Melatonin is a potent modulator of antioxidative defense and cellular proliferation against aluminum toxicity in rats

Aluminum is the most abundant metal on earth, known for its toxicity to humans and laboratory animals. Melatonin, produced by the pineal gland, has been shown to be an effective antioxidant. In this study, we investigated the possible protective role of melatonin in modulating toxicity and oxidative stress induced by chronic exposure to aluminum in the small intestine of rats. Wistar albino rats were divided into five groups. Group I served as the control and received only physiological saline, Group II served as the control for the melatonin group and received ethanol and physiological saline, Group III received melatonin, Group IV received aluminum sulfate, and Group V received aluminum sulfate and melatonin, injected three times per week for 1 month. Administration of aluminum caused degenerative changes in small intestine tissues, such as histological damage, increase in metallothionein immunoreactivity, and decrease in cellular proliferation index. Moreover, intestinal glutathione levels, and catalase, superoxide dismutase, glutathione peroxidase, sodium/potassium-ATPase, and glucose-6-phosphate dehydrogenase activities decreased, while lipid peroxidation and myeloperoxidase levels, and alkaline phosphatase, lactate dehydrogenase, and xanthine oxidase activities increased in the aluminum group. Administration of melatonin mostly prevented these effects. Consequently, we can say that melatonin protects the intestine from aluminum toxicity through its antioxidant and proliferative effects.

Melatonin is a potent modulator of antioxidative defense and cellular proliferation against aluminum toxicity in rats

Aluminum is the most abundant metal on earth, known for its toxicity to humans and laboratory animals. Melatonin, produced by the pineal gland, has been shown to be an effective antioxidant. In this study, we investigated the possible protective role of melatonin in modulating toxicity and oxidative stress induced by chronic exposure to aluminum in the small intestine of rats. Wistar albino rats were divided into five groups. Group I served as the control and received only physiological saline, Group II served as the control for the melatonin group and received ethanol and physiological saline, Group III received melatonin, Group IV received aluminum sulfate, and Group V received aluminum sulfate and melatonin, injected three times per week for 1 month. Administration of aluminum caused degenerative changes in small intestine tissues, such as histological damage, increase in metallothionein immunoreactivity, and decrease in cellular proliferation index. Moreover, intestinal glutathione levels, and catalase, superoxide dismutase, glutathione peroxidase, sodium/potassium-ATPase, and glucose-6-phosphate dehydrogenase activities decreased, while lipid peroxidation and myeloperoxidase levels, and alkaline phosphatase, lactate dehydrogenase, and xanthine oxidase activities increased in the aluminum group. Administration of melatonin mostly prevented these effects. Consequently, we can say that melatonin protects the intestine from aluminum toxicity through its antioxidant and proliferative effects.

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  • Abdel Moneim AE, Othman MS, Mohmoud SM, El-Deib KM (2013). Pomegranate peel attenuates aluminum-induced hepatorenal toxicity. Toxicol Mech Methods 23: 624–633.
  • Aebi H (1984). Catalase in vitro. Methods Enzymol 105: 121–126.
  • Aguilar-Nascimento JE (2006). Evaluation of intestinal trophism: review of current methods and techniques. Curr Opin Clin Nutr Metab Care 9: 257–262.
  • Albendea CD, Gomez-Trullen EM, Fuentes-Broto I, Miana-Mena FJ, Millan-Plano S, Reyes-Gonzales MC, Martinez-Ballarin E, Garcia JJ (2007). Melatonin reduces lipid and protein oxidative damage in synaptosomes due to aluminum. J Trace Elem Med Biol 21: 261–268.
  • Akinrinade ID,  Memudu AE,  Ogundele OM (2015). Fluoride and aluminium disturb neuronal morphology, transport functions, cholinesterase, lysosomal and cell cycle activities. Pathophysiology 22: 105–115.
  • Alfrey AC, Legendre GR, Kaehny WD (1976). The dialysis encephalopathy syndrome-possible aluminum intoxication. N Engl J Med 294: 184–188.
  • Al Kahtani MA (2010). Renal damage mediated by oxidative stress in mice treated with aluminium chloride: protective effects of taurine. J Biol Sci 10: 584–595.
  • Allegra M, Reiter RJ, Tan DX, Gentile C, Tesoriere L, Livrea MA (2003) The chemistry of melatonin’s interaction with reactive species. J Pineal Res 34: 1–10.
  • Amaral A, Cabral C, Gueder C, Rodrigues A (2007). Apoptosis, metallothionein and bioavailable metals in domestic mice (Mus musculus L.) from a human-inhabited volcanic area. Ecotoxicology 16: 475–482.
  • Amer MAL (2008). Effects of aluminum exposure on the kidney, liver and brain of albino rats and the possible protective role of vitamin E. MD, Ain Shams University Faculty of Medicine.
  • Anane  R,  Creppy  EE (2001). Lipid peroxidation as pathway of aluminium cytotoxicity in  human  skin fibroblast cultures: prevention by superoxide dismutase+catalase and vitamins E and C. Hum Exp Toxicol 20: 477–481.
  • Andreyev AY, Kushnareva YE, Starkov AA (2005). Mitochondrial metabolism of reactive oxygen species. Biochemistry (Mosc) 70: 200–214.
  • Aslan A, Polat G, Atik E, Temiz M, Bağdatoğlu ÖT, Aban N (2008). Effect ofselenium in experimental ulcerative colitis. Mersin Univ Saglik Bilim Derg 1: 7–11 (article in Turkish with an abstract in English).
  • Bancroft JD, Stevens A (1982). Theory and Practice of Histological Techniques. Edinburgh, UK: Churchill Livingstone.
  • Becaria A, Campbell A, Bondy SC 2002, Aluminum as a toxicant. Toxicol Ind Health 18: 309–320.
  • Belaïd-Nouira Y, Bakhta H, Haouas Z, Flehi-Slim I, Ben Cheikh H (2013). Fenugreek seeds reduce aluminum toxicity associated with renal failure in rats. Nutr Res Pract 7: 466–474.
  • Betke K, Brewer GJ, Kirkman HN, Luzzato L, Motulsky AG, Ramot B, Siniscalco M (1967). Standardized method for G-6-PD assay of haemolysates. WHO Tech Rep Ser 366: 30–32.
  • Bogdanovic M, Begic-Janeva A, Bulat P (2008). Histopathological changes in rat liver after a single high dose of aluminum. Arch Hyg Rada Toksikol 59: 97–101.
  • Carpene E, Andreani G, Isani G (2007). Metallothionein functions and structural characteristics. J Trace Elem Med Biol  21: 35– 39.
  • Chance B, Sies H, Boveris A (1979). Hydroperoxide metabolism in mammalian organs. Physiol Rev 59: 529–605.
  • Chavan S, Sava L, Saxena V, Pillai S, Sontakke A, Ingole D (2005). Reduced glutathione: importance of specimen collection. Ind J Clin Biochem 20: 150–152.
  • Cheng D, Xi Y, Cao J, Cao D, Ma Y, Jiang W (2014). Protective effect of apple (Ralls) polyphenol extract against aluminum- induced cognitive impairment and oxidative damage in rat. Neurotoxicology 45: 111–120.
  • Cobbett C, Goldsbrough P (2002). Phytochelatins and metallothioneins: roles in heavy metal detoxification and homeostasis. Annu Rev Plant Biol 53: 159–182.
  • Çokuğraş F (2011). Kronik inflamatuvar barsak hastalıkları. Turk Arch Pediatr 46: 70–78 (in Turkish).
  • Corte DS, Stirpe F (1968). Regulation of xanthine oxidase in rat liver: modifications of the enzyme activity of rat liver supernatant on storage at –20°. Biochem J 108: 349–350.
  • Cunat L, Lanhers MC, Joyeux M, Burnel D (2000). Bioavailability and intestinal absorption of aluminum in rats. Biol Trace Elem Res 76: 31–55.
  • Dahlquist A, Olsson I, Norden A (1965). The periodate-Schiff reaction: specificity, kinetics and reaction products with pure substrate. J Histochem Cytochem 13: 423–430.
  • Ekmekcioglu C (2006). Melatonin receptors in humans: biological role and clinical relevance. Biomed Pharm 60: 97–108.
  • El-Maraghy S, Gad MZ, Fahim AT, Hamdy MA (2001). Effect of cadmium and aluminum intake on the antioxidant status and lipid peroxidation in rat tissues. J Biochem Mol Toxicol 15: 207–214.
  • Esparza JL, Gomez M, Romeu M, Mulero M, Sanchez DJ, Mallol J, Domıngo JL (2003). Aluminum-induced pro-oxidant effects in rats: protective role of exogenous melatonin. J Pineal Res 35: 32–39.
  • Exley C (2004). The pro-oxidant activity of aluminum. Free Radic Biol Med 36: 380–387.
  • Farias JG, Zepeda AB, Calaf GM (2012). Melatonin protects the heart, lungs and kidneys from oxidative stress under intermittent hypobaric hypoxia in rats. Biol Res 45: 81–85.
  • Fernandez M, Medina A, Santos F, Carbajo E, Rodriguez J, Alvarez J, Cobo A (2001). Exacerbated inflammatory response induced by insulin-like growth factor-I treatment in rats with ischemic acute renal failure. J Am Soc Nephrol 12: 1900–1907.
  • Ganrot PO (1986). Metabolism and possible health effects of aluminum. Environ Health Perspect 65: 363–441.
  • Garrec J, Monari A, Assfeld X, Mir LM, Tarek M (2014).  Lipid peroxidation in membranes: the peroxyl radical does not float. J Phys Chem Lett 5: 1653–1658.
  • Gawish M (2005). Histological study of the effect of zinc sulphate on the toxicity of aluminium sulphate in liver and kidney of male albino rats. Egyptian J Hosp Med (EJHM) 19: 189–197.
  • Güçlü M, Serin E (2004). Mikroskopik kolit. Güncel Gastroenterol 8: 104–110 (in Turkish).
  • Honda H, Ueda M, Kojima S, Mashiba S, Hirai Y, Hosaka N, Suzuki H, Mukai M, Watanabe M, Takahashi K et al. (2009). Assessment of myeloperoxidase and oxidative α1-antitrypsin in patients on hemodialysis. Clin J Am Soc Nephrol 4: 142–151.
  • Hussein MSH, Azza H, Abd-El-Rahman H, Mohamed ET (2010). The protective effect of vitamin E against the neurotoxic effect of aluminum chlorid in male albino rat. J Am Sci 6: 978–991.
  • Ichikawa I, Kiyama S, Yoshioka T (1994). Renal antioxidant enzymes: their regulation and function. Kidney Int 45: 1–9.
  • Jones DP (2008). Radical-free biology of oxidative stres. Am J Physiol Cell Physiol 295: 849–868.
  • Karabulut-Bulan O, Bayrak BB, Arda-Pirincci P, Sarikaya-Unal G, Us H, Yanardag R. (2015). Role of exogenous melatonin on cell proliferation and oxidant/antioxidant system in aluminum- induced renal toxicity. Biol Trace Elem Res doi: 10.1007/ s12011-015-0320-9.
  • Karbownik M, Reiter RJ (2000). Antioxidative effects of melatonin in protection against cellular damage caused by ionizing radiation. Proc Soc Exp Biol Med 22: 9–22.
  • Khattab FKI (2007). Histological and ultrastructural studies on the testis of rat after treatment with aluminium chloride. Aus J Basic Appl Sci 1: 63–72.
  • Kierszenbaum AL (2006). Histoloji ve Hücre Biyolojisi Patolojiye Giriş. İstanbul, Turkey: Palme Yayıncılık (in Turkish).
  • Klein GL (1993). Aluminum and hepatobiliary complications of total parenteral nutrition. Gastroenterology 104: 1583–1584.
  • Krewski D, Yokel RA, Nieboer E, Borchelt D, Cohen J, Harry J, Kacew S, Lindsay J, Mahfouz AM, Rondeau V (2007). Human health risk assessment for aluminum, aluminum oxide and aluminum hydroxide. J Toxicol Environ Health B Crit Reviews 10: 1–269.
  • Kruidenier L, Kuiper I, Duijn W, Mieremet-Ooms MAC, Hogezand RA, Lamers CBHW, Verspaget HW (2003). Imbalanced secondary mucosal antioxidant response in inflammatory bowel disease. J Pathol 201: 17–27.
  • Kruidenier L, Verspaget HW (2002). Oxidative stress as a pathogenic factor in inflammatory bowel disease—radicals or ridiculous? Aliment Pharmacol Ther 16: 1997–2015.
  • Ledwozyw A, Michalak J, Stepien A, Kadziolka A (1986). The relationship between plasma triglycerides, cholesterol, total lipids and lipid peroxidation products during human atherosclerosis. Clin Chim Acta 155: 275–283.
  • Lerner A (2007). Aluminum is a potential environmental factor for Crohn’s disease induction. Ann N Y Acad Sci 1107: 329–345.
  • Li JY, Yin HZ, Gu X, Zhou Y, Zhang WH, Qin YM (2008). Melatonin protects liver from intestine ischemia reperfusion injury in rats. World J Gastroenterol 14: 7392–7396.
  • Loria V, Dato I, Grazian F, Biasucci LM (2008). Myeloperoxidase: a new biomarker of inflammation in ischemic heart disease and acute coronary syndromes. Mediators Inflamm 1155: 1–4.
  • Lowry OH, Rosebrough WI, Farr AL, Randall RJ (1951). Protein measurement with the folin phenol reagent. J Biol Chem 193: 265–275.
  • Ma P, Yan B, Zeng Q, Liu X, Wu Y, Jiao M, Liu C, Wu J, Yang X (2014). Oral exposure of Kunming mice to diisononyl phthalate induces hepatic and renal tissue injury through the accumulation of ROS. Protective effect of melatonin. Food Chem Toxicol 68: 247–256.
  • Mahmoud ME, Elsoadaa SS (2013). Protective effect of ascorbic acid, biopropolis and royal jelly against aluminum toxicity in rats. J Nat Sci Res 3: 102–111.
  • Malekshah AK, Torabizadeh Z, Naghshwar F (2005). Developmental toxicity of aluminum from high doses of AlCl3 in mice. J Appl Res 5: 575–579.
  • Mercan U (2004). Importance of free radicals in toxicology. YYU Vet Fak Derg 15: 91–96 (article in Turkish with an abstract in English).
  • Merle A, Delagrange PH, Renard P, Lesieur D, Cuber JC, Roche M, Pellissier S (2000). Effect of melatonin on motility pattern of small intestine in rats and its inhibition by melatonin receptor antagonist S 22153. J Pineal Res 29: 116–124.
  • Millán JL (2006). Alkaline phosphatases: structure, substrate specificity and functional relatedness to other members of a large superfamily of enzymes. Purinergic Signal 2: 335–341.
  • Millan-Plano S, Piedrafita E, Miana-Mena FJ, Fuentes-Broto L, Martinez-Ballarin E, Lopez-Pingarron L, Saenz MA, Garcia JJ (2010). Melatonin and structurally-related compounds protect synaptosomal membranes from free radical damage. Int J Mol Sci 11: 312–328.
  • Mylorie AA, Collins H, Umbles C, Kyle J (1986). Erythrocyte superoxide dismutase activity and other parameters of copper status in rats ingesting lead acetate. Toxicol Appl Pharmacol 82: 512–520.
  • Nayak P (2002). Aluminum: impacts and disease. Environ Res 89: 101–115.
  • Nazıroğlu M (2012). Molecular role of catalase on oxidative stress- induced Ca2+ signaling and TRP cation channel activation in nervous system. J Recept Signal Transduct Res 32: 134–141.
  • Nazıroğlu M, Tokat S, Demirci S (2012). Role of melatonin on electromagnetic radiation-induced oxidative stress and Ca2+ signaling molecular pathways in breast cancer. J Recept Signal Transduct Res 32: 290–297.
  • Nordberg M (1998). Metallothioneins: historical review and state of knowledge. Talanta 46: 243–253.
  • Oktay E (2001). İnflamatuvar barsak hastalıkları: etyopatogenez, semptomatoloji, tanı ve komplikasyonları. İ.Ü. Cerrahpaşa Tıp Fakültesi Sürekli Tıp Eğitimi Etkinlikleri Gastrointestinal Sistem Hastalıkları Sempozyumu, 11–12 Ocak 2001, İstanbul, 199–206 (in Turkish).
  • Oktay S, Alev B, Tunali S, Emekli-Alturfan E, Tunali-Akbay T, Koc- Ozturk L, Yanardag, R, Yarat A (2015). Edaravone ameliorates the adverse effects of valproic acid toxicity in small intestine. Hum Exp Toxicol 34: 654–661.
  • Paglia DE, Valentine WN (1967). Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70: 158–169.
  • Perl DP, Fogarty U, Harpaz N, Sachar DB (2004). Bacterial-metal interactions: the potential role of aluminum and other trace elements in the etiology of Crohn’s disease. Inflamm Bowel Dis 10: 881–883.
  • Reiter RJ, Guerrero JM, Escames G, Pappolla MA, Acuña-Castroviejo (1997). Prophylactic actions of melatonin in oxidative neurotoxicity. Ann N Y Acad Sci 825: 70–78.
  • Reiter RJ, Tan DX, Gitto E, Sainz RN, Mayo JC, Leon J, Manchester LC, Vijayalaxmi, Kilic E, Kilic U (2004). Pharmacological utility of melatonin in reducing oxidative cellular and molecular damage. Pol J Pharmacol 56: 159–170.
  • Reiter RJ, Tan DX, Mayo JC, Sainz RM, Leon J, Czarnocki Z (2003). Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochim Pol 50: 1129–1146.
  • Ridderstap AS, Bonting SL (1969). Na+-K+ activated ATPase and exocrine pancreatic secretion in vitro. Am J Physiol 217: 1721– 1727.
  • Salido EM, Bordone M, De Laurentiis A, Chianelli M, Keller Sarmiento MI, Dorfman D, Rosenstein RE (2013). Therapeutic efficacy of melatonin in reducing retinal damage in an experimental model of early type 2 diabetes in rats. J Pineal Res 54: 179–189.
  • Sartor RB (2006). Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol 3: 390–407.
  • Schetinger MRC, Bonan CD, Morsch VM, Bohrer D, Valentim LM, Rodrigues SR (1999). Effects of aluminum sulfate on delta– aminolevulinate dehydratase from kidney, brain, and liver of adult mice. Braz J Med Biol Res 32: 761–766.
  • Sharma V, Sharma S, Pracheta SS (2011). Lead induced hepatotoxicity in male Swiss albino mice the protective potential of the hydromethanolic extract of Withania somnifera. Int J Pharm Sci Rev Res 7: 116–121.
  • Sido B, Seel C, Hochlehnert A, Breitkreutz R, Dröge W (2006). Low intestinal glutamine level and low glutaminase activity in Crohn’s disease: a rational for glutamine supplementation? Dig Dis Sci 51: 2170–2179.
  • Silva VS, Duarte AI, Rego AC, Oliveira CR, Gonçalves PP (2005). Effect of chronic exposure to aluminium on isoform expression and activity of rat (Na+/K+)ATPase. Toxicol Sci 88: 485–494.
  • Silva VS, Oliveira L, Gonçalves PP (2013). Alteration of aluminium inhibition of synaptosomal (Na+/K+) ATPase by colestipol administration. J Inorg Biochem 128: 208–214.
  • Sumathi T, Shobana C, Thangarajeswari M, Usha R (2015). Protective effect of L-theanine against aluminium induced neurotoxicity in cerebral cortex, hippocampus and cerebellum of rat brain - histopathological, and biochemical approach. Drug Chem Toxicol 38: 22–31.
  • Turgut S, Bor-Kucukatay M, Emmungil G, Atsak P, Turgut G (2007). The effects of low dose aluminum on hemorheological and hematological parameters in rats. Arch Toxicol 81: 11–17.
  • Vardi N, Iraz M, Öztürk F, Gül M, Uçar M, Çetin A, Nalçaci N, Otlu A (2007). Improving effects of melatonin against on the histologic alterations of rat liver in diabetes. Türkiye Klinikleri J Med Sci 27: 641–648 (article in Turkish with an abstract in English).
  • Walter K, Schütt C (1974). Acid and alkaline phosphatase in serum (two point method) Methods of Enzymatic Analysis. Vol. 2. Bergmeyer HU editor, Boca Raton, FL, USA: Verlag Chemie GmbH, pp. 856–860.
  • Wendel A (1981). Glutathione peroxidase. Methods Enzymol 77: 325–333.
  • Wroblewski F (1957). Clinical significance of serum enzyme alterations associated with myocardial infarction. Am Heart J 54: 219–224.
  • Yenigül E (2006). Alüminyum ve bazı organik asitlerin etkileşiminin spektrometrik ve kromatografik yöntemlerle tayini. Yüksek lisans tezi, Yıldız Teknik Üniversitesi Fen Bilimleri Enstitüsü (in Turkish).
  • Yokel RA, McNamara PJ (2001) Aluminium toxicokinetics: an updated minireview. Pharmacol Toxicol 88: 159–167.
  • Zatta P, Kissb T, Suwalsky M, Berthon G (2002). Aluminium(III) as a promoter of cellular oxidation. Coord Chem Rev 228: 271–284.
  • Zhou G, Xu Y, Li J, Yang L, Liu JY (2006). Molecular analyses of the metallothionein gene family in rice (Oryza sativa L.). J Biochem Mol Biol 39: 595–606.
Turkish Journal of Biology-Cover
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Sayıdaki Diğer Makaleler

Melatonin is a potent modulator of antioxidative defense and cellular proliferation against aluminum toxicity in rats

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