The Therapeutic Effects of Quercetin in a Canine Model of Low-dose Lipopolysaccharide-Induced Sepsis Compared with Hydrocortisone

Document Type: Pharmacology

Authors

1 Department of Clinical Sciences, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran

2 Department of Clinical Sciences, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz,Iran

3 Department of Basic Sciences, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran

4 Department of Pathobiology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran

Abstract

BACKGROUND: Canine low-dose sepsis model provides a reliable setting to study innovative drugs. Li- popolysaccharides (LPS), a major constituent of bacterial outer membrane, have been demonstrated to play a critical role in the initiation of pathogenesis. Lipopolysaccharide-induced sepsis has been extensively studied in laboratory animals; but its importance has mainly remained unknown in dogs.
OBJECTIVES: The aim of the present survey was to examine the effectiveness of quercetin, along with hydrocortisone on clinical and hematological alterations, and organ failure (liver and heart) in low-dose lipo- polysaccharide-induced canine sepsis model.
METHODS: For this purpose, fifteen clinically healthy mixed dogs were randomly divided into three equal groups. Lipopolysaccharide (0.1 μg/kg, IV) was injected to dogs in group A (control). Group B was similar to group A, but quercetin bolus (2 mg/kg, IV, once) was injected 40 minutes after LPS injection. Group C was similar to group B; however, hydrocortisone bolus (2 mg/kg, IV, once) was administered instead of quercetin. Serum levels of glucose, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), creatine kinase isoenzyme muscle/brain (CK-MB), lactate dehydrogenase (LDH) and cardiac troponin I (cTn-I) concentration were measured by commercial kits.
RESULTS: In control group, red blood cells (RBCs), hemoglobin (Hb), and hematocrit (HCT) significant-  ly decreased and serum activities of AST, ALP, LDH, CK-MB, and plasma cTn-I significantly increased (P<0.05). RBCs, Hb, and HCT significantly increased in quercetin group, compared with hydrocortisone and control groups (P<0.05). Quercetin group significantly decreased LDH, CK-MB, and cTn-I compared with hydrocortisone and control groups (P<0.05). Quercetin significantly decreased AST in comparison to control group and ALP in comparison to hydrocortisone group, also (P<0.05).
CONCLUSIONS: These results suggest that quercetin protects RBCs in the early stages of sepsis and de- creases organs dysfunction (heart and liver), therefore it has a positive influence on sepsis and may be more effective than routine corticosteroid (hydrocortisone) therapy.

Keywords


Article Title [Persian]

اثرات درمانی کوئرستین در مدل سپسیس القایی با لیپوپلی‌ساکارید در دوز پایین در سگ و مقایسه آن با هیدروکورتیزون

Authors [Persian]

  • آلاله سلطانیان 1
  • بهمن مصلی نژاد 1
  • محمد راضی جلالی 2
  • حسین نجف زاده 3
  • مسعود قربانپور 4
1 گروه علوم درمانگاهی، دانشکده دامپزشکی شهید چمران اهواز، اهواز، ایران
2 گروه علوم درمانگاهی، دانشکده دامپزشکی دانشگاه شهید چمران اهواز، اهواز، ایران
3 گروه علوم پایه، دانشکده دامپزشکی دانشگاه شهید چمران اهواز، اهواز، ایران
4 گروه پاتوبیولوژی، دانشکده دامپزشکی دانشگاه شهید چمران اهواز، اهواز، ایران
Abstract [Persian]

زمینه: مدل سپسیس با دوز پایین در سگ، شرایط مناسبی را برای مطالعه داروهای جدید در دسترس قرار می‌دهد. لیپوپلی-ساکاریدها (LPS) ، یکی از اجزاء اصلی غشای بیرونی باکتری‌ها، نقش مهمی در شروع پاتوژنز بیماری دارند. سپسیس ناشی از القاء لیپوپلی‌ساکارید، تا حد زیادی در حیوانات آزمایشگاهی مطالعه شده است، اما اهمیت آن در سگ‌ها، عمدتا ناشناخته است. هدف: هدف از انجام تحقیق حاضر، ارزیابی تأثیرگذاری کوئرستین در مقایسه با هیدروکورتیزون، بر تغییرات بالینی، هماتولوژیکی و نارسایی اندام‌ها (کبد و قلب)، در مدل سپسیس القاء شده توسط لیپوپلی‌ساکارید با دوز پایین، در سگ بود. روش‌کار: بدین منظور، 15 قلاده سگ سالم از نظر بالینی و از نژاد مخلوط، به‌صورت تصادفی، به سه گروه مساوی تقسیم شدند. سگ‌های گروه A (کنترل)،LPS (g/kgμ 1/0 ،IV) را دریافت کردند. گروه B، مشابه گروه A بود، با این تفاوت که،40 دقیقه پس از تزریق LPS، کوئرستین (mg/kg 2، IV، یک‌بار) تزریق شد. گروه C، مشابه گروه B بود؛ با این تفاوت که به‌جای کوئرستین، هیدروکورتیزون (mg/kg 2، IV، یک‌بار)، تجویز شد. مقادیر سرمی گلوکز، پروتئین تام، آلبومین، ALT، AST، ALP، کراتین کیناز ایزوآنزیم ماهیچه/مغز (CK-MB)، LDH و تروپونین قلبی I (cTn-I)، با استفاده از کیت‌های تجاری اندازه‌گیری شدند. نتایج: در گروه کنترل، پس از تزریق LPS، کاهش معنی‌داری در تعداد تام گلبول‌های قرمز (RBCs)، هموگلوبین (Hb) و هماتوکریت(HCT) ؛ و هم‌چنین، افزایش معنی‌داری در فعالیت سرمی آنزیم‌های AST، ALP ، LDH ، ایزوآنزیم CK-MB و cTn-I نشان دادند) 05/0(P

Keywords [Persian]

  • سگ
  • هیدروکورتیزون
  • لیپوپلی ساکارید
  • کوئرستین
  • سپسیس
Afshari, M., Rahimmalek, M., Miroliaei, M. (2018) Variation in polyphenolic profiles, antioxidant and antimicrobial activity of different  achil- lea species as natural sources of antiglycative compounds. Chem Biodivers, 15(8), e1800075. https://doi.     org/10.1002/cbdv.     201800075.

PMID:  29779268.

Asgary, S., Naderi, G.H., Askari, M.S. (2005) Pro- tective effect of flavonoids against red blood cell hemolysis by free radicals. Exp Clin Cardi- ol, 10(2), 88-90. PMID: 19641665.

Balk,   R.A.   (2014)   Systemic   inflammatory re-


sponse syndrome (SIRS). Virulence, 5(1),  20-

26.   https://doi.   org/10.4161/viru.27135.

PMID: 24280933.

Baskurt, O.K., Gelmont, D., Meiselman, H.J. (1998) Red blood cell deformability in sepsis. Am J Respir Crit Care Med, 157(2), 421-427. https://doi. org/10.1164/ajrccm.157.2.9611103. PMID:  9476853.

Ceylan-Isik, A.F., Zhao, P., Zhang, B., Xiao, X., Su,

G. and Ren, J. (2010) Cardiac overexpression of metallothionein rescues cardiac contractile dysfunction and endoplasmic reticulum stress but not autophagy in sepsis. J Mol Cell Cardi- ol, 48(2), 367–378. https://doi. org/10.1016/j. yjmcc.2009.11.003.  PMID: 19914257.

Das, D.K., Chakraborty, A., Sinha, M., Manna, K., Mukherjee, D., Chakraborty, A., Bhattacharjee, S., Dey, S. (2013) Modulatory role of quer- cetin against gamma radiation-mediated bio- chemical and morphological alterations of red blood cells. Int J Radiat Biol, 89(6), 471-481. https://doi. org/10.3109/09553002.2013.76798 9.  PMID: 23363054.

De David, C., Rodrigues,  G.,  Bona,  S.,  Meur- er, L., Gonzalez-Gallego, J., Tunon, M.J. (2011) Role of quercetin in preventing thio- acetamide-induced liver injury in rats. Tox-  icol Pathol, 39(6), 949-957. https://doi. org/10.1177/0192623311418680.

PMID: 21885874.

De Vries, F., Leuschner, J., Jilma, B., Derhaschnig,

U. (2013) Establishment of a low dose canine endotoxemia model to test  anti-inflammato-  ry drugs: effects of prednisolone. Int J Immu- nopathol Pharmacol, 26(4), 861-869. https:// doi. org/ 10.1177/039463201302600404. PMID: 24355221.

Egert, S., Wolffram, S., Bosy-Westphal, A., Boesch-Saadatmandi, C., Wagner, A.E., Frank, J., Rimbach, G., Mueller, M.J. (2008) Daily quercetin supplementation dose-dependently increases plasma quercetin concentrations in healthy humans. J Nutr, 138(9), 1615-1621. https://doi. org/10.1093/jn/138.9.1615. PMID: 18716159.

Geraets, L., Moonen, H., Brauers, K., Wouters, E.F.,   Bast,  A.,   Hageman,   G.J.   (2007). Di-

 

 

 

etary flavones and flavonoles are inhibitors of poly(ADP-ribose)polymerase-1 in pulmonary epithelial cells. J Nutr, 137(10), 2190-2195. https://doi. org/10.1093/jn/137.10.2190. PMID: 17884996.

Goyette, R.E., Key, N.S., Ely, E.W. (2004) Hema- tologic changes in sepsis and their therapeu-  tic implications. Semin Respir Crit Care Med, 25(6), 645-659. https://doi. org/10.1016/10.105

5/s-2004-860979.  PMID: 16088507.

Ikizler, M., Erkasap, N., Dernek, S., Kural, T., Kaygisiz, Z. (2007) Dietary polyphenol quer- cetin protects rat hearts during reperfusion: en- hanced antioxidant capacity with chronic treat- ment. Anadolu Kardiyol Derg, 7(4),   404-410.

PMID: 18065337.

Javadi, B., Sahebkar, A. (2017) Natural products with anti-inflammatory and immunomodula- tory activities against autoimmune myocar- ditis. Pharmacol Res, 124, 34-42. https://doi. org/10.1016/j.phrs.2017.07.022.

PMID: 28757189.

Kitagawa, S., Sakamoto, H., Tano, H. (2004) In- hibitory effects of flavonoids on free radical-in- duced hemolysis and their oxidative effects on hemoglobin. Chem Pharm Bull (Tokyo), 52(8), 999-1001. https://doi. org/10.1248/cpb.52.999.

PMID: 15305001.

Landry, D.W., Oliver, J.A. (2001) The pathogene- sis of vasodilatory shock. N Engl J Med, 45(8), 588–595. https://doi. org/ 10.1056/NEJM- ra002709.  PMID: 11529214.

Liao, Y., Lin, J. (2015) Quercetin intraperitoneal ad- ministration ameliorates lipopolysaccharide-in- duced systemic inflammation in mice. Life Sci, 137(1),   89-97.   https://doi.  org/10.1016/j.lfs.

2015.07.015. PMID: 26209141.

Penalva, R., Gonzalez-Navarro, C.J., Gamazo, C., Esparza, I., Irache, J.M. (2017) Zein nanoparti- cles for oral delivery of quercetin: Pharmaco- kinetic studies and preventive anti-inflamma- tory effects in a mouse model of endotoxemia. Nanomedicine, 13(1), 103-110. https://doi. org/

10.1016/j.nano.2016.08.033. PMID: 27615118.

Punithavathi, V.R., Stanely Mainzen Prince, P. (2011) The cardioprotective effects of a com- bination of quercetin and α-tocopherol on   iso-


proterenol-induced myocardial infarcted rats. J Biochem Mol Toxicol, 25(1), 28-40. https://doi. org/  10.1002/jbt.20339.  PMID: 20979156.

Reinboth, M., Wolffram, S., Abraham, G., Unge- mach, F.R., Cermak, R. (2010) Oral bioavail- ability of quercetin from different quercetin glycosides in dogs. Br J Nutr, 104, 198-203. https://doi. org/ 10.1017/S000711451000053X. PMID:  20230651.

