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The protective effects of MPLC isolated glycyrrhizin and mangiferin against brain toxicity in rats

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Abstract

The present study was conducted to demonstrate a method for preparative isolation of glycyrrhizin and mangiferin using medium-pressure liquid chromatography (MPLC) and to further investigate their protective effects against aluminum-induced brain toxicity in rats compared to melatonin (classical neuroprotective drug). Brain toxicity was determined through assessment of lipid profile, B-cell lymphoma 2 (Bcl2), Bcl-2-associated X protein (Bax), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), lipid peroxide (malondialdehyde), nitric oxide (NO), cytokines level such as tumor necrosis factor-alpha (TNF-α) and interleukins (IL-22 and IL-1β), as well as gene expression of brain SOD, CAT, and IL-22. Glycyrrhizin and mangiferin were isolated employing reverse phase MPLC and their structures were confirmed using NMR spectroscopy. Glycyrrhizin and/or mangiferin alone or in combination, as well as melatonin co-treatment prior to AlCl3 entoxication in rats revealed significant amelioration in all biochemical parameters relevant to brain function. Enhanced brain functions in AlCl3 intoxicated rats was attributed to a mechanism related to their antioxidant and anti-inflammatory potential.

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References

  • Afkhami-Goli A, Noorbakhsh F, Keller A, Vergnolle N, Westaway D, Jhamandas J, Andrade-Gordon P, Hollenberg MD, Arab H, Dyck R (2007) Proteinase-activated receptor-2 exerts protective and pathogenic cell type-specific effects in Alzheimer’s disease. J Immunol 179:5493–5503

    Article  CAS  PubMed  Google Scholar 

  • Al-Kahtani A (2010) Renal damage mediated by oxidative stress in mice treated with aluminium chloride: protective effects of taurine. J Biol Sci 10(7):584–95

    Article  CAS  Google Scholar 

  • Al-Olayan EM, El-Khadragy MF, Abdel Moneim AE (2015) The protective properties of melatonin against aluminium-induced neuronal injury. Int J Exp Pathol 96:196–202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allain CC, Poon LS, Chan CG, Richmond WC, Fu PC (1974) Enzymatic determination of total serum cholesterol. Clin Chem 20:470–475

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Chainy GB, Samanta L, Rout NB (1996) Effect of aluminum on superoxide dismutase, catalase and lipid peroxidation of rat liver. Res Commun Mol Pathol Pharmacol 94:217–220

    CAS  PubMed  Google Scholar 

  • Chanarin I (1989) Text book of laboratory haematology: an account of laboratory techniques. Churchill Livingstone, New York, NY

    Google Scholar 

  • Corti A, Fassina G, Marcucci F, Barbanti E, Cassani G (1992) Oligomeric tumour necrosis factor α slowly converts into inactive forms at bioactive levels. Biochem J 284:905–910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cory S, Jerry MA (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2:647–656

    Article  CAS  PubMed  Google Scholar 

  • Curreli F, Alvin EF, Ornella F (2005) Glycyrrhizic acid alters kaposi sarcoma--associated herpesvirus latency, triggering p53-mediated apoptosis in transformed B lymphocytes. J Clin Invest 115:642–652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Daeiparizi N, Baghizadeh A, Mehrabani M (2010) The percent of extract and glycyrrhizin content of glycyrrhiza glabra root grown in kerman province and some samples from fars province by HPLC method. J Kerman Univ Med Sci 17:316–327

    Google Scholar 

  • Dua R, Gill KD (2001) Aluminium phosphide exposure: implications on rat brain lipid peroxidation and antioxidant defence system. Basic Clin Pharmacol Toxicol 89:315–319

    Article  CAS  Google Scholar 

  • Escames G, Guerrero JM, Reiter RJ, Garcia JJ, Munoz-Hoyos A, Ortiz GG, Oh CS (1997) Melatonin and vitamin e limit nitric oxide-induced lipid peroxidation in rat brain homogenates. Neurosci Lett 230:147–150

    Article  CAS  PubMed  Google Scholar 

  • Esterbauer H, Rudolf JS, Helmward Z (1991) Chemistry and biochemistry of 4-Hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11:81–128

    Article  CAS  PubMed  Google Scholar 

  • Exley C (2004) The pro-oxidant activity of aluminum. Free Radic Biol Med 36:380–387

    Article  CAS  PubMed  Google Scholar 

  • Falholt K, Lund B, Falholt W (1973) An easy colorimetric micromethod for routine determination of free fatty acids in plasma. Clin Chim Acta 46:105–111

    Article  CAS  PubMed  Google Scholar 

  • Fossati P, Prencipe L (1982) Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem 28:2077–2080

    CAS  PubMed  Google Scholar 

  • Friedewald WT, Robert IL, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502

    CAS  PubMed  Google Scholar 

  • Geyikoglu F, Hasan T, Tülay OB, Mustafa C (2013) The genotoxic, hepatotoxic, nephrotoxic, haematotoxic and histopathological effects in rats after aluminium chronic intoxication. Toxicol Ind Health 29:780–791

    Article  CAS  PubMed  Google Scholar 

  • Guerri C, Grisolia S (1980) Influence of prolonged ethanol intake on the levels and turnover of alcohol and aldehyde dehydrogenases and glutathione. In: Begleiter H. (eds) Biological Effects of Alcohol, Advances in Experimental Medicine and Biology, vol 126. Springer, Boston, MA, 365–384

  • Guha S, Ghosal S, Chattopadhyay U (1996) Antitumor, immunomodulatory and anti-hiv effect of mangiferin, a naturally occurring glucosylxanthone. Chemotherapy 42:443–451

    Article  CAS  PubMed  Google Scholar 

  • Haleagrahara N, Julian V, Srikumar C (2011) Cardioprotective effects of glycyrrhizic acid against isoproterenol-induced myocardial ischemia in rats. Int J Mol Sci 12:7100–7113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Halliwell B, Gutteridge JM (1999) Free radicals,‘reactive species’ and toxicology. Free Radicals in Biology and Medicine. Oxford University Press, New York, NY, pp 544–616

    Google Scholar 

  • Kawahara M, Midori K (2011) Link between aluminum and the pathogenesis of Alzheimer’s disease: the integration of the aluminum and amyloid cascade hypotheses. Int J Alzheimer’s Dis 2011:1–17

    Google Scholar 

  • Lee C, Park S, Kim YS, Kang SS, Kim JA, Lee SH, Lee S (2007) Protective mechanism of glycyrrhizin on acute liver injury induced by carbon tetrachloride in mice. Biol Pharm Bull 30:1898–1904

    Article  CAS  PubMed  Google Scholar 

  • Leiro J, Arranz JA, Yáñez M, Ubeira FM, Sanmartin ML, Orallo F (2004) Expression profiles of genes involved in the mouse nuclear factor-kappa b signal transduction pathway are modulated by mangiferin. Int Immunopharmacol 4:763–78

    Article  CAS  PubMed  Google Scholar 

  • León J, Escames G, Rodr’iguez MI, López LC, Tapias V, Entrena A, Camacho E, Carrión MD, Gallo MA, Espinosa A (2006) Inhibition of neuronal nitric oxide synthase activity by N1-acetyl-5-methoxykynuramine, a brain metabolite of melatonin. J Neurochem 98:2023–2033

    Article  PubMed  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  • Lu D, Zhang S, Wang J, Li H, Dai Y (2008) Adsorption separation of 3 β-D-monoglucuronyl-18 β - glycyrrhetinic acid from directional biotransformation products of glycyrrhizin. Afr J Biotechnol 7:3995–4003

    CAS  Google Scholar 

  • Lukiw WJ, Maire EP, Theo PK (2005) Nanomolar aluminum induces pro-inflammatory and pro-apoptotic gene expression in human brain cells in primary culture.”. J Inorg Biochem 99:1895–1898

    Article  CAS  PubMed  Google Scholar 

  • Masibo M, He Q (2009) In-vitro antimicrobial activity and the major polyphenol in leaf extract of mangifera indica L. Malaysian. J Microbiol 5:73–80

    Google Scholar 

  • McLachlan DR, Theo PK, Walter JL, Sivarama SK (1991) Would decreased aluminum ingestion reduce the incidence of Alzheimer’s disease? CMAJ: Can Med Assoc J 145:793–805

    CAS  Google Scholar 

  • Miura T, Hiroyuki I, Hashimoto I, Iwamoto N, Kao M, Kubo M, Ishihara E, Komatsu Y, Okada M, Ishida T (2001a) Antidiabetic activity of a xanthone compound, mangiferin. Phytomedicine 8:85–87

    Article  CAS  PubMed  Google Scholar 

  • Miura T, Naoki I, Iwamoto N, Kato M, Ichiki H, Kubo M, Komatsu Y, Ishida T, Okada M, Tanigawa K (2001b) The suppressive effect of mangiferin with exercise on blood lipids in type 2 diabetes. Biol Pharm Bull 24:1091–1092

    Article  CAS  PubMed  Google Scholar 

  • Moneim AE (2012) Evaluating the potential role of pomegranate peel in aluminum-induced oxidative stress and histopathological alterations in brain of female rats. Biol Trace Elem Res 150:328–336

    Article  PubMed  Google Scholar 

  • Moshage H, Bart K, Johannes RH, Jansen PL (1995) Nitrite and nitrate determinations in plasma: a critical evaluation. Clin Chem 41:892–896

    CAS  PubMed  Google Scholar 

  • Muruganandan S, Gupta S, Kataria M, Lal J, Gupta PK (2002) Mangiferin protects the streptozotocin-induced oxidative damage to cardiac and renal tissues in rats. Toxicology 176:165–173

    Article  CAS  PubMed  Google Scholar 

  • Nehru B, Anand P (2005) Oxidative damage following chronic aluminium exposure in adult and pup rat brains. J Trace Elem Med Biol 19:203–208

    Article  CAS  PubMed  Google Scholar 

  • O’Barr S, James S, Joseph R (1996) Expression of the protooncogene Bcl-2 in Alzheimer’s disease brain. Neurobiol Aging 17:131–136

    Article  PubMed  Google Scholar 

  • Pfaffl MW, Graham WH, Leo D (2002) Relative expression software tool (rest©) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30:1–10

    Article  Google Scholar 

  • Prakash NT, Jagannatha R (1995) Modulations in antioxidant enzymes in different tissues of marine bivalve perna viridis during heavy metal exposure. Mol Cell Biochem 146:107–113

    Article  CAS  PubMed  Google Scholar 

  • Reiter RJ, Tan DX, Qi W, Manchester LC, Karbownik M, Calvo JR (2000) Pharmacology and physiology of melatonin in the reduction of oxidative stress in-vivo. Neurosignals 9(3–4):160–71

    Article  CAS  Google Scholar 

  • Reiter RJ, Tan DX, Manchester LC, Qi W (2001) Biochemical reactivity of melatonin with reactive oxygen and nitrogen species. Cell Biochem Biophys 34:237–256

    Article  CAS  PubMed  Google Scholar 

  • Reiter R, Lei T, Joaquin JG, Antonio M (1997) Pharmacological actions of melatonin in oxygen radical pathophysiology. Life Sci 60:2255–2271

    Article  CAS  PubMed  Google Scholar 

  • Sabbioni C, Mandrioli R, Ferranti A, Bugamelli F, Addolorata M, Cantelli G, Fanali S, Augusta M (2005) Separation and analysis of glycyrrhizin, 18 β -glycyrrhetic acid and 18 α-glycyrrhetic acid in liquorice roots by means of capillary zone electrophoresis. J Chromatogr A 1081:65–71

    Article  CAS  PubMed  Google Scholar 

  • Sánchez GM, Re L, Giuliani A, Nunez-Selles AJ, Davison GP, Leon-Fernandez OS (2000) Protective effects of Mangifera indica L. extract, mangiferin and selected antioxidants against TPA-induced biomolecules oxidation and peritoneal macrophage activation in mice. Pharmacol Res 42:565–573

    Article  PubMed  Google Scholar 

  • Schröfelbauer B, Raffetseder J, Hauner M, Wolkerstorfer A, Ernst W, Szolar OJ (2009) Glycyrrhizin, the main active compound in liquorice, attenuates pro-inflammatory responses by interfering with membrane-dependent receptor signalling. Biochem J 421:473–482

    Article  PubMed  Google Scholar 

  • Sellamuthu PS, Arulselvan P, Muniappan BP, Fakurazi S, Kandasamy M (2012) Nfluence of mangiferin on membrane bound phosphatases and lysosomal hydrolases in streptozotocin induced diabetic rats. Lat Am J Pharm 31:1013–1020

    CAS  Google Scholar 

  • Sellamuthu PS, Muniappan BP, Sathiya MP, Murugesan K (2009) Antihyperglycemic effect of mangiferin in streptozotocin induced diabetic rats. J Health Sci 55:206–214

    Article  CAS  Google Scholar 

  • Severi JA, Lima ZP, Kushima H, Brito AR, Lourdes CS, Wagner V, Hiruma-Lima CA (2009) Polyphenols with antiulcerogenic action from aqueous decoction of mango leaves (mangifera indica L.). Molecules 14:1098–1110

    Article  CAS  PubMed  Google Scholar 

  • Shiota G, Masato I, Yasushi T, Michiko O, Shunsuke K, Hisao I, Hironaka K (1999) Inhibition of hepatocellular carcinoma by glycyrrhizin in diethylnitrosamine-treated mice. Carcinogenesis 20:59–63

    Article  CAS  PubMed  Google Scholar 

  • Shitashige M, Toi M, Yano T, Shibata M, Matsuo Y, Shihasaki F (2001) Dissociation of Bax from a Bc1-2/Bax heterodimer triggered by phosphorylation of serine 70 of Bc1-2. J Biochem 130:741–748

    Article  CAS  PubMed  Google Scholar 

  • Sims JE, Smith DE (2010) The IL-1 family: regulators of immunity. Nat Rev Immunol 10:89–102

    Article  CAS  PubMed  Google Scholar 

  • Sinha AK (1972) Colorimetric assay of catalase. Anal Biochem 47:389–394

    Article  CAS  PubMed  Google Scholar 

  • Stacchiotti A, Borsani E, Ricci F, Lavazza A, Rezzani R, Bianchi R, Rodella LF (2006) Bimoclomol ameliorates mercuric chloride nephrotoxicity through recruitment of stress proteins. Toxicol Lett 166:168–177

    Article  CAS  PubMed  Google Scholar 

  • Stoilova I, Gargova S, Stoyanova A, Ho I (2005) Antimicrobial and antioxidant activity of the polyphenol mangiferin. Herba Pol 51:37–44

    CAS  Google Scholar 

  • Suttle NF (1986) Copper deficiency in ruminants; recent developments. Vet Rec 119:519–522

    Article  CAS  PubMed  Google Scholar 

  • Takeda S, Ishihara K, Wakui Y, Amagaya S, Maruno M, Akao T, Kobashi K (1996) Bioavailability study of glycyrrhetic acid after oral administration of glycyrrhizin in rats; relevance to the intestinal bacterial hydrolysis. J Pharm Pharmacol 48:902–905

    Article  CAS  PubMed  Google Scholar 

  • Tan DX, Manchester LC, Reiter RJ, Plummer BF, Hardies LJ, Weintraub ST, Shepherd AM (1998) A novel melatonin metabolite, cyclic 3-hydroxymelatonin: a biomarker of in-vivo hydroxyl radical generation. Biochem Biophys Res Commun 253:614–620

    Article  CAS  PubMed  Google Scholar 

  • Tomljenovic L (2011) Aluminum and Alzheimer’s disease: after a century of controversy, is there a plausible link? J Alzheimer’s Dis 23:567–598

    CAS  Google Scholar 

  • Verstraeten SV, Lucila A, Patricia IO (2008) Aluminium and lead: molecular mechanisms of brain toxicity. Arch Toxicol 82:789–802

    Article  CAS  PubMed  Google Scholar 

  • Verstraeten SV, Mari SG, Carl LK, Patricia IO (1997) Myelin is a preferential target of aluminum-mediated oxidative damage. Arch Biochem Biophys 344:289–294

    Article  CAS  PubMed  Google Scholar 

  • Wolk K, Stefanie K, Khusru A, Robert S (2002) Cutting edge: immune cells as sources and targets of the IL-10 family members? J Immunol 168:5397–5402

    Article  CAS  PubMed  Google Scholar 

  • Yokel RA, McNamara PJ (2001) Aluminium toxicokinetics: an updated minireview. Basic Clin Pharmacol Toxicol 88:159–167

    Article  CAS  Google Scholar 

  • Yoosook C, Bunyapraphatsara N, Boonyakiat Y, Kantasuk C (2000) Anti-herpes simplex virus activities of crude water extracts of thai medicinal plants. Phytomedicine 6:411–419

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Sylvia A. Boshra or Alaadin E. El-Haddad.

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Boshra, S.A., El-Haddad, A.E. The protective effects of MPLC isolated glycyrrhizin and mangiferin against brain toxicity in rats. Med Chem Res 27, 1449–1459 (2018). https://doi.org/10.1007/s00044-018-2162-4

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