12), 15105-15117.
[http://dx.doi.org/10.18632/oncotarget.7874] [PMID: 26943777]
Fukuda, K.; Uehara, Y.; Nakata, E.; Inoue, M.; Shimazu, K.; Yoshida, T.; Kanda, H.; Nanjo, H.; Hosoi, Y.; Yamakoshi, H.; Iwabuchi, Y.; Shibata, H. A diarylpentanoid curcumin analog exhibits improved radioprotective potential in the intestinal mucosa. Int. J. Radiat. Biol., 2016, 92(7), 388-394.
[http://dx.doi.org/10.3109/09553002.2016.1164910] [PMID: 27043482]
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), 245-250.
[http://dx.doi.org/10.4103/jmp.JMP_9_17] [PMID: 29296039]
Kim, S.H.; Cho, C.K.; Yoo, S.Y.; Koh, K.H.; Yun, H.G.; Kim, T.H. In vivo radioprotective activity of Panax ginseng and diethyldithiocarbamate. In Vivo, 1993, 7(5), 467-470.
[PMID: 8110994]
Moon, C.; Kim, S.H.; Kim, J.C.; Hyun, J.W.; Lee, N.H.; Park, J.W.; Shin, T. Protective effect of phlorotannin components phloroglucinol and eckol on radiation-induced intestinal injury in mice. Phytother. Res., 2008, 22(2), 238-242.
[http://dx.doi.org/10.1002/ptr.2298] [PMID: 17886227]
Hanson, W.R. Radiation protection of murine intestine by WR-2721, 16,16-dimethyl prostaglandin E2, and the combination of both agents. Radiat. Res., 1987, 111(2), 361-373.
[http://dx.doi.org/10.2307/3576992] [PMID: 2819937]
Topkan, E.; Tufan, H.; Yavuz, A.A.; Bacanli, D.; Onal, C.; Kosdak, S.; Yavuz, M.N. Comparison of the protective effects of melatonin and amifostine on radiation-induced epiphyseal injury. Int. J. Radiat. Biol., 2008, 84(10), 796-802.
[http://dx.doi.org/10.1080/09553000802389678] [PMID: 18979313]
Kopjar, N.; Miocić, S.; Ramić, S.; Milić, M.; Viculin, T. Assessment of the radioprotective effects of amifostine and melatonin on human lymphocytes irradiated with gamma-rays in vitro. Arh. Hig. Rada Toksikol., 2006, 57(2), 155-163.
[PMID: 16832970]
Zangeneh, M.; Mozdarani, H.; Mahmoudzadeh, A. Potent radioprotective effects of combined regimens of famotidine and vitamin C against radiation-induced micronuclei in mouse bone marrow erythrocytes. Radiat. Environ. Biophys., 2015, 54(2), 175-181.
[http://dx.doi.org/10.1007/s00411-015-0586-5] [PMID: 25634516]
Morales, A.I.; Detaille, D.; Prieto, M.; Puente, A.; Briones, E.; Arévalo, M.; Leverve, X.; López-Novoa, J.M.; El-Mir, M.Y. Metformin prevents experimental gentamicin-induced nephropathy by a mitochondria-dependent pathway. Kidney Int., 2010, 77(10), 861-869.
[http://dx.doi.org/10.1038/ki.2010.11] [PMID: 20164825]
Gao, Y.; Xiao, X.; Zhang, C.; Yu, W.; Guo, W.; Zhang, Z.; Li, Z.; Feng, X.; Hao, J.; Zhang, K.; Xiao, B.; Chen, M.; Huang, W.; Xiong, S.; Wu, X.; Deng, W. Melatonin synergizes the chemotherapeutic effect of 5-fluorouracil in colon cancer by suppressing PI3K/AKT and NF-κB/iNOS signaling pathways. J. Pineal Res., 2017, 62(2) e12380
[http://dx.doi.org/10.1111/jpi.12380 ] [PMID: 27865009]
Feng, T.; Li, L.; Ling, S.; Fan, N.; Fang, M.; Zhang, H.; Fang, X.; Lan, W.; Hou, Z.; Meng, Q-C.; Jin, D.; Xu, F.; Li, Y. Metformin enhances radiation response of ECa109 cells through activation of ATM and AMPK. Biomed. Pharmacother., 2015, 69, 260-266.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 25 April, 2020
Page: [479 - 484]
Pages: 6
DOI: 10.2174/1570180816666190617153004
Price: $65

Article Metrics

PDF: 14