Ameliorative Action of Mn-Salen Derivatives on CCl₄-Induced Destructive Effects and Lipofuscin-Like Pigment Formation in Rats’ Liver and Brain: Post-Treatment of Young Rats with EUKs

Sakineh Meftah, Razieh Yazdanparast, Mahsa Molaei

Applied Chemistry Research Group, ACECR-Tehran Branch, Tehran, Iran; Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
Research Center Gastroenterology and Liver Disease, Shaheed Beheshti University of Medical Sciences and Academy of Medical Sciences, Tehran, Iran.

DOI: 10.4236/cellbio.2014.33010                

Abstract

Lipofuscin-like pigments (LFPs) are highly oxidized cross-linked aggregates of oxidized protein and lipids which are formed under oxidative state conditions by free radicals produced. The present study aimed to evaluate the probable ameliorative effects of some of the Mn-salens namely EUKs 8, 134, 15, 115, 122 and 132 (compounds 1-6) and vitamin C against carbon tetrachloride (CCl₄)-induced acute damage on rats’ livers and brains. Exposure to CCl₄ is believed to induce oxidative stress and cause tissue damage due to the formation of trichloromethyl (·CCl₃) and peroxy trichloromethyl (·OOCCl₃) radicals. In this study, 54 rats were randomly divided into 9 groups of six each: normal group received only vehicle (olive oil; 2 ml/kg b.w.) for 6 consecutive days; CCl₄- intoxicated group received the vehicle and CCl₄ (50% solution of CCl₄ in olive oil, 2 ml/kg b.w.) on the first and second days and the vehicle on the third to sixth days; test rats received Mn-salens or vitamin C (20 mg/kg b.w.) and CCl₄ (2 ml/kg b.w.) on the first and second days and Mn-salens or vitamin C (20 mg/kg b.w.) on the third to sixth days. Mn-salens administration ameliorated the effects of CCl₄ by decreasing the levels of ROS, lipid and protein oxidations and LFPs formation on liver and brain as well as cholesterol and triglycerides, aminotransferases and alkaline phosphatase contents in sera of rats whereas increased the activities of catalase, superoxide dismutase,glutathione reductase, glutathione peroxidase and reduced glutathione in liver and brain tissues. Histopathological studies confirmed the toxic effects of CCl₄ and ameliorative action of Mn-salens on tissues. These results suggest that the evaluated EUKs were able to attenuate LFPs accumulation and morphological changes caused by CCl₄ in rats and thus, confirming the ameliorative role of Mn-salens against CCl₄-induced oxidative damage and age-related diseases.

Keywords

Lipofuscin, Aging, Antioxidant, Mn-Salen Derivaties, Oxidative Stress

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Delori, F.C., Dorey, C.K., Staurenghi, G., Arend, O., Goger, D.G. and Weiter J.J. (1995) In Vivo Fluorescence of the Ocular Fundus Exhibits Retinal Pigment Epithelium Lipofuscin Characteristics. Investigative Ophthalmology & Visual Science, 36, 718-729.
[2]	Brunk, U.T. and Terman, A. (2002) Lipofuscin: Lipofuscin: Mechanisms of Age-Related Accumulation and Influence on Cell Function. Free Radical Biology and Medicine, 33, 611-619.
[3]	Yin, D. (1996) Biochemical Basis of Lipofuscin, Ceroid, and Age Pigment-Like Fluorophores. Free Radical Biology and Medicine, 21, 871-888.
[4]	Sparrow, J.R. and Boulton, M. (2005) RPE Lipofuscin and Its Role in Retinal Pathobiology. Experimental Eye Research, 80, 595-606.
[5]	Brunk, U.T. and Terman, A. (2004) Lipofuscin. International Journal of Biochemistry & Cell Biology, 36, 1400-1404.
[6]	Jung, T., Bader, N. and Grune, T. (2007) Lipofuscin: Formation, Distribution and Metabolic Consequences. Annals of the New York Academy of Sciences, 19, 97-111.
[7]	Brunk, U.T. and Terman, A. (2002) The Mitochondrial-Lysosomal Axis Theory of Aging Accumulation of Damaged Mitochondria as a Result of Imperfect Autophagocytosis. European Journal of Biochemistry, 269, 1996-2002.
[8]	Kalkan, Y., Kapakin, K.A., Kara, A., Atabay, T., Karadeniz, A., Simsek, N., Karakus, E., Can, I., Yildirim, S., Ozkanlar, S. and Sengul, E. (2011) Protective Effect of Panax Ginseng against Serum Biochemical Changes and Apoptosis in Liver of Rats Treated with Carbon Tetrachloride (CCl4). Journal of Hazardous Materials, 195, 208-213. http://dx.doi.org/10.1016/j.jhazmat.2011.08.027
[9]	Tripathi, S., Mahdi, A.A., Nawab, A., Chander. R., Hasan, M., Siddiqui, M.S., Mahdi, Mitra, K. and Bajpai, V.K. (2009) Influence of Age on Aluminum Induced Lipid Peroxidation and Neurolipofuscin in Frontal Cortex of Rat Brain: A Behavioral, Biochemical and Ultrastructural Study. Brain Research, 1253, 107-116. http://dx.doi.org/10.1016/j.brainres.2008.11.060
[10]	Castillo, T., Koop, D.R., Kamimura, S., Triadafilopoulos, G. and Tsukamoto, H. (1992) Role of Cytochrome P-450 2E1 in Ethanol-, Carbon Tetrachloride- and Iron-Dependent Microsomal Lipid Peroxidation. Hepatology, 16, 992-996.
[11]	Tirkey, N., Pilkhwal, S., Kuhad, A. and Chopra, K. (2005) Hesperidin, a Citrus Bioflavonoid, Decreases the Oxidative stress Produced by Carbon Tetrachloride in Rat Liver and Kidney. BMC Pharmacology, 5, 2-9. http://dx.doi.org/10.1186/1471-2210-5-2
[12]	Soni, B., Visavadiya, N.P. and Madamwar, D. (2008) Ameliorative Action of Cyanobacterial Phycoerythrin on CCl4- Induced Toxicity in Rats. Toxicology, 248, 59-65. http://dx.doi.org/10.1016/j.tox.2008.03.008
[13]	Pong, K., Doctrow, S.R., Huffman, K., Adinolfi, C.A. and Baudry, M. (2001) Attenuation of Staurosporine-Induced Apoptosis, Oxidative Stress, and Mitochondrial Dysfunction by Synthetic Superoxide Dismutase and Catalase Mimetics, in Cultured Cortical Neurons, in Cultured Cortical Neurons. Experimental Neurology, 171, 84-97.
[14]	Zhang, H.J., Doctrow, S.R., Xu, L., Oberley, L.W, Beecher, B., Morrison, J., Oberley, T.D. and Kregel, K.C. (2004) Redox Modulation of the Liver with Chronic Antioxidant Enzyme Mimetic Treatment Prevents Age-Related Oxidative Damage Associated with Environmental Stress. The FASEB Journal, 18, 547-1549.
[15]	Rong, Y., Doctrow, S.R., Tocco, G. and Baudry, M. (1999) EUK-134, a Synthetic Superoxide Dismutase and Catalase Mimetic, Prevents Oxidative Stress and Attenuates Kainate-Induced Neuropathology. Proceedings of the National Academy of Sciences of the United States of America, 96, 9897-9902. http://dx.doi.org/10.1073/pnas.96.17.9897
[16]	Rosenthal, R.A., Huffman, K.D., Fisette, L.W., Damphousse, C.A., Callaway, W.B., Malfroy, B. and Doctrow, S.R. (2009) Orally Available Mn Porphyrins with Superoxide Dismutase and Catalase Activities. JBIC: Journal of Biological Inorganic Chemistry, 14, 979-991. http://dx.doi.org/10.1007/s00775-009-0550-4
[17]	Peng, J., Stevenson, F.F., Doctrow, S.R. and Andersen, J.K. (2005) Superoxide Dismutase/Catalase Mimetics Are Neuroprotective against Selective Paraquat-Mediated Dopaminergic Neuron Death in the Substantial Nigra. The Journal of Biological Chemistry, 280, 29194-29198. http://dx.doi.org/10.1074/jbc.M500984200
[18]	Doctrow, S.R., Huffman, K., Marcus, C.B., Tocco, G., Malfroy, E., Adinolfi. C.A., Kruk, H., Baker, K., Lazarowych, N., Mascarenhas, J. and Malfroy, B. (2002) Salen-Manganese Complexes as Catalytic Scavengers of Hydrogen Peroxide and Cytoprotective Agents: Structure-Activity Relationship Studies. Journal of Medicinal Chemistry, 45, 4549-4558.
[19]	Lowry, O.H., Rosebrough, N.J., Farr, A.L. and Randall, R.J. (1951) Protein Measurement with the Folin Phenol Reagent. The Journal of Biological Chemistry, 193, 265-275.
[20]	Yazdanparast, R. and Ardestani, A. (2007) In Vitro Antioxidant and Free Radical Scavenging Activity of Cyperus rotundus. Journal of Medicinal Food, 10, 667-674. http://dx.doi.org/10.1089/jmf.2006.090
[21]	Draper, H.H. and Hadley, M. (1990) Malondialdehyde Determination as Index of Lipid Peroxidation. Methods Enzymol, 186, 421-431.
[22]	Reznick, A.Z. and Packer, L. (1994) Oxidative Damage to Proteins: Spectrophotometric Method for Carbonyl Assay. Methods in Enzymology, 233, 357-363.
[23]	Fletcher, B.L., Dillard, C.J. and Tappel, A.L. (1973) Measurement of Fluorescent Lipid Peroxidation Products in Biological Systems and Tissues. Analytical Biochemistry, 52, 1-9.
[24]	Aebi, H. (1984) Catalase in Vitro. Methods in Enzymology, 105, 121-126. http://dx.doi.org/10.1016/S0076-6879(84)05016-3
[25]	Kakkar, P. and Das, B. (1984) Viswanathan PN, A Modified Spectrophotometric Assay of Superoxide Dismutase. Indian Journal of Biochemistry & Biophysics, 21, 130-132.
[26]	Jollow, D.J., Mitchell, J.R., Zampaglione, N. and Gillette, J.R. (1974) Bromobenzene-Induced Liver Necrosis: Protective Role of Glutathione and Evidence for 3,4-Bromobenzeneoxide as the Hepatotoxic Intermediate. Pharmacology, 11, 151-169. http://dx.doi.org/10.1159/000136485
[27]	Paglia, D.E. and Valentine, W.N. (1967) Studies on the Quantitative and Qualitative Characterization of Erythrocyte Glutathione Peroxidase. Journal of Laboratory and Clinical Medicine, 70, 158-169.
[28]	Kleiner, D.E., Brunt, E.M., Van Natta, M., Behling, C., Contos, M.J., Cummings, O.W., Ferrell, L.D., Liu, Y.C., Torbenson, M.S. and Unalp-Arida, A. (2005) Design and Validation of a Histological Scoring System for Nonalcoholic Fatty Liver Disease. Hepatology, 41, 1313-1321.
[29]	Weber, L.W., Boll, M. and Stampfl, A. (2003) Hepatotoxicity and Mechanism of Action of Haloalkanes: Carbon Tetrachloride as a Toxicological Model. Chemico-Biological Interactions, 33, 105-136. http://dx.doi.org/10.1080/713611034
[30]	Jayakumar, T., Sakthive, M., Thomas, P.A. and Geraldine, P. (2008) Pleurotus ostreatus, an Oyster Mushroom, Decreases the Oxidative Stress Induced by Carbon Tetrachloride in Rat Kidneys, Heart and Brain. Chemico-Biological Interactions, 176, 108-120. http://dx.doi.org/10.1016/j.cbi.2008.08.006
[31]	Burk, R.F., Lane, J.M. and Patel, K. (1984) Relationship of Oxygen and Glutathione in Protection against Carbon Tetrachloride-Induced Hepatic Microsomal Lipid Peroxidation and Covalent Binding in the Rat. Rationale for the Use of Hyperbaric Oxygen to Treat Carbon Tetrachloride Ingestion. Journal of Clinical Investigation, 74, 1996-2001. http://dx.doi.org/10.1172/JCI111621
[32]	Mohammadi, M. and Yazdanparast, R. (2009) Methoxy VO-Salen Complex: In Vitro Antioxidant Activity, Cytotoxicity Evaluation and Protective Effect on CCl4-Induced Oxidative Stress in Rats. Food and Chemical Toxicology, 47, 716-721. http://dx.doi.org/10.1016/j.fct.2008.12.029
[33]	Manna, P., Sinha, M. and Sil, P.C. (2006) Aqueous Extract of Terminalia arjuna Prevents Carbon Tetrachloride Induced Hepatic and Renal Disorders. BMC Complementary and Alternative Medicine, 6, 33. http://dx.doi.org/10.1186/1472-6882-6-33
[34]	Rezazadeh, A., Yazdanparast, R. and Molaei, M. (2012) Amelioration of Diet-Induced Nonalcoholic Seatohepatitis in Rats by Mn-Salen Complexes via Reduction of Oxidative Stress. Journal of Biomedical Science, 19, 26. http://dx.doi.org/10.1186/1423-0127-19-26
[35]	Meftah, S., Sajadimajd, S. and Yazdanparast, R. (2013) Structure-Activity Relationship of 15 Different Mn-Salen Derivatives against Free Radicals. Drug and Chemical Toxicology, 36, 9-18. http://dx.doi.org/10.3109/01480545.2011.644560
[36]	Bayati, S., Yazdanparast, R., Majd, S.S. and Oh, S. (2011) Protective Effects of 1,3-Diaryl-2-Propen-1-One Derivatives against H2O2-Induced Damage in SK-N-MC Cells. Journal of Applied Toxicology, 31, 545-553. http://dx.doi.org/10.1002/jat.1594
[37]	Gutteridge, J.M. (1985) Inhibition of the Fenton Reaction by the Protein Ceruloplasmin and Other Copper Complex. Chemico-Biological Interactions, 56, 113-120.
[38]	Yazdanparast, R., Bahramikia, S. and Ardestani, A. (2008) Nasturtium Officinale Reduces Oxidative Stress and Enhances Antioxidant Capacity in Hypercholesterolaemic Rats. Chemico-Biological Interactions, 172, 176-184. http://dx.doi.org/10.1016/j.cbi.2008.01.006
[39]	Nwafor, P.A., Jacks, T.W. and Longe, O.O. (2004) Acute Toxicity Study of Methanolic Extract of Asparagus Pubescens Root in Rats. African Journal of Biomedical Research, 7, 19-21.
[40]	Akowuah, G.A., Zhari, I., Mariam, A. and Yam, M.F. (2009) Absorption of Andrographolides from Andrographis paniculata and Its Effect on CCl4-Induced Oxidative Stress in Rats. Food and Chemical Toxicology, 47, 2321-2326. http://dx.doi.org/10.1016/j.fct.2009.06.022
[41]	Chiu, C. and Taylo, A. (2011) Dietary Hyperglycemia, Glycemic Index and Metabolic Retinal Diseases. Progress in Retinal and Eye Research, 30, 18-53. http://dx.doi.org/10.1016/j.preteyeres.2010.09.001
[42]	Paget, C., Lecomte, M., Ruggiero, D., Wiernsperger, N. and Lagarde, M. (1998) Modification of Enzymatic Antioxidants in Retinal Microvascular Cells by Glucose or Advanced Glycation End Products. Free Radical Biology and Medicine, 25, 121-129. http://dx.doi.org/10.1016/S0891-5849(98)00071-9
[43]	Assuncao, M., Santos-Marques, M.J., Carvalho, F. and Andrade, J.P. (2010) Green Tea Averts Age-Dependent Decline of Hippocampal Signaling Systems Related to Antioxidant Defenses and Survival. Free Radical Biology and Medicine, 48, 831-838. http://dx.doi.org/10.1016/j.freeradbiomed.2010.01.003
[44]	Solomons, T.W.G. (1996) Organic Chemistry. 6th Edition, John Wiley & Sons Ltd., Hoboken, 675-693.