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Morin a flavonoid exerts antioxidant potential in chronic hyperammonemic rats: a biochemical and histopathological study

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Abstract

Plant flavonoids are emerging as potent therapeutic drugs effective against a wide range of free radical-mediated diseases. Morin (3,5,7,2′,4′-pentahydroxyflavone), a member of flavonols, is an important bioactive compound by interacting with nucleic acids, enzymes and protein. In this study, we found that morin (30 mg/kg body weight) by oral administration offers protection against hyperammonemia by means of reducing blood ammonia, oxidative stress and enhancing antioxidant status in ammonium chloride-induced (100 mg/kg body weight; i.p) hyperammonemic rats. Enhanced blood ammonia, plasma urea, lipid peroxidation in circulation and tissues (liver and brain) of ammonium chloride-treated rats was accompanied by a significant decrease in the tissues levels of superoxide dismutase (SOD), catalase, reduced glutathione (GSH) and glutathione peroxidase (GPx). Morin administered rats showed a significant reduction in ammonia, urea, lipid peroxidation with a simultaneous elevation in antioxidant levels. Cotreatment with morin prevented the elevation of liver marker enzymes induced by ammonium chloride. The body weight of the animals decreased significantly on ammonium chloride administration when compared with control group. However, cotreatment with morin significantly prevented the decrease of the body weight caused by ammonium chloride. Hyperammonemic rats show liver fibrosis, steatosis, sinusoidal dilatation, etc., along with necrosis, microcystic degeneration in brain. All these changes were reduced in hyperammonemic rats treated with Morin, which too correlated with the biochemical observations. In conclusion, these findings indicate that morin exert antioxidant potential and offer protection against ammonium chloride-induced hyperammonemia. But the exact underlying mechanism needs to be elucidated.

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References

  1. Monfort P, Felipo V (2005) Long-term potentiation in hippocampus involves sequential activation of soluble guanylate cyclase, cGMP-dependent protein kinase and cGMP-degrading phosphodiesterase, alterations in hyperammonemia. BMC Pharmacol 5:66. doi:10.1186/1471-2210-5-S1-P66

    Article  Google Scholar 

  2. Yu BP (1994) Cellular defenses against damage from reactive oxygen species. Physiol Rev 74:139–162

    PubMed  CAS  Google Scholar 

  3. Halliwell B, Gutteridge JMC (1999) Free radicals in biology and medicine. Oxford University Press, Oxford

    Google Scholar 

  4. Steinberg D, Parathasarathy S, Carew TE, Khow JC, Wiatum JL (1989) Modifications of low density lipoproteins that increase its atherogenicity. N Engl J Med 320:915–918

    PubMed  CAS  Google Scholar 

  5. Hilgier W, Albrecht J, Lisy V, Stastny F (1994) The effect of acute and repeated hyperammonemia on gamma-glutamyl transpeptidase in homogenates and capillaries of various rat brain regions. Mol Chem Neuropathol 13:47–56

    Google Scholar 

  6. Kosenko E, Kaminsky A, Valencia M, Lee L, Hermenegildo C, Felipo V (1997) Superoxide production and antioxidant enzymes in ammonia intoxication in rats. Free Radic Res 27:637–644. doi:10.3109/10715769709097867

    Article  PubMed  CAS  Google Scholar 

  7. Lena PJ, Subramanian P (2004) Effects of melatonin on the levels of antioxidants and lipid peroxidation products in rats treated with ammonium acetate. Pharmazie 59:636–639

    PubMed  CAS  Google Scholar 

  8. Majeed KI (2005) Hyperammonemia is associated with an increase in inhibitory neurotransmission as a consequence of two factors. Med J 2:2–15

    Google Scholar 

  9. Essa MM, Subramanian P (2006) Pongamia pinnata modulates oxidant–antioxidant imbalance during hyperammonemic rats. Fundam Clin Pharmacol 3:299–303. doi:10.1111/j.1472-8206.2006.00410.x

    Article  CAS  Google Scholar 

  10. Srinivasan K, Muruganandan S, Lal J, Chandra S, Tandan SK, Prakash VR (2001) Evaluation of anti-inflammatory activity of Pongamia pinnata leaves in rats. J Ethnopharmacol 78:151–157. doi:10.1016/S0378-8741(01)00333-6

    Article  PubMed  CAS  Google Scholar 

  11. Das KD (1994) Naturally occurring flavonoids: structure, chemistry, and high-performance liquid chromatography methods for separation and characterization. Methods Enzymol 234:410–420. doi:10.1016/0076-6879(94)34111-7

    Article  PubMed  CAS  Google Scholar 

  12. Holiman PCH, Hertog MGL, Katanc MB (1996) Analysis and health effects of flavonoids. Food Chem 57:43–46. doi:10.1016/0308-8146(96)00065-9

    Article  Google Scholar 

  13. Harborne JB, Williams CA (2000) Advances in flavonoid research since 1992. Phytochemistry 55:481–504. doi:10.1016/S0031-9422(00)00235-1

    Article  PubMed  CAS  Google Scholar 

  14. Hou YC, Chao PDL, Ho HJ, Wen CC, Hsiu SL (2003) Profound difference in pharmacokinetics between morin and its isomer quercetin in rats. J Pharm Pharmacol 55:199–203. doi:10.1211/002235702487

    Article  PubMed  CAS  Google Scholar 

  15. Windholz M (1989) The Merck index, 11th edn. Merck & Co., Inc., Rahway, pp 986–987

    Google Scholar 

  16. Wijeratne SSK, Abou-Zaid MM, Shahidi F (2006) Antioxidant polyphenols in almond and its coproducts. J Agric Food Chem 54:312–318. doi:10.1021/jf051692j

    Article  PubMed  CAS  Google Scholar 

  17. Aggarwal BB, Shishodia S (2006) Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol 71:1397–1421. doi:10.1016/j.bcp.2006.02.009

    Article  PubMed  CAS  Google Scholar 

  18. Lotito SB, Frei B (2006) Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon? Free Radic Biol Med 41:1727–1746. doi:10.1016/j.freeradbiomed.2006.04.033

    Article  PubMed  CAS  Google Scholar 

  19. Xie MX, Long M, Liu Y, Qin C, Wang YD (2006) Characterisation of the interaction of human serum albumin and morin. Biochim Biophys Acta 1760:1184–1191

    PubMed  CAS  Google Scholar 

  20. Francis AR, Shetty TK, Bhattacharya RK (1989) Modulating effect of plant flavonoids on the mutagenicity of N-methyl-N-nitro-N-nitrosoguanidine. Carcinogenesis 10:1953–1955. doi:10.1093/carcin/10.10.1953

    Article  PubMed  CAS  Google Scholar 

  21. Hanasaki Y, Ogawa S, Fukui S (1994) The correlation between active oxygens scavenging and antioxidative effects of flavonoids. Free Radic Biol Med 16:845–850. doi:10.1016/0891-5849(94)90202-X

    Article  PubMed  CAS  Google Scholar 

  22. Fang SH, Hou YC, Chang WC, Hsiu SL, Chao PD, Chiang BL (2003) Morin sulfates/glucuronides exert anti-inflammatory activity on activated macrophages and decreased the incidence of septic shock. Life Sci 74:743–756. doi:10.1016/j.lfs.2003.07.017

    Article  PubMed  CAS  Google Scholar 

  23. Cook NC, Samman SJ (1996) Flavonoids: chemistry, metabolism, cardioprotective effects and dietary sources. Nutr Biochem 7:66–76. doi:10.1016/0955-2863(95)00168-9

    Article  CAS  Google Scholar 

  24. Middleton JRE, Kandaswami C, Theoharides TC (2000) The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease and cancer. Pharmacol Rev 52:673–751

    PubMed  CAS  Google Scholar 

  25. Brown J, O’Prey J, Harrison PR (2003) Enhanced sensitivity of human oral tumours to the flavonol, morin, during cancer progression: involvement of the Akt and stress kinase pathways. Carcinogenesis 24:171–177. doi:10.1093/carcin/24.2.171

    Article  PubMed  CAS  Google Scholar 

  26. Yu ZF, Fong WP, Cheng CHK (2006) The dual actions of morin (3, 5, 7, 2′, 4′-penta-hydroxyl flavone) as a hypouricemic agent: uricosuric effect and xanthine oxidase inhibitory activity. J Pharmacol Exp Ther 316:169–175. doi:10.1124/jpet.105.092684

    Article  PubMed  CAS  Google Scholar 

  27. Cao J, Boucher W, Theoharides TC, Kempuraj D, Madhappan B, Christodoulou S (2005) Flavonoids inhibit proinflammatory mediator release, intracellular calcium ion levels, and protein kinase C theta phosphorylation in human mast cells. Br J Pharmacol 145:934–944. doi:10.1038/sj.bjp.0706268

    Article  PubMed  CAS  Google Scholar 

  28. Kuo HM, Chang LS, Lin YL, Lu HF, Yang JS, Lee JH, Chung (2007) Morin inhibits the growth of human leukemia HL-60 cells via cell cycle arrest and induction of apoptosis through mitochondria dependent pathway. Anticancer Res 27:395–406

    PubMed  CAS  Google Scholar 

  29. Hodek P, Trefil P, Stiborova M (2002) Flavonoids-potent and versatile biologically active compounds interacting with cytochromes P450. Chem Biol Interact 139:1–21. doi:10.1016/S0009-2797(01)00285-X

    Article  PubMed  CAS  Google Scholar 

  30. Lee SF, Lin JK (1997) Inhibitory effects of phytopolyphenols on TPA induced transformation, PKC activation, and c-Jun expression in mouse fibroblast cells. Nutr Cancer 28:177–183

    Article  PubMed  CAS  Google Scholar 

  31. Iwase Y, Takemura Y, Juichi M, Mukainaka T, Ichiishi E, Ito C, Furukawa H, Yano M, Tokuda H, Nishino H (2001) Inhibitory effect of flavonoid derivatives on Epstein-Barr virus activation and two-stage carcinogenesis of skin tumors. Cancer Lett 173:105–109. doi:10.1016/S0304-3835(01)00615-2

    Article  PubMed  CAS  Google Scholar 

  32. Kawabata K, Tanaka T, Honjo S, Kakumoto M, Hara A, Makita H, Tatematsu N, Ushida J, Tsuda H, Mori H (1999) Chemopreventive effect of dietary flavonoid morin on chemically induced rat tongue carcinogenesis. Int J Cancer 83:381–386. doi:10.1002/(SICI)1097-0215(19991029)83:3<381::AID-IJC14>3.0.CO;2-X

    Article  PubMed  CAS  Google Scholar 

  33. Song YM, Kang JW, Zhou J, Wang ZH, Lua XQ, Wang LF, Gao JZ (2000) Study on the fluorescence spectra and electrochemical behavior of ZnL2 and morin with DNA. Spectrochim Acta A Mol Biomol Spectrosc 56:2491–2497. doi:10.1016/S1386-1425(00)00340-1

    Article  Google Scholar 

  34. Cheng CHK (1997) In vitro and in vivo inhibitory actions of morin on rat brain phosphatidylinositolphosphate kinase activity. Life Sci 61:2035–2047. doi:10.1016/S0024-3205(97)00862-X

    Article  PubMed  CAS  Google Scholar 

  35. Subash S, Subramanian P, Sivaperumal R (2007) Antihyperammonemic effect of morin: a dose dependent study. Cell Tissue Res 7:1043–1046

    CAS  Google Scholar 

  36. Wolheim DF (1984) Preanalytical increase of ammonia in blood specimens from healthy subjects. Clin Chem 30:906–908

    Google Scholar 

  37. Varley H, Gowenlock AH, Bell M (1998) Practical clinical biochemistry, 4th edn, vol 1. CBS Publishers, New Delhi, pp 161–210

  38. Reitman S, Frankel AS (1957) A colorimetric method for the determination of serum glutatmic oxaloacetic and glutamic pyruvic transaminases. Am J Clin Pathol 28:56–63

