The Effects of Pentoxifylline on Serum Levels of Interleukin 10 and Interferon Gamma and Memory Function in Lipopolysaccharide-induced Inflammation in Rats

Dolatabadi, Hamid Reza Dehghani; Zarrindast, Mohammad Reza; Reisi, Parham; Nasehi, Mohammad

The Effects of Pentoxifylline on Serum Levels of Interleukin 10 and Interferon Gamma and Memory Function in Lipopolysaccharide-induced Inflammation in Rats

Authors

¹ Institute for Cognitive Science Studies, Tehran University of Medical Sciences, Tehran, Iran

² Institute for Cognitive Science Studies; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

³ Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

⁴ Cognitive and Neuroscience Research Center, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran

Abstract

Background: Studies have shown that pentoxifylline (PTX) in addition to protective effects on blood vessels probably has positive influence against the brain inflammation. Therefore, the aim of this study was to evaluate the effects of PTX on serum levels of interleukin 10 (IL-10) and interferon gamma (IFN-γ) and passive avoidance learning in lipopolysaccharide (LPS)-induced inflammation in rats. Materials and Methods: Inflammation was induced by intraperitoneal (i.p.) injection of LPS (0.5 and 5 mg/kg) in male Wistar rats. After a week, PTX (25 mg/kg; i.p.) was injected for 14 days. Passive avoidance learning test was used for evaluation of learning and memory. Serum levels of cytokines were measured by enzyme-linked immunosorbent assay. Results: The behavioral results did not show any significant effect of LPS and PTX on learning and memory. Both doses of LPS (0.5 and 5 mg/kg) decreased IL-10 significantly (P < 0.05). PTX prevented this reduction just in the LPS 0.5 mg/kg + PTX 25 mg/kg group. Serum level of IFN-γ was increased only in the LPS 0.5 mg/kg + PTX 25 mg/kg group comparing to the LPS 0.5 mg/kg group (P < 0.05). Conclusions: The results showed that LPS-induced inflammation decreased the serum levels of IL-10. PTX could prevent these decreases only in mild inflammation. Both PTX and LPS-induced inflammation had no significant effects on learning and memory; therefore, their effects on CNS require further study.

Keywords

References

1.	Kreth S, Ledderose C, Luchting B, Weis F, Thiel M. Immunomodulatory properties of pentoxifylline are mediated via adenosine-dependent pathways. Shock 2010;34:10-6.
2.	Renke M, Rutkowski P, Tylicki L, Zietkiewicz M, Larczynski W, Rutkowski B. Pentoxifylline old drug or new hope for nephrology? Przegl Lek 2008;65:358-61.
3.	Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R. Insights into the regulation of TNF-alpha production in human mononuclear cells: The effects of non-specific phosphodiesterase inhibition. Clinics (Sao Paulo) 2008;63:321-8.
4.	Bruno Rde B, Marques TF, Batista TM, Lima JC, de Arruda KG, Lima PF, et al. Pentoxifylline treatment improves neurological and neurochemical deficits in rats subjected to transient brain ischemia. Brain Res 2009;1260:55-64.
5.	Vakili A, Zahedi khorasani M. Post-ischemic treatment of pentoxifylline reduces cortical not striatal infarct volume in transient model of focal cerebral ischemia in rat. Brain Res 2007;1144:186-91.
6.	Sirin BH, Yilik L, Coskun E, Ortaç R, Sirin H. Pentoxifylline reduces injury of the brain in transient ischaemia. Acta Cardiol 1998;53:89-95.
7.	Ukraintseva SV, Arbeev KG, Michalsky AI, Yashin AI. Antiaging treatments have been legally prescribed for approximately thirty years. Ann N Y Acad Sci 2004;1019:64-9.
8.	Zhu DJ, Xia B, Bi Q, Zhang SJ, Qiu BS, Zhao C. Functional protection of pentoxifylline against spinal cord ischemia/reperfusion injury in rabbits: Necrosis and apoptosis effects. Chin Med J (Engl) 2008;121:2444-9.
9.	Hein AM, O'Banion MK. Neuroinflammation and memory: The role of prostaglandins. Mol Neurobiol 2009;40:15-32.
10.	Biesmans S, Meert TF, Bouwknecht JA, Acton PD, Davoodi N, De Haes P, et al. Systemic immune activation leads to neuroinflammation and sickness behavior in mice. Mediators Inflamm 2013;2013:271359.
11.	Nasoohi S, Hemmati AA, Moradi F, Ahmadiani A. The γ-secretase blocker DAPT impairs recovery from lipopolysaccharide-induced inflammation in rat brain. Neuroscience 2012;210:99-109.
12.	Anderson ST, Commins S, Moynagh PN, Coogan AN. Lipopolysaccharide-induced sepsis induces long-lasting affective changes in the mouse. Brain Behav Immun 2015;43:98-109.
13.	Abdelwahed OM, Gamal M, Abdelwahab Z, Zickri M, Eraky WE, Saleh DO. Role of estrogen hormone in lipopolysaccharide-induced Alzheimer's disease in female rats possible underlying mechanisms and modulation by progesterone hormone. Med J Cairo Univ 2014;82:175-93.
14.	Neves KR, Nobre HV Jr., Leal LK, de Andrade GM, Brito GA, Viana GS. Pentoxifylline neuroprotective effects are possibly related to its anti-inflammatory and TNF-alpha inhibitory properties, in the 6-OHDA model of Parkinson's disease. Parkinsons Dis 2015;2015:108179.
15.	Babaei S, Bayat M, Nouruzian M, Bayat M. Pentoxifylline improves cutaneous wound healing in streptozotocin-induced diