OBJECTIVE: To assess and compare anti-inflammatory effect of pioglitazone and gemfibrozil by measuring C-reactive protein (CRP) levels in high fat fed non-diabetic rats.
METHODS: A comparative animal study was conducted at the Post Graduate Medical Institute, Lahore, Pakistan in which 27, adult healthy male Sprague Dawley rats were used. The rats were divided into three groups. Hyperlipidemia was induced in all three groups by giving hyperlipidemic diet containing cholesterol 1.5%, coconut oil 8.0% and sodium cholate 1.0%. After four weeks, Group A (control) was given distilled water, Group B was given pioglitazone 10mg/kg body weight and Group C was given gemfibrozil 10mg/kg body weight as single morning dose by oral route for four weeks. CRP was estimated at zero, 4th and 8th week.
RESULTS: There was significant increase in the level of CRP after giving high lipid diet from mean±SD of 2.59±0.28mg/L, 2.63±0.32mg/L and 2.67±0.23mg/L at 0 week to 3.55±0.44mg/L, 3.59±0.34mg/L and 3.6±0.32mg/L at 4th week in groups A, B and C respectively.
Multiple comparisons by ANOVA revealed significant difference between groups at 8th week only. Post hoc analysis disclosed that CRP level was significantly low in pioglitazone treated group having mean±SD of 2.93±0.33mg/L compared to control group’s 4.42±0.30mg/L and gemfibrozil group’s 4.28±0.39mg/L. The p-value in each case was <0.001, while difference between control and gemfibrozil was not statistically significant.
CONCLUSION: Pioglitazone is effective in reducing hyperlipidemia associated inflammation, evidenced by decreased CRP level while gemfibrozil is not effective.
KEY WORDS: Pioglitazone (MeSH); Gemfibrozil (MeSH); Hyperlipidemia (MeSH); Anti-inflammatory (MeSH); C-reactive protein (MeSH).
Mangge H, Becker K, Fuchs D, Gostner JM. Antioxidants, inflammation and cardiovascular disease. World J cardiol 2014 Jun 26;6(6):462-77. DOI: 10.4330/wjc.v6.i6.462
Ridker PM. Inflammation, C-reactive protein, and cardiovascular disease: moving past the marker versus mediator debate. Cir Res 2014 Feb 14;114(4):594-5. DOI: 10.1161/CIRCRESAHA.114.303215
Stancel N, Chen CC, Ke LY, Chu CS, Lu J, Sawamura T, et al. Interplay between CRP, atherogenic LDL, and LOX-1 and its potential role in the pathogenesis of atherosclerosis. Clin Chem 2016;62(2):320-7. DOI: 10.1373/clinchem.2015.243923
St-Onge MP, Zhang S, Darnell B, Allison DB. Baseline serum C-reactive protein is associated with lipid responses to low-fat and high-polyunsaturated fat diets. J Nutr 2009; 139(4):680-3. DOI: 10.3945/jn.108.098251
Rabkin SW, Langer A, Ur E, Calciu CD, Leiter LA. Inflammatory biomarkers CRP, MCP-1, serum amyloid alpha and interleukin-18 in patients with HTN and dyslipidemia: impact of diabetes mellitus on metabolic syndrome and the effect of statin therapy. Hypertens Res 2013;36(6):550-8. DOI: 10.1038/hr.2012.214
Cunningham ML, Collins BJ, Hejtmancik MR, Herbert RA, Travlos GS, Vallant MK, Stout MD. Effect of PPAR-α agonist and widely used antihyperlipidemic drug gemfibrozil on hepatic toxicity and lipid metabolism. PPAR Res 2010;2010:681963. DOI: 10.1155/2010/681963
Paumelle R, Staels B. Peroxisome proliferator- activated receptors mediate Pleiotropic action of statins. Circ Res 2007;100:1394-5. DOI: 10.1161/01.RES.0000269334.42814.d2
Sulaiman AA, Hussain SA, Jum'ma KM, Sigar AH. Evaluation of the anti-inflammatory effect of Pioglitazone in experimental models of inflammation in rats. Iraqi J Pharm Sci 2009:30;18(Suppl):1-6.