    PubMed  CAS  Google Scholar 

  39. King E, Armstrong AR (1934) Determination of serum and bile phosphatase activity. Can Med Assoc J 31:376–378

    CAS  Google Scholar 

  40. Yagi K (1987) Lipid peroxides and human disease. Chem Phys Lipids 45:337–351. doi:10.1016/0009-3084(87)90071-5

    Article  PubMed  CAS  Google Scholar 

  41. Fraga CG, Leibovitz BF, Toppel AL (1988) Lipid peroxidation measured as TBARS in tissue slices. Characterization and comparison with homogenate and microsomes. Free Radic Biol Med 4:155–161. doi:10.1016/0891-5849(88)90023-8

    Article  PubMed  CAS  Google Scholar 

  42. Jiang ZY, Hunt JV, Wolff SP (1992) Ferrous ion oxidation in the presence of xylenol orange for detection of lipid hydroperoxides in low-density lipoprotein. Anal Biochem 202:384–389. doi:10.1016/0003-2697(92)90122-N

    Article  PubMed  CAS  Google Scholar 

  43. Kakkar P, Das B, Viswanathan PN (1984) A modified spectrophotometric assay of SOD. Indian J Biochem Biophys 21:130–132

    PubMed  CAS  Google Scholar 

  44. Sinha KA (1972) Colorimetric assay of catalase. Anal Biochem 47:389–394. doi:10.1016/0003-2697(72)90132-7

    Article  PubMed  CAS  Google Scholar 

  45. Ellman GC (1959) Tissue sulfhydyl groups. Arch Biochem Biophys 82:70–77. doi:10.1016/0003-9861(59)90090-6

    Article  PubMed  CAS  Google Scholar 

  46. Rotruck JT, Pope AL, Ganther HE, Swason AB (1973) Selenium: biochemical role as a component of glutathione peroxidase. Science 179:588–590. doi:10.1126/science.179.4073.588

    Article  PubMed  CAS  Google Scholar 

  47. Lowry OH, Rosebrough MJ, Farr AL, Randall RJ (1951) Protein measurement with Folin-phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  48. Nelson DL, Cox MM (2000) Lehninger principles of biochemistry. Macmillan, London

    Google Scholar 

  49. Fedele E, Jin Y, Varnier G, Raiteri M (1996) In vivo microdialysis study of a specific inhibitor of soluble guanylyl cyclase on the glutamate receptor/nitric oxide/cyclic GMP pathway. Br J Pharmacol 119:590–594

    PubMed  CAS  Google Scholar 

  50. Gottlieb M, Leal-Campanario R, Campos-Esparza MR, Sanchez-Gomez MV, Alberdi E, Arranz A, Delqado-Garcia JM, Gruart A, Matutea C (2006) Neuroprotection by two polyphenols following excitotoxicity and experimental ischemia. Neurobiol Dis 23:374–386

    Article  PubMed  CAS  Google Scholar 

  51. Bartosikova L, Necas J, Suchy V, Jankovsa E, Bartosik T, Klusakova J, Jurica J, Florian T, Frydrych M, Krcmar J, Frana P, Franova J (2006) Morin in the therapy of the ischemia-reperfusion damage model of the rat kidney. Ceska Slov Farm 55:78–83

    PubMed  CAS  Google Scholar 

  52. Beal MF (1992) Role of excitotoxicity in human neurological disease. Curr Opin Neurobiol 2:657–662. doi:10.1016/0959-4388(92)90035-J

    Article  PubMed  CAS  Google Scholar 

  53. Kosenko E, Kaminski Y, Lopata O, Muravyov N, Felipo V (1999) Blocking NMDA receptors prevents the oxidative stress induced by acute ammonia intoxication. Free Radic Biol Med 26:1369–1374. doi:10.1016/S0891-5849(98)00339-6

    Article  PubMed  CAS  Google Scholar 

  54. Choi DW (1987) Ionic dependence of glutamate neurotoxicity. J Neurosci 7:369–379

    PubMed  CAS  Google Scholar 

  55. Manev H, Favaron M, Guidotti A, Costa E (1989) Delayed increase of Ca influx elicited by glutamate: role in neuronal death. Mol Pharmacol 36:106–112

    PubMed  CAS  Google Scholar 

  56. Hermenegildo C, Monfort P, Felipo V (2000) Activation of N-methyl-d-aspartate receptors in rat brain in vivo following acute ammonia intoxication: characterization by in vivo brain microdialysis. Hepatology 31:709–715. doi:10.1002/hep.510310322

    Article  PubMed  CAS  Google Scholar 

  57. Hensley K, Tabatabaie T, Stewart CA, Pye Q, Floyd RA (1997) Nitric oxide and derived species as toxic agents in stroke, AIDS dementia, and chronic neurodegenerative disorders. Chem Res Toxicol 10:527–532. doi:10.1021/tx960132z

    Article  PubMed  CAS  Google Scholar 

  58. Schliess F, Gorg B, Fischer R, Desjardins P, Bidmon HJ, Herrmann A, Butterworth RF, Zilles K, Haussinger D (2002) Ammonia induces MK-801-sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes. FASEB J 16:739–741

    PubMed  CAS  Google Scholar 

  59. Norenberg MD, Rama Rao KV, Jayakumar AR (2004) Ammonia neurotoxicity and the mitochondrial permeability transition. J Bioenerg Biomembr 36:303–307. doi:10.1023/B:JOBB.0000041758.20071.19

    Article  PubMed  CAS  Google Scholar 

  60. Affany A, Salvayre R, Douste-Blazy L (1987) Comparison of the predictive effect of various flavonoids against lipid peroxidation of erythrocyte membranes (induced by cumen hydroperoxide). Fundam Clin Pharmacol 1:451–457

    PubMed  CAS  Google Scholar 

  61. Kok LDS, Wong YP, Wu TW, Chan HC, Kwok TT, Fung KP (2000) Morin hydrate A potential antioxidant in minimizing the free-radicals-mediated damage to cardiovascular cells by anti-tumor drugs. Life Sci 67:91–99. doi:10.1016/S0024-3205(00)00605-6

    Article  PubMed  CAS  Google Scholar 

  62. Jagetia GC, Rajanikant GK, Rao SK, Baliga MS (2003) Alteration in glutathione, glutathione peroxidase, superoxide dismutase, and lipid peroxidation by ascorbic acid in the skin of mice exposed to fractionated gamma radiation. Clin Chim Acta 332:111–121. doi:10.1016/S0009-8981(03)00132-3

    Article  CAS  Google Scholar 

  63. Makris DP, Rossiter JT (2002) Hydroxyl free radical-mediated oxidative degradation of quercetin and morin: a preliminary investigation. J Food Compost Anal 15:103–113. doi:10.1006/jfca.2001.1030

    Article  CAS  Google Scholar 

  64. Rahman I, MacNee W (1999) Lung glutathione and oxidative stress: implications in cigarette smoking-induced airway disease. Am J Physiol 277:1067–1088

    Google Scholar 

  65. Jagetia GC, Reddy TK, Kedlaya R (2004) Influence of naringin on ferric iron induced oxidative damage in vitro. Clin Chim Acta 347:189–197. doi:10.1016/j.cccn.2004.04.022

    Article  PubMed  CAS  Google Scholar 

  66. Bartosikova L, Necas J, Suchy V, Kubinova R, Vesela D, Benes L, Bartosik T, Illek J, Salplachta J, Klusakova J, Bartosova L, Strnadova V, Frana P, Franova J (2003) Monitoring of antioxidative effect of morine in alloxan-induced diabetes mellitus in the laboratory rat. Acta Vet Brno 72:191–200

    CAS  Google Scholar 

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Acknowledgement

S. Subash gratefully acknowledge the financial assistance awarded by the Indian Council of Medical Research (ICMR), New Delhi, India, in the form of Senior Research Fellowship.

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Correspondence to Perumal Subramanian.

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Subash, S., Subramanian, P. Morin a flavonoid exerts antioxidant potential in chronic hyperammonemic rats: a biochemical and histopathological study. Mol Cell Biochem 327, 153–161 (2009). https://doi.org/10.1007/s11010-009-0053-1

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