Crocin Improves Lipid Dysregulation in Subacute Diazinon Exposure through ERK1/2 Pathway in Rat Liver

P. Lari; M. Rashedinia; K. Abnous; H. Hosseinzadeh

doi:10.1055/s-0033-1357196

Drug Research, Table of Contents

Drug Res (Stuttg) 2014; 64(6): 301-305
DOI: 10.1055/s-0033-1357196

Original Article

Crocin Improves Lipid Dysregulation in Subacute Diazinon Exposure through ERK1/2 Pathway in Rat Liver

P. Lari

¹Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

,

M. Rashedinia

¹Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

,

K. Abnous

²Department of Medicinal Chemistry, Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

,

H. Hosseinzadeh

³Department of Pharmacodynamy and Toxicology, Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

› Author Affiliations

Abstract

Introduction: Diazinon Yis one of the most broadly used organophosphorus insecticides in agriculture. It has been shown that exposure to diazinon may interfere with lipid metabolism. Moreover, the hypolipidemic effect of crocin has been established. Earlier studies revealed the major role of Extracellular signal-regulated kinase (ERK) pathways in low-density lipoprotein receptor (LDLr) expression. The aim of this study was to evaluate changes in the regulation of lipid metabolism, ERK and LDLr expression in the liver of rats exposed to subacute diazinon. Furthermore ameliorating effect of crocin on diazinon induced disturbed cholesterol homeostasis was studied.

Methods: 24 Rats were divided into 4 groups and received following treatments for 4 weeks; Corn oil (control), diazinon (15mg/kg per day, orally) and crocin (12.5 and 25mg/kg per day, intraperitoneally) in combination with diazinon (15mg/kg). The levels of cholesterol, triglyceride and LDL in blood of rats were analyzed. Moreover mRNA levels of LDLr and ERK1/2 as well as protein levels of total and activated forms of ERK1/2 in rat liver were evaluated by Western blotting and quantitative real time polymerase chain reaction analysis.

Results: Our data showed that subacute exposure to diazinon significantly increased concentrations of cholesterol, triglyceride and LDL. Moreover diazinon decreased ERK1/2 protein phosphorylation and LDLr transcript. Crocin reduced inhibition of ERK activation and diazinon-induced hyperlipemia and increased levels of LDLr transcript.

Conclusions: Crocin may be considered as a novel protective agent in diazinon-induced hyperlipemia through modulating of ERK pathway and increase of LDLr expression.

Key words

crocin - diazinon - extracellular signal-regulated kinase (ERK1/2) - hyperlipemia - LDL receptor - cholesterol