Genovese S, De Berardis G, Nicolucci A, Mannucci E, Evangelista V, Totani L, et al. Effect of pioglitazone versus metformin on cardiovascular risk markers in type 2 diabetes. Adv Ther 2013 Feb 1;30(2):190-202. DOI: 10.1007/s12325-013-0003-x
Shokouh P, Joharimoghadam A, Roohafza H, Sadeghi M, Golabchi A, Boshtam M, et al. Effects of pioglitazone on asymmetric dimethylarginine and components of the metabolic syndrome in nondiabetic patients (EPICAMP Study): a double-blind, randomized clinical trial. PPAR Res 2013;2013:358074. DOI: 10.1155/2013/358074
Grosso AF, de Oliveira SF, Higuchi Mde L, Favarato D, Dallan LA, da Luz PL. Synergistic anti-inflammatory effect: simvastatin and pioglitazone reduce inflammatory markers of plasma and epicardial adipose tissue of coronary patients with metabolic syndrome. Diabetol Metab Syndr 2014 March;31;6(1):47. DOI: 10.1186/1758-5996-6-47
Hussian M, Arain AQ, Chiragh S. Pioglitazone improves serum lipid profile in diet induced hyperlipidaemicnon diabetic rats. J Pak Med Assoc 2016 Oct;66(10):1286-90.
Darwish SA, Abdel-Azeim T, Noureldeen NM, Abou Zeid A, Toussoun N. Fructose induced metabolic syndrome in rats, A role for glitazones, fibrates and statins. Bull Alex Fac Med 2006;42(4):1182-90.
Kim, M. PAR-5359, a well balanced PPARα/γ dual agonist, exhibits equivalent antidiabetic and hypolipidemic activities in vitro and in vivo. Eur J Pharmacol 2008 Oct 24;595(1-3):119-25. DOI: 10.1016/j.ejphar.2008.07.066.
Willeit P, Thompson SG, Agewall S, Bergström G, Bickel H, Catapano AL, et al. Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration. Eur J Prev Cardiol 2016;23(2):194-205. DOI: 10.1177/2047487314560664
Shrivastava AK, Singh HV, Raizada A, Singh SK. C-reactive protein, inflammation and coronary heart disease. Egyptian Heart J 2015;67(2):89-97.
Roberts CK, Barnard RJ, Sindhu RK, Jurczak M, Ehdaie A, Vaziri ND. A high-fat, refined-carbohydrate diet induces endothelial dysfunction and oxidant/antioxidant imbalance and depresses NOS protein expression. J Appl Physiol 2005 Jan;98(1):203-10. DOI: 10.1152/japplphysiol.00463.2004
Xu J, Nie M, Li J, Xu Z, Zhang M, Yan Y, et al. Effect of pioglitazone on inflammation and calcification in atherosclerotic rabbits. Herz 2017. DOI: 10.1007/s00059-017-4620-z
Moon JH, Kim HJ, Kim SK, Kang ES, Lee BW, Ahn CW, et al. Fat redistribution preferentially reflects the anti-inflammatory benefits of pioglitazone treatment. Metabolism 2011;60(2):165-72. DOI: 10.1016/j.metabol.2009.12.007
Sakatani Y, Miyoshi T, Oe H, Nakamura K, Saito Y, Morita H, et al. Pioglitazone prevents endothelial dysfunction induced by ischemia and reperfusion via up-regulating anti-oxidative effects: a human study. Eur Heart J 2013 ;34(suppl_1): P590.
Bhatt S. Adiponectin receptor: a potential target for diabetes, obesity and other disorders. Pharmacologyonline 2010;1:117-30.
Ohashi K, Ouchi N, Matsuzawa Y. Anti-inflammatory and anti-atherogenic properties of adiponectin. Biochimie 2012 Oct 31;94(10):2137-42. DOI: 10.1016/j.biochi.2012.06.008