Rochwerg, B., Oczkowski, S.J., Siemieniuk, R.A.C., Agoritsas, T., Belley-Cote, E., D'Ara- gon, F., Duan, E., English, S., Gossack-Keenan, K., Alghuroba,  M.,  Szczeklik,  W., Menon, K.,  Alhazzani,  W., Sevransky,  J.,   Vandvik, P., Annane, D., Guyatt, G. (2018) Cortico- steroids in Sepsis: An Updated Systematic Review and Meta-Analysis. Crit Care Med, 46(9),  1411-1420.  https://doi.  org/   10.1097/

CCM.0000000000003262.  PMID:  29979221.

Shapiro, H., Lev, S., Cohen, J., Singer P. (2009) Polyphenols in the  prevention  and  treatment of sepsis syndromes: rationale and pre-clinical evidence. Nutrition, 25(10), 981-997. https:// doi. org/ 10.1016/j.nut.2009.02.010. PMID: 19502006.

Valentova, K., Sima, P., Rybkova, Z., Krizan, J., Malachova, K., Kren V. (2016) (Anti) muta- genic and immunomodulatory properties of quercetin glycosides. J Sci Food Agric, 96(5), 1492-1499.  https://doi. org/10.1002/jsfa.7251.

PMID:  25960089.

Vasquez-Garzon, V.R., Arellanes-Robledo, J., Garcia-Roman, R., Aparicio-Rautista, D.I., Villa-Trevino, S. (2009) Inhibition of reac-  tive oxygen species and pre-neoplastic lesions by quercetin through an antioxidant defense mechanism. Free Radic Res, 43(2), 128-137. https://doi. org/ 10.1080/10715760802626535. PMID: 19115120.

Virginia, D.V., Owen, H., Poapolathep, A., Mario,

G. (2017) Natural substances as new potential strategies for the treatment of  leishmaniosi- sin dogs. Am J Anim Vet Sci, 12(3), 169-175. https://doi.     org/10.3844/ajavsp.2017.169.175.

Volbeda, M., Wetterslev, J., Gluud, C., Zijlstra, J.G., van der Horst, I.C.C., Keus, F. (2015) Glu- cocorticosteroids for sepsis: systematic review with  meta-analysis  and  trial  sequential anal-

 

 

ysis. Intensive Care Med, 41(7), 1220-1234. https://doi. org/ 10.1007/s00134-015-3899-6. PMID: 26100123.

Wan,  Y.,   Tang,  M.H.,  Chen,  X.C.,  Chen,   L.J.,

Wei, Y.Q., Wang, Y.S. (2014) Inhibitory ef-  fect of liposomal quercetin  on  acute  hepati- tis and hepatic fibrosis induced by concanav- alin A. Braz J Med Biol Res, 47(8), 655-661. https://doi. org/10.1590/1414-431x20143704. PMID: 25098714.

Yang, H., Song, Y., Liang, Y.N., Li, R. (2018) Quer- cetin treatment improves renal function and protects the kidney in a rat model of adenine-in- duced chronic kidney disease. Med Sci Monit, 24,    4760-4766.    https://doi.    org/10.12659/

MSM.909259.  PMID: 29987270.

Yao, Z., Gu, Y., Zhang, Q., Liu, L., Meng, G., Wu,

H., Xia, Y., Bao, X., Shi, H., Sun, S., Wang, X.,

Zhou, M., Jia, Q., Wu, Y., Song, K., Gao, W., Guo, C., Niu, K. (2018) Estimated daily querce- tin intake and association with the prevalence of type 2 diabetes mellitus in Chinese adults. Eur J Nutr, 11(1), e0144179. https://doi. org/ 10.1007/ s00394-018-1713-2. PMID: 29754250.

Zhang, J., Shi, L., Xu, X., Huang, S., Lu, B., Ji, L. (2014) Therapeutic detoxification of quercetin against carbon tetrachloride-induced acute liver injury in mice and its mechanism. J Zhejiang Univ Sci B, 15(12), 1039-1047. https://doi. org/ 10.1631/jzus.B1400104. PMID: 25471833.