Full Text

References

References
1 Costa LG. Current issues in organophosphate toxicology. Clinica chimica Acta 2006; 366: 1-13
2 Galloway T, Handy R. Immunotoxicity of organophosphorous pesticides. Ecotoxicology 2003; 12: 345-363
3 Weber C, Noels H. Atherosclerosis. Current pathogenesis and therapeutic options. Nat Med 2011; 17: 1410-1422
4 Chang T-Y, Chang CC, Ohgami N et al. Cholesterol sensing, trafficking, and esterification. Annu Rev Cell Dev Biol 2006; 22: 129-157
5 Chiang JY. III. Bile acids and nuclear receptors. Am J Physiol-Endoc 2003; 284: 349-356
6 Kang S, Davis RA. Cholesterol and hepatic lipoprotein assembly and secretion. Biochim Biophys Acta 2000; 1529: 223-230
7 Bose C, Bhuvaneswaran C, Udupa KB. Age-related alteration in hepatic acyl-CoA: cholesterol acyltransferase and its relation to LDL receptor and MAPK. Mech Ageing Dev 2005; 126: 740-751
8 Iles KE, Wright MM, Cole MP et al. Fatty acid transduction of nitric oxide signaling: nitrolinoleic acid mediates protective effects through regulation of the ERK pathway. Free Radical Bio Med 2009; 46: 866-875
9 Roth G, Kotzka J, Kremer L et al. MAP kinases Erk1/2 phosphorylate sterol regulatory element-binding protein (SREBP) -1a at serine 117 in vitro. J Biol Chem 2000; 275: 33302-33307
10 Morikawa K, Kondo I, Kanamaru Y et al. A novel regulatory pathway for cholesterol degradation via lactostatin. Biochem Biophys Res Commun 2007; 352: 697-702
11 Mohamadpour AH, Ayati Z, Parizadeh MR et al. Safety evaluation of crocin (a constituent of saffron) tablets in healthy volunteers. Iran J Basic Med Sci 2013; 16: 39-46
12 Mohammadpour AH, Ramezani M, Anaraki NT et al. Development and validation of HPLC method for determination of crocetin, a constituent of saffron, in human serum samples. Iran J Basic Med Sci 2013; 16: 47-55
13 Rios J, Recio M, Giner R et al. An update review of saffron and its active constituents. Phytother Res 1996; 10: 189-193
14 Konoshima T, Takasaki M, Tokuda H et al. Crocin and crocetin derivatives inhibit skin tumour promotion in mice. Phytother Res 1998; 12: 400-404
15 Hosseinzadeh H, Karimi G, Niapoor M. Antidepressant effect of Crocus sativus L. stigma extracts and their constituents, crocin and safranal, in mice. Acta Hort 2004; 650: 435-445
16 Mehdizadeh R, Parizadeh MR, Khooei A-R et al. Cardioprotective Effect of Saffron Extract and Safranal in Isoproterenol-Induced Myocardial Infarction in Wistar Rats. Iran J Basic Med Sci 2013; 16: 56-63
17 Razavi M, Hosseinzadeh H, Abnous K et al. Crocin Restores Hypotensive Effect of Subchronic Administration of Diazinon in Rats. Iran J Basic Med Sci 2013; 16: 64-72
18 Hosseinzadeh H, Sadeghnia HR. Effect of safranal, a constituent of Crocus sativus (saffron), on methyl methanesulfonate (MMS) -induced DNA damage in mouse organs: an alkaline single-cell gel electrophoresis (comet) assay. DNA Cell Biol 2007; 26: 841-846
19 Asdaq SMB, Inamdar MN. Potential of Crocus sativus (saffron) and its constituent, crocin, as hypolipidemic and antioxidant in rats. Appl Biochem Biotechnol 2010; 162: 358-372
20 Lee I-A, Lee JH, Baek N-I et al. Antihyperlipidemic effect of crocin isolated from the fructus of Gardenia jasminoides and its metabolite crocetin. Biol Pharm Bull 2005; 28: 2106-2110
21 Sheng L, Qian Z, Zheng S et al. Mechanism of hypolipidemic effect of crocin in rats: crocin inhibits pancreatic lipase. Eur J Pharmacol 2006; 543: 116-122
22 Hadizadeh F, Mohajeri S, Seifi M. Extraction and purification of crocin from saffron stigmas employing a simple and efficient crystallization method. Pak J Biol Sci 2010; 13: 691-698
23 Ibrahim NA, El-Gamal BA. Effect of diazinon, an organophosphate insecticide, on plasma lipid constituents in experimental animals. J Biochem Mol Biol 2003; 36: 499-504
24 Kalender S, Ogutcu A, Uzunhisarcikli M et al. Diazinon-induced hepatotoxicity and protective effect of vitamin E on some biochemical indices and ultrastructural changes. Toxicology 2005; 211: 197-206
25 Maliwal BP, Guthrie FE. Interaction of insecticides with human plasma lipoproteins. Chemico-Biol Interact 1981; 35: 177-188
26 Kumar A, Middleton A, Chambers TC et al. Differential Roles of Extracellular Signal-regulated Kinase-1/2 and p38MAPK in Interleukin-1β-and Tumor Necrosis Factor-α-induced Low Density Lipoprotein Receptor Expression in HepG2 Cells. J Biol Chem 1998; 273: 15742-15748
27 Li C, Kraemer FB, Ahlborn TE et al. Induction of low density lipoprotein receptor (LDLR) transcription by oncostatin M is mediated by the extracellular signal-regulated kinase signaling pathway and the repeat 3 element of the LDLR promoter. J Biol Chem 1999; 274: 6747-6753
28 Nakahara M, Fujii H, Maloney PR et al. Bile acids enhance low density lipoprotein receptor gene expression via a MAPK cascade-mediated stabilization of mRNA. J Biol Chem 2002; 277: 37229-37234
29 Costet P. Molecular pathways and agents for lowering LDL-cholesterol in addition to statins. Pharmacol Ther 2010; 126: 263-278
30 Peschel D, Koerting R, Nass N. Curcumin induces changes in expression of genes involved in cholesterol homeostasis. J Nutr Biochem 2007; 18: 113-119
31 Kong W, Wei J, Abidi P et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 2004; 10: 1344-1351
32 Lu N, Li Y, Qin H. Gossypin up-regulates LDL receptor through activation of ERK pathway: a signaling mechanism for the hypocholesterolemic effect. J Agri Food Chem 2008; 56: 11526-11532
33 Sheng L, Qian Z, Zheng S et al. Mechanism of hypolipidemic effect of crocin in rats: Crocin inhibits pancreatic lipase. Eur J Pharmacol 2006; 543: 116-122
34 Luyong Z, Huifang J, Sudi Z et al. Effect of Crocins on Experimental Atherosclerosis Formation in Korean Quails. J China Pharma Univ 1999; 30: 383-386
35 Xu G, Yu S, Gong Z et al. Study of the effect of crocin on rat experimental hyperlipemia and the underlying mechanisms. China J materia medica 2005; 30: 369-372