Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Inflammation
Published in: Journal of Inflammation 1/2015

Open Access 01-12-2015 | Research

Pentoxifylline reduces the inflammatory process in diabetic rats: relationship with decreases of pro-inflammatory cytokines and inducible nitric oxide synthase

Authors: Francisca Adilfa de Oliveira Garcia, Jéssica Farias Rebouças, Teresa Queiroz Balbino, Teresinha Gonçalves da Silva, Carlson Hélder Reis de Carvalho-Júnior, Gilberto Santos Cerqueira, Gerly Anne de Castro Brito, Glauce Socorro de Barros Viana

Published in: Journal of Inflammation | Issue 1/2015

Login to get access

Abstract

Studies suggest that inflammation is a key factor in the pathogenesis of diabetes mellitus. Pro-inflammatory cytokines, such as IL-6 and TNF-alpha, are produced by adipose tissue in large quantities, in obese and especially in diabetic individuals. Pentoxifylline (PTX) is a non-selective phosphodiesterase inhibitor with anti-inflammatory and antioxidant actions that may contribute to alleviate diabetes side effects, as neuropathy, retinopathy and nephropathy. This study aims to investigate PTX anti-inflammatory effects on the carrageenan-induced paw edema model, in alloxan-induced diabetic rats. Diabetic animals (male Wistar rats, 200–250 g) were daily treated with PTX (25, 50, 100 mg/kg, p.o.), glibenclamide (GLI, 5 mg/kg, p.o., as reference) or water, for 5 days. Afterwards, carrageenan-treated paws were dissected, their skin removed and the tissue used for preparation of homogenates and measurements of IL-6 and TNF-alpha by Elisa. Serum levels of nitrite were also determined and paw slices used for iNOS immunohistochemistry assays. We showed that diabetic rats presented an amplification of the inflammatory response, as related to non-diabetic rats, what was evident 48 h after the edema-induction. The PTX-treatment of diabetic rats reduced glycemia (as related to untreated-diabetic ones) and the paw edema. It also brought edema volumes to values similar to those of non-diabetic rats, at the same observation time. The increased TNF-alpha and IL-6 levels in paws of untreated-diabetic rats were reduced in diabetic animals after PTX treatments. Besides, the increased levels of nitrite in the serum of diabetic rats were also decreased by PTX. Furthermore, a higher number of iNOS immunostained cells was demonstrated in paw tissues from untreated-diabetic rats, as related to those of PTX-treated diabetic animals. Our results show that PTX reduces inflammatory parameters, as pro-inflammatory cytokines and iNOS expression, indicating the potential benefit of the drug for the treatment of diabetes and related pathologic conditions.
Literature
1.
Navarro JF, Mora C. Role of inflammation in diabetic complications. Nephrol Dial Transplant. 2005;20:2601–4.CrossRefPubMed
2.
Nakamura Y, Horii Y, Nishino T, Shiiki H, Sakaguchi Y, Kagoshima T, et al. Immunohistochemical localization of advanced glycosylation end products in coronary atheroma and cardiac tissue in diabetes mellitus. Am J Pathol. 1993;143:1649–56.PubMedCentralPubMed
3.
Ortiz A, Gonzalez-Cuadrado S, Bustos C, Alonso J, Homez-Guerrero C, Lopez-Armada MJ, et al. Tumor necrosis factor and glomerular damage. J Nephrol. 1995;8:27–34.
4.
Schmidt AM, Yan SD, Wautier JL, Stern DM. Activation of receptor for advanced glycation end products—a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ Res. 1999;84:489–97.CrossRefPubMed
5.
