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Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5230
ISSN (Online): 1875-614X

Research Article

Mitigation of Radiation-induced Gastrointestinal System Injury using Resveratrol or Alpha-lipoic Acid: A Pilot Histopathological Study

Author(s): Bagher Farhood, Gholamreza Hassanzadeh, Peyman Amini, Dheyauldeen Shabeeb, Ahmed Eleojo Musa, Ehsan Khodamoradi, Mehran Mohseni, Akbar Aliasgharzadeh, Habiballah Moradi and Masoud Najafi*

Volume 19, Issue 4, 2020

Page: [413 - 424] Pages: 12

DOI: 10.2174/1871523018666191111124028

Price: $65

Abstract

Aim: In this study, we aimed to determine possible mitigation of radiationinduced toxicities in the duodenum, jejunum and colon using post-exposure treatment with resveratrol and alpha-lipoic acid.

Background: After the bone marrow, gastrointestinal system toxicity is the second critical cause of death following whole-body exposure to radiation. Its side effects reduce the quality of life of patients who have undergone radiotherapy. Resveratrol has an antioxidant effect and stimulates DNA damage responses (DDRs). Alpha-lipoic acid neutralizes free radicals via the recycling of ascorbic acid and alpha-tocopherol.

Objective: This study is a pilot investigation of the mitigation of enteritis using resveratrol and alpha-lipoic acid following histopathological study.

Methods: 60 male mice were randomly assigned to six groups; control, resveratrol treatment, alpha-lipoic acid treatment, whole-body irradiation, irradiation plus resveratrol, and irradiation plus alpha-lipoic acid. The mice were irradiated with a single dose of 7 Gy from a cobalt-60 gamma-ray source. Treatment with resveratrol or alpha-lipoic acid started 24 h after irradiation and continued for 4 weeks. All mice were sacrificed after 30 days for histopathological evaluation of radiation-induced toxicities in the duodenum, jejunum and colon.

Results and Discussion: Exposure to radiation caused mild to severe damages to vessels, goblet cells and villous. It also led to significant infiltration of macrophages and leukocytes, especially in the colon. Both resveratrol and alpha-lipoic acid were able to mitigate morphological changes. However, they could not mitigate vascular injury.

Conclusion: Resveratrol and alpha-lipoic acid could mitigate radiation-induced injuries in the small and large intestine. A comparison between these agents showed that resveratrol may be a more effective mitigator compared to alpha-lipoic acid.

Keywords: Alpha-lipoic acid, gastrointestinal system, intestine, mitigation, radiation, resveratrol.

Graphical Abstract

[1]
Parkhill, K.A.; Pidgeon, N.F.; Henwood, K.L.; Simmons, P.; Venables, D. From the familiar to the extraordinary: local residents’ perceptions of risk when living with nuclear power in the UK. Trans. Inst. Br. Geogr., 2010, 35(1), 39-58.
[http://dx.doi.org/10.1111/j.1475-5661.2009.00364.x]
[2]
Rodemann, H.P.; Blaese, M.A. Responses of normal cells to ionizing radiation. Semin. Radiat. Oncol., 2007, 17(2), 81-88.
[http://dx.doi.org/10.1016/j.semradonc.2006.11.005] [PMID: 17395038]
[3]
Popanda, O.; Marquardt, J.U.; Chang-Claude, J.; Schmezer, P. Genetic variation in normal tissue toxicity induced by ionizing radiation. Mutat. Res., 2009, 667(1-2), 58-69.
[http://dx.doi.org/10.1016/j.mrfmmm.2008.10.014] [PMID: 19022265]
[4]
Rosen, E.M.; Fan, S.; Rockwell, S.; Goldberg, I.D. The molecular and cellular basis of radiosensitivity: implications for understanding how normal tissues and tumors respond to therapeutic radiation. Cancer Invest., 1999, 17(1), 56-72.
[http://dx.doi.org/10.1080/07357909909011718] [PMID: 10999050]
[5]
Fabbrizi, M.R.; Warshowsky, K.E.; Zobel, C.L.; Hallahan, D.E.; Sharma, G.G. Molecular and epigenetic regulatory mechanisms of normal stem cell radiosensitivity. Cell Death Discov., 2018, 4(1), 117.
[http://dx.doi.org/10.1038/s41420-018-0132-8] [PMID: 30588339]
[6]
Hamada, N. Ionizing radiation sensitivity of the ocular lens and its dose rate dependence. Int. J. Radiat. Biol., 2017, 93(10), 1024-1034.
[http://dx.doi.org/10.1080/09553002.2016.1266407] [PMID: 27899034]
[7]
Gupta, M.L.; Verma, S. Prophylactic strategies to minimize the effect of whole body irradiation on hematopoietic, gastrointestinal and respiratory system leading to morbidity/mortality in animals. J. Radiat. Cancer Res., 2018, 9(1), 4.
[http://dx.doi.org/10.4103/jrcr.jrcr_2_18]
[8]
Shukla, P.K.; Gangwar, R.; Manda, B.; Meena, A.S.; Yadav, N.; Szabo, E.; Balogh, A.; Lee, S.C.; Tigyi, G.; Rao, R. Rapid disruption of intestinal epithelial tight junction and barrier dysfunction by ionizing radiation in mouse colon in vivo: protection by N-acetyl-l-cysteine. Am. J. Physiol. Gastrointest. Liver Physiol., 2016, 310(9), G705-G715.
[http://dx.doi.org/10.1152/ajpgi.00314.2015] [PMID: 26822914]
[9]
Yeoh, E.K.; Krol, R.; Dhillon, V.S.; Botten, R.; Di Matteo, A.; Butters, J.; Brock, A.R.; Esterman, A.; Salisbury, C.; Fenech, M. Predictors of radiation-induced gastrointestinal morbidity: A prospective, longitudinal study following radiotherapy for carcinoma of the prostate. Acta Oncol., 2016, 55(5), 604-610.
[http://dx.doi.org/10.3109/0284186X.2015.1118658] [PMID: 27046049]
[10]
Becciolini, A. In Advances in radiation biology; Elsevier, 1987, Vol. 12, pp. 83-128.
[11]
Schaue, D.; Micewicz, E.D.; Ratikan, J.A.; Xie, M.W.; Cheng, G.; McBride, W.H. Radiation and inflammation. Semin. Radiat. Oncol., 2015, 25(1), 4-10.
[http://dx.doi.org/10.1016/j.semradonc.2014.07.007] [PMID: 25481260]
[12]
Muñoz, L.E.; Berens, C.; Lauber, K.; Gaipl, U.S.; Herrmann, M. Apoptotic cell clearance and its role in the origin and resolution of chronic inflammation. Front. Immunol., 2015, 6, 139.
[PMID: 25859248]
[13]
Shea-Donohue, T.; Fasano, A.; Zhao, A.; Notari, L.; Yan, S.; Sun, R.; Bohl, J.A.; Desai, N.; Tudor, G.; Morimoto, M.; Booth, C.; Bennett, A.; Farese, A.M.; MacVittie, T.J. Mechanisms involved in the development of the chronic gastrointestinal syndrome in nonhuman primates after total-body irradiation with bone marrow shielding. Radiat. Res., 2016, 185(6), 591-603.
[http://dx.doi.org/10.1667/RR14024.1] [PMID: 27223826]
[14]
Szumiel, I. Ionizing radiation-induced oxidative stress, epigenetic changes and genomic instability: the pivotal role of mitochondria. Int. J. Radiat. Biol., 2015, 91(1), 1-12.
[http://dx.doi.org/10.3109/09553002.2014.934929] [PMID: 24937368]
[15]
Singh, V.K.; Romaine, P.L.; Newman, V.L.; Seed, T.M. Medical countermeasures for unwanted CBRN exposures: part II radiological and nuclear threats with review of recent countermeasure patents. Expert Opin. Ther. Pat., 2016, 26(12), 1399-1408.
[http://dx.doi.org/10.1080/13543776.2016.1231805] [PMID: 27610458]
[16]
Zakeri, K.; Narayanan, D.; Vikram, B.; Evans, G.; Coleman, C.N.; Prasanna, P.G. Decreasing the toxicity of radiation therapy: radioprotectors and radiomitigators being developed by the national cancer institute through small business innovation research contracts. Int. J. Radiat. Oncol. Biol. Phys., 2018, 104(1), 188-196.
[http://dx.doi.org/10.1016/j.ijrobp.2018.12.027]
[17]
Pınar, N.; Çakırca, G.; Özgür, T.; Kaplan, M. The protective effects of alpha lipoic acid on methotrexate induced testis injury in rats. Biomed. Pharmacother., 2018, 97, 1486-1492.
[http://dx.doi.org/10.1016/j.biopha.2017.11.078]] [PMID: 29793311]
[18]
Aydın, S.; Şahin, T.T.; Bacanlı, M.; Taner, G.; Başaran, A.A.; Aydın, M.; Başaran, N. Resveratrol protects sepsis-induced oxidative DNA damage in liver and kidney of rats. Balkan Med. J., 2016, 33(6), 594-601.
[http://dx.doi.org/10.5152/balkanmedj.2016.15516] [PMID: 27994910]
[19]
Lan, F.; Weikel, K.A.; Cacicedo, J.M.; Ido, Y. Resveratrol-induced AMP-activated protein kinase activation is cell-type dependent: lessons from basic research for clinical application. Nutrient, 2017, 9(7), 751.
[20]
Mortezaee, K.; Najafi, M.; Farhood, B.; Ahmadi, A.; Shabeeb, D.; Musa, A.E. Resveratrol as an adjuvant for normal tissues protection and tumor sensitization. Curr. Cancer Drug Targets, 2020, 20(2), 130-145.
[http://dx.doi.org/10.2174/1568009619666191019143539] [PMID: 31738153]
[21]
Ergür, B.U.; Çilaker Mıcılı, S.; Yılmaz, O.; Akokay, P. The effects of α-lipoic acid on aortic injury and hypertension in the rat remnant kidney (5/6 nephrectomy) model. Anatol. J. Cardiol., 2015, 15(6), 443-449.
[http://dx.doi.org/10.5152/akd.2014.5483] [PMID: 25430409]
[22]
Kim, E.; Lim, J.; Kim, M.; Ban, T.; Yoon, H.; Park, C.; Chang, Y.; Choi, B. Effects of resveratrol on the renin-angiotensin system in the aging kidney. Nutrient, 2018, 10(11), 1741.
[http://dx.doi.org/10.3390/nu10111741]
[23]
Carsten, R.E.; Bachand, A.M.; Bailey, S.M.; Ullrich, R.L. Resveratrol reduces radiation-induced chromosome aberration frequencies in mouse bone marrow cells. Radiat. Res., 2008, 169(6), 633-638.
[http://dx.doi.org/10.1667/RR1190.1] [PMID: 18494544]
[24]
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]
[25]
Andreo, P.; Huq, M.S.; Westermark, M.; Song, H.; Tilikidis, A.; DeWerd, L.; Shortt, K. Protocols for the dosimetry of high-energy photon and electron beams: a comparison of the IAEA TRS-398 and previous international codes of practice. Phys. Med. Biol., 2002, 47(17), 3033-3053.
[http://dx.doi.org/10.1088/0031-9155/47/17/301] [PMID: 12361209]
[26]
Chang, P.; Qu, Y.; Liu, Y.; Cui, S.; Zhu, D.; Wang, H.; Jin, X. Multi-therapeutic effects of human adipose-derived mesenchymal stem cells on radiation induced intestinal injury. Cell Death Dis., 2013, 4(6)e685
[http://dx.doi.org/10.1038/cddis.2013.178] [PMID: 23788042]
[27]
Rubio, C.A.; Jalnäs, M. Dose-time-dependent histological changes following irradiation of the small intestine of rats. Dig. Dis. Sci., 1996, 41(2), 392-401.
[http://dx.doi.org/10.1007/BF02093834] [PMID: 8601388]
[28]
Madani, Z.S.; Azarakhsh, S.; Shakib, P.A.; Karimi, M. Histopathological changes in dental pulp of rats following radiotherapy. Dent. Res. J. (Isfahan), 2017, 14(1), 19-24.
[http://dx.doi.org/10.4103/1735-3327.201139] [PMID: 28348613]
[29]
MacPherson, B.R.; Pfeiffer, C.J. Experimental production of diffuse colitis in rats. Digestion, 1978, 17(2), 135-150.
[http://dx.doi.org/10.1159/000198104] [PMID: 627326]
[30]
Malago, J.J.; Nondoli, H. Sodium arsenite reduces severity of dextran sulfate sodium-induced ulcerative colitis in rats. J. Zhejiang Univ. Sci. B, 2008, 9(4), 341-350.
[http://dx.doi.org/10.1631/jzus.B0720198] [PMID: 18381811]
[31]
Erben, U.; Loddenkemper, C.; Doerfel, K.; Spieckermann, S.; Haller, D.; Heimesaat, M.M.; Zeitz, M.; Siegmund, B.; Kühl, A.A. A guide to histomorphological evaluation of intestinal inflammation in mouse models. Int. J. Clin. Exp. Pathol., 2014, 7(8), 4557-4576.
[PMID: 25197329]
[32]
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]
[33]
Somosy, Z.; Horváth, G.; Telbisz, A.; Réz, G.; Pálfia, Z. Morphological aspects of ionizing radiation response of small intestine. Micron, 2002, 33(2), 167-178.
[http://dx.doi.org/10.1016/S0968-4328(01)00013-0] [PMID: 11567886]
[34]
Datta, K.; Suman, S.; Kallakury, B.V.; Fornace, A.J., Jr Exposure to heavy ion radiation induces persistent oxidative stress in mouse intestine. PLoS One, 2012, 7(8)e42224
[http://dx.doi.org/10.1371/journal.pone.0042224] [PMID: 22936983]
[35]
Trajković, S.; Dobrić, S.; Jaćević, V.; Dragojević-Simić, V.; Milovanović, Z.; Dordević, A. Tissue protective effects of fullerenol C60(OH)24 and amifostine in irradiated rats. Colloids Surf. B Biointerfaces, 2007, 58(1), 39-43.
[http://dx.doi.org/10.1016/j.colsurfb.2007.01.005] [PMID: 17317115]
[36]
Sieber, F.; Muir, S.A.; Cohen, E.P.; Fish, B.L.; Mäder, M.; Schock, A.M.; Althouse, B.J.; Moulder, J.E. Dietary selenium for the mitigation of radiation injury: effects of selenium dose escalation and timing of supplementation. Radiat. Res., 2011, 176(3), 366-374.
[http://dx.doi.org/10.1667/RR2456.1] [PMID: 21867430]
[37]
Teo, M.T.; Sebag-Montefiore, D.; Donnellan, C.F. Prevention and management of radiation-induced late gastrointestinal toxicity. Clin. Oncol. (R. Coll. Radiol.), 2015, 27(11), 656-667.
[http://dx.doi.org/10.1016/j.clon.2015.06.010] [PMID: 26129746]
[38]
Stacey, R.; Green, J.T. Radiation-induced small bowel disease: latest developments and clinical guidance. Ther. Adv. Chronic Dis., 2014, 5(1), 15-29.
[http://dx.doi.org/10.1177/2040622313510730] [PMID: 24381725]
[39]
Stein, A.; Voigt, W.; Jordan, K. Chemotherapy induced diarrhea: pathophysiology, frequency and guideline-based management. Ther. Adv. Med. Oncol., 2010, 2(1), 51-63.
[http://dx.doi.org/10.1177/1758834009355164] [PMID: 21789126]
[40]
Thorpe, D.; Stringer, A.; Butler, R. Chemotherapy-induced mucositis: the role of mucin secretion and regulation, and the enteric nervous system. Neurotoxicology, 2013, 38, 101-105.
[http://dx.doi.org/10.1016/j.neuro.2013.06.007] [PMID: 23827812]
[41]
Brown, S.L.; Kolozsvary, A.; Liu, J.; Jenrow, K.A.; Ryu, S.; Kim, J.H. Antioxidant diet supplementation starting 24 hours after exposure reduces radiation lethality. Radiat. Res., 2010, 173(4), 462-468.
[http://dx.doi.org/10.1667/RR1716.1] [PMID: 20334518]
[42]
Jia, D.; Koonce, N.A.; Griffin, R.J.; Jackson, C.; Corry, P.M. Prevention and mitigation of acute death of mice after abdominal irradiation by the antioxidant N-acetyl-cysteine (NAC). Radiat. Res., 2010, 173(5), 579-589.
[http://dx.doi.org/10.1667/RR2030.1] [PMID: 20426657]
[43]
Patil, R.; Szabó, E.; Fells, J.I.; Balogh, A.; Lim, K.G.; Fujiwara, Y.; Norman, D.D.; Lee, S-C.; Balazs, L.; Thomas, F.; Patil, S.; Emmons-Thompson, K.; Boler, A.; Strobos, J.; McCool, S.W.; Yates, C.R.; Stabenow, J.; Byrne, G.I.; Miller, D.D.; Tigyi, G.J. Combined mitigation of the gastrointestinal and hematopoietic acute radiation syndromes by an LPA2 receptor-specific nonlipid agonist. Chem. Biol., 2015, 22(2), 206-216.
[http://dx.doi.org/10.1016/j.chembiol.2014.12.009] [PMID: 25619933]
[44]
Deng, W.; Kimura, Y.; Gududuru, V.; Wu, W.; Balogh, A.; Szabo, E.; Thompson, K.E.; Yates, C.R.; Balazs, L.; Johnson, L.R.; Miller, D.D.; Strobos, J.; McCool, W.S.; Tigyi, G.J. Mitigation of the hematopoietic and gastrointestinal acute radiation syndrome by octadecenyl thiophosphate, a small molecule mimic of lysophosphatidic acid. Radiat. Res., 2015, 183(4), 465-475.
[http://dx.doi.org/10.1667/RR13830.1] [PMID: 25807318]
[45]
Kim, B.H.; Jung, H-W.; Seo, S.H.; Shin, H.; Kwon, J.; Suh, J.M. Synergistic actions of FGF2 and bone marrow transplantation mitigate radiation-induced intestinal injury. Cell Death Dis., 2018, 9(3), 383-383.
[http://dx.doi.org/10.1038/s41419-018-0421-4] [PMID: 29515101]
[46]
Zhang, L.; Sun, W.; Wang, J.; Zhang, M.; Yang, S.; Tian, Y.; Vidyasagar, S.; Peña, L.A.; Zhang, K.; Cao, Y.; Yin, L.; Wang, W.; Zhang, L.; Schaefer, K.L.; Saubermann, L.J.; Swarts, S.G.; Fenton, B.M.; Keng, P.C.; Okunieff, P. Mitigation effect of an FGF-2 peptide on acute gastrointestinal syndrome after high-dose ionizing radiation. Int. J. Radiat. Oncol. Biol. Phys., 2010, 77(1), 261-268.
[http://dx.doi.org/10.1016/j.ijrobp.2009.11.026] [PMID: 20394858]
[47]
Casey-Sawicki, K.; Zhang, M.; Kim, S.; Zhang, A.; Zhang, S.B.; Zhang, Z.; Singh, R.; Yang, S.; Swarts, S.; Vidyasagar, S.; Zhang, L.; Zhang, A.; Okunieff, P. A basic fibroblast growth factor analog for protection and mitigation against acute radiation syndromes. Health Phys., 2014, 106(6), 704-712.
[http://dx.doi.org/10.1097/HP.0000000000000095] [PMID: 24776903]
[48]
Banerjee, S.; Shah, S.K.; Melnyk, S.B.; Pathak, R.; Hauer-Jensen, M.; Pawar, S.A. Cebpd is essential for gamma-tocotrienol mediated protection against radiation-induced hematopoietic and intestinal injury. Antioxidants, 2018, 7(4), 55.
[http://dx.doi.org/10.3390/antiox7040055] [PMID: 29642403]
[49]
Berbée, M.; Fu, Q.; Boerma, M.; Wang, J.; Kumar, K.S.; Hauer-Jensen, M. γ-Tocotrienol ameliorates intestinal radiation injury and reduces vascular oxidative stress after total-body irradiation by an HMG-CoA reductase-dependent mechanism. Radiat. Res., 2009, 171(5), 596-605.
[http://dx.doi.org/10.1667/RR1632.1] [PMID: 19580495]
[50]
Williams, L.D.; Burdock, G.A.; Edwards, J.A.; Beck, M.; Bausch, J. Safety studies conducted on high-purity trans-resveratrol in experimental animals. Food Chem. Toxicol., 2009, 47(9), 2170-2182.
[http://dx.doi.org/10.1016/j.fct.2009.06.002] [PMID: 19505523]
[51]
Bhat, K.P.; Lantvit, D.; Christov, K.; Mehta, R.G.; Moon, R.C.; Pezzuto, J.M. Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models. Cancer Res., 2001, 61(20), 7456-7463.
[PMID: 11606380]
[52]
Kapetanovic, I.M.; Muzzio, M.; Huang, Z.; Thompson, T.N.; McCormick, D.L. Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemother. Pharmacol., 2011, 68(3), 593-601.
[http://dx.doi.org/10.1007/s00280-010-1525-4] [PMID: 21116625]
[53]
Hofer, M.; Hoferová, Z.; Falk, M. Pharmacological modulation of radiation damage. Does it exist a chance for other substances than hematopoietic growth factors and cytokines? Int. J. Mol. Sci., 2017, 28, 18(7), pii: E1385.
[http://dx.doi.org/10.3390/ijms18071385]
[54]
Kim, J.H.; Jung, M.H.; Kim, J.P.; Kim, H-J.; Jung, J.H.; Hahm, J.R.; Kang, K.M.; Jeong, B-K.; Woo, S.H. Alpha lipoic acid attenuates radiation-induced oral mucositis in rats. Oncotarget, 2017, 8(42), 72739-72747.
[http://dx.doi.org/10.18632/oncotarget.20286] [PMID: 29069822]
[55]
Carlson, D.A.; Smith, A.R.; Fischer, S.J.; Young, K.L.; Packer, L. The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects. Altern. Med. Rev., 2007, 12(4), 343-351.
[PMID: 18069903]
[56]
Teichert, J.; Hermann, R.; Ruus, P.; Preiss, R. Plasma kinetics, metabolism, and urinary excretion of alpha lipoic acid following oral administration in healthy volunteers. J. Clin. Pharmacol., 2003, 43(11), 1257-1267.
[http://dx.doi.org/10.1177/0091270003258654] [PMID: 14551180]

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