Romano M, Pomilio M, Vigneri S, Falco A, Chiesa PL, Chiarelli F, et al. Endothelial perturbation in children and adolescents with type 1diabetes: association with markers of the inflammatory reaction. Diabetes Care. 2001;24:1674–8.CrossRefPubMed
6.
Hayaishi-Okano R, Yamasaki Y, Katakami N, Ohtoshi K, Gorogawa S, Kuroda A, et al. Elevated C-reactive protein associates with early-stage carotida therosclerosis in young subjects with type 1 diabetes. Diabetes Care. 2002;25:1432–8.CrossRefPubMed
7.
Spranger J, Kroke A, Möhlig M, Hoffmann K, Bergman MM, Ristow MM, et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes. 2003;52:812–7.CrossRefPubMed
8.
King GL. The role of inflammatory cytokines in diabetes and its complications. J Periodontol. 2008;79:1527–34.CrossRefPubMed
9.
Chen TL, Xu EL, Lu HJ, Xu H, Wang SF, Zhao HJ, et al. The influence of diabetes enhanced inflammation on cell apoptosis and periodontitis. Adv Biosci Biotechnol. 2012;3:712–9.CrossRef
10.
Wisse BE. The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol. 2004;15:2792–800.CrossRefPubMed
11.
Bulló M, Garcia-Lorda P, Megias I, Salas-Salvadó J. Systemic inflammation, adipose tissue tumor necrosis fator and leptin expression. Obes Res. 2003;11:525–31.CrossRefPubMed
12.
Sattar N, Perry CG, Petrie JR. Type 2 diabetes as an inflammatory disorder. Br J Diabetes Vasc Dis. 2003;3:36–41.CrossRef
13.
Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259:87–91.CrossRefPubMed
14.
Sethi JK, Hotamisligil GS. The role of TNF-alpha in adipocyte metabolism. Semin Cell Dev Biol. 1999;10:19–29.CrossRefPubMed
15.
Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Investig. 1995;95:2409–15.CrossRefPubMedCentralPubMed
16.
17.
Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature. 1997;389:610–4.CrossRefPubMed
18.
Renke M, Tylicki L, Rutkowski P, Knap N, Zietkiewicz M, Neuwelt A, et al. Effect of pentoxifylline on proteinuria, markers of tubular injury and oxidative stress in non-diabetic patients, with chronic kidney disease-placebo controlled, randomized, cross-over study. Acta Biochim Pol. 2010;57:119–23.PubMed
19.
Hecht M, Müller M, Lohmann-Mathes ML, Emmendörffer A. In vitro and in vivo effects of pentoxifylline on macrophages and lymphocytes derived from autoimmune MRL-lpr/lpr mice. J Leukoc Biol. 1995;57:242–9.PubMed
20.
Pollice PF, Rosier RN, Looney RJ, Puzas JE, Schwarz EM, O’Keefe RJ. Oral pentoxifylline inhibits release of tumor necrosis factor-alpha from human peripheral blood monocytes: a potential treatment for aseptic loosening of total joint components. J Bone Joint Surg Am. 2001;83:1057–61.PubMed
21.
Luna T, Santos SB, Nascimento M, Porto MAF, Muniz AL, Carvalho EM, et al. Effect of TNF-alpha production inhibitors on the production of pro-inflammatory cytokines by peripheral blood mononuclear cells from HTLV-1-infected individuals. Braz J Med Biol Res. 2011;44:1134–40.CrossRefPubMedCentralPubMed
22.
Cooper A, Mikhail A, Lethbridge MW, Kemeny DM, Macdougall IC. Pentoxifylline improves hemoglobin levels in patients with erythropoietin-resistant anemia in renal failure. J Am Soc Nephrol. 2004;15:1877–82.CrossRefPubMed
23.
Bilsborough W, O’Driscoll G, Stanton K, Weerasooriya R, Dembo L, Taylor R, et al. Effect of lowering tumour necrosis factor-α on vascular endothelial function in type II diabetes. Clin Sci. 2002;103:163–9.CrossRefPubMed
24.
Dorner GT, Zawinka C, Resch H, Wolzt M, Schmetterer L, Garhofer G. Effects of pentoxifylline and alprostadil on ocular hemodynamics in health humans. Invest Olphtalmol Vis Sci. 2007;48:815–9.CrossRef
25.
Flint H, Cotter MA, Cameron NF. Pentoxifylline effects on nerve conduction velocity and blood flow in diabetic rats. Int J Exp Diabetes Res. 2000;1:49–58.CrossRefPubMedCentralPubMed
26.
Schwartz RW, Logan NM, Johnson PJ, Strodel WE, Fine JG, Kazmers A, et al. Pentoxifylline increases extremity blood flow in diabetixc atherosclerotic patients. Arch Surg. 1989;124:434–7.CrossRefPubMed
27.
Sonkin PL, Kelly LW, Sinclair SH, Hatcheli DL. Pentoxifylline increases retinal capillary blood flow velocity in patients with diabetes. Arch Olphthalmol. 1993;111:1647–52.CrossRef
28.
Pitocco D, Zaccardi F, Di Stasio E, Romitelli F, Santini AS, Zuppi C, et al. Oxidative stress, nitric oxide, and diabetes. Rev Diabet Stud. 2010. doi:10.1900/RDS. 2019.7.15.
29.
Guay J, Bateman K, Gordon R, Mancini J, Riendeau D. Carrageenan-induced paw edema in rat elicits a predominant prostaglandin E2 (PGE2) response in the central nervous system associated with the induction of microsomal PGE2 synthase-1. J Biol Chem. 2004;279:24866–72.CrossRefPubMed
30.
McCormick BB, Sydor A, Akbari A, Fergusson D, Doucette S, Knoll G. The effect of pentoxifylline on proteinuria in diabetic kidney disease: a meta-analysis. Am J Kidney Dis. 2008;52:454–63.CrossRefPubMed
31.
Navarro JF, Mora C, Rivero A, Gallego E, Chahin J, Macia M, et al. Urinary protein excretion and serum tumor necrosis factor in diabetic patients with advanced renal failure: effects of pentoxifylline administration. Am J Kidney Dis. 1999;33:458–63.CrossRefPubMed
32.
Navarro JF, Mora C, Muros M, Garcia J. Additive antiproteinuric effect of pentoxifylline in patients with type 2 diabetes under angiotensin II receptor blockade: a short-term, randomized, controlled trial. J Am Soc Nephrol. 2005;16:2119–26.CrossRefPubMed
33.
DiRosa M, Girould JP, Willoughby DA. Studies of mediators of the acute inflammatory response induced in rats in different sites by carrageenan and turpentine. J Pathol. 1971;104:15–29.CrossRef
34.
Siebert K, Zhang Y, Leahy K, Hauser S, Masferrer J, Perkins W, et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci U S A. 1994;91:12013–7.CrossRef
35.
Fantone JC, Ward PA. Role of oxygen-derived free radicals and metabolites in leukocyte-dependent inflammatory reactions. Ann J Pathol. 1982;107:397–418.
36.
Salvemini D, Wang Z-Q, Wyatt PS, Bourdon DM, Marino MH, Manning PT, et al. Nitric oxide: a key mediator in the early and late phase of carrageenan-induced rat paw inflammation. Br J Pharmacol. 1996;118:829–38.CrossRefPubMedCentralPubMed
37.
Vinegar R, Macklin AM, Truax JF, Selph JL. Histopathological and pharmacological study of carrageenin inflammation in the rat. Pharmacologist. 1971;13:284–90.
38.
Boughton-Smith NK, Deakin AM, Follenfant RL, Whittle BJR, Garland LG. Role of oxygen radicals and arachidonic acid metabolites in the reverse passive Arthus reaction and carrageenan paw oedema in the rat. Br J Pharmacol. 1993;110:896–902.CrossRefPubMedCentralPubMed
39.
Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev. 1991;43:109–41.PubMed
40.
41.
Francés DE, Ingarano PI, Ronco MT, Carnovale CE. Diabetes, an inflammatory process: oxidative stress and TNF-alpha involved in hepatic complication. J Biomed Sci Eng. 2013;6:645–53.CrossRef
42.
Donath MY, Schumann DM, Faulenbach M, Ellingsgaard H, Perren A, Ehses JA. Islet inflammation in type e diabetes: from metabolic stress to therapy. Diabetes Care. 2008;34 Suppl 2:S161–4.CrossRef
43.
Graves DT, Liu R, Alikhani M, Al-Mashat H, Trackman PC. Diabetes-enhanced inflammation and apoptosis- impact on periodontal pathology. J Dental Res. 2006;85:15–21.CrossRef
44.
Festa A, D’Agostino JR, Williams K, Karter AJ, Mayer-Davis EJ, Tracy RP, et al. The relation of body fat mass and distribution to marker of chronic inflammation. Int J Obes. 2000;25:1407–15.CrossRef
45.
Crook M. Type 2 diabetes mellitus: a disease of the innate immune system? An update. Diabet Med. 2004;21:203–7.CrossRefPubMed
46.
Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans. Role of oxidative stress. Circulation. 2002;106:2067–72.CrossRefPubMed
47.
Doherty GM, Jensen JC, Alexander HR, Buresh CM, Norton JA. Pentoxifylline suppression of tumor necrosis factor gene transcription. Surgery. 1991;110:192–8.PubMed
48.
DiPetrillo K, Gesek FA. Pentoxifylline ameliorates renal tumor necrosis factor expression, sodium retention, and renal hypertrophy in diabetic rats. Am J Nephrol. 2004;24:352–9.CrossRefPubMed
49.
50.
Loram LC, Fuller A, Fick LG, Cartmell T, Poole S, Mitchell D. Cytokine profiles during carrageenan-induced inflammatory hyperalgesia in rat muscle and hind paw. J Pain. 2007;8:127–36.CrossRefPubMed
51.
Seifi B, Kadkhodaee M, Delavari F, Mikaeili S, Shams S, Ostad SN. Pretreatment with pentoxifylline and N-acetylcysteine in liver ischemia reperfusion-induced renal injury. Ren Fail. 2012;34:610–5.CrossRefPubMed
52.
Barkhordari K, Karimi A, Shafiee A, Soltaninia H, Khatami MR, Abbasi K, et al. Effect of pentoxifylline on preventing acute kidney injury after cardiac surgery by measuring urinary neutrophil gelatinase - associated lipocalin. J Cardiothorac Surg. 2011;6:8. doi:10.1186/1749-8090-6-8.CrossRefPubMedCentralPubMed
53.
Sun HK, Lee YM, Han KH, Kim HS, Ahn SH, Han SY. Phosphodiesterase inhibitor improves renal tubulointerstitial hypoxia of the diabetic rat kidney. Korean J Intern Med. 2012;27:163–70.CrossRefPubMedCentralPubMed
54.
Lucchesi AN, Freitas NT, Cassetari LL, Marques SFG, Spadella CT. Diabetes mellitus triggers oxidative stress in the liver of alloxan-treated rats: a mechanism for diabetic chronic liver disease. Acta Cir Bras. 2013;28:502–8.CrossRefPubMed
55.
Ji Q, Zhang L, Jia H, Yang J, Xu J. Pentoxifylline inhibits endotoxin-induced NF-kappa B activation and associated production of proinflammatory cytokines. Ann Clin Lab Sci. 2004;34:427–36.PubMed
56.
57.
Fujimoto M, Shimizu N, Kunii K, Martyn JA, Ueki K, Kaneki M. A role for iNOS in fasting hyperglycemia and impaired insulin signaling in the liver of obese diabetic mice. Diabetes. 2005;54:1340–8.CrossRefPubMed
58.
Stevens RB, Sutherland DE, Ansite JD, Saxena M, Rossini TJ, Levay-Young BK, et al. Insulin down-regulates the inducible nitric oxide synthase pathway: nitric oxide as cause and effect of diabetes? J Immunol. 1997;159:5329–35.PubMed
59.
Johansen JS, Harris AK, Rychly DJ, Ergul A. Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice. Cardiovasc Diabetol. 2005;4:5. doi:10.1186/475-2840-4-5.CrossRefPubMedCentralPubMed
60.
Li D-L, Ma Z-Y, Fu Z-J, Ling M-Y, Yan C-Z, Zhang Y. Glibenclamide decreases ATP-induced intracellular calcium transient elevation via inhibiting reactive oxygen species and mitochondrial activity in macrophages. PLoS ONE. 2014;9:e89083.CrossRefPubMedCentralPubMed
61.
Schmid D, Svoboda M, Sorgner A, Moraycevic I, Thalhammer T, Chiba P, et al. Glibenclamide reduces pro-inflammatory cytokines in an ex vivo model of human endotoxinaemia under hypoxic conditions. Life Sci. 2011;89:725–34.CrossRefPubMed
62.
Cai J, Lu S, Yao Z, Deng Y-P, Zhang L-D, Yu J-W, et al. Glibenclamide attenuates myocardial injury by lipopolysaccharides in streptozotocin-induced diabetic mice. Cardiovasc Diabetol. 2014;13:106.CrossRefPubMedCentralPubMed
63.
Kewcharoenwong C, Rinchai D, Utispan K, Suwannasaen D, Bancroft GJ, Ato M, et al. Glibenclamide reduces pro-inflammatory cytokine production by neutrophils of diabetes patients in response to bacterial infection. Sci Rep. 2013;3:3363. doi:10.1038/srep03363.CrossRefPubMedCentralPubMed
64.
Koh CCKW, Maude RR, Schreiber MF, Limmathurotsakul D, Wiersinga WJ, Wuthiekanun V, et al. Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis. Clin Infect Dis. 2011;52:717–25.CrossRefPubMedCentralPubMed
65.
Sartoretto JL, Melo GA, Bersani-Amado CA, Oliuveira MA, Santos RA, Passaglia RT, et al. Chlorpropamide treatment restores the reduced carrageenan-induced paw edema and pleural exudate volume in diabetic rats. Inflamm Res. 2008;57:438–43.CrossRefPubMed
66.
Thompson MK, Tuma RF, Young WF. The effects of pentoxifylline on spinal cord blood flow after experimental spinal cord injury. J Assoc Acad Minor Phys. 1999;10:23–6.PubMed
67.
Vakili A, Mojarrad S. Effect of pentoxifylline on brain edema in a rat model of transient focal cerebral ischemia. Physiol Pharmacol. 2009;12:320–7.
68.
Elmarakby AA, Sullivan JC. Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. Cardiovasc Ther. 2012;30:49–59.CrossRefPubMed
69.
Radfar M, Larijani B, Hadjibabaie M, Rajabipour B, Mojtahedi A, Abdolhari M. Effects of pentoxifylline on oxidative stress and levels of EGF and NO in blood of diabetic type 2 patients: a randomized, double-blind placebo-controlled clinical trial. Biomed Pharmacother. 2005;59:302–6.CrossRefPubMed
70.
Maiti R, Agrawal NK, Dash D, Pandey BL. Effect of pentoxifylline on inflammatory burden, oxidative stress and platelet aggregability in hypertensive type 2 diabetes mellitus patients. Vasc Pharmacol. 2007;47:118–24.CrossRef
Metadata
Title
Pentoxifylline reduces the inflammatory process in diabetic rats: relationship with decreases of pro-inflammatory cytokines and inducible nitric oxide synthase
Authors
Francisca Adilfa de Oliveira Garcia
Jéssica Farias Rebouças
Teresa Queiroz Balbino
Teresinha Gonçalves da Silva
Carlson Hélder Reis de Carvalho-Júnior
Gilberto Santos Cerqueira
Gerly Anne de Castro Brito
Glauce Socorro de Barros Viana
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Inflammation / Issue 1/2015
Electronic ISSN: 1476-9255
DOI
https://doi.org/10.1186/s12950-015-0080-5

Other articles of this Issue 1/2015

Journal of Inflammation 1/2015 Go to the issue

Research

Milk-derived bioactive peptides inhibit human endothelial-monocyte interactions via PPAR-γ dependent regulation of NF-κB

Research

Antioxidant polyphenol-rich extracts from the medicinal plants Antirhea borbonica, Doratoxylon apetalum and Gouania mauritiana protect 3T3-L1 preadipocytes against H2O2, TNFα and LPS inflammatory mediators by regulating the expression of superoxide dismutase and NF-κB genes

Short Report

Dimethylfumarate protects against TNF-α-induced secretion of inflammatory cytokines in human endothelial cells

Research

Cellular cytokine and chemokine responses to parasite antigens and fungus and mite allergens in children co-infected with helminthes and protozoa parasites

Short Report

Δ9-Tetrahydrocannabinol (THC) enhances lipopolysaccharide-stimulated tissue factor in human monocytes and monocyte-derived microvesicles

Research

Association of serum TNF-α, IL-8 and free light chain with HLA-DR B alleles expression in pulmonary and extra-pulmonary sarcoidosis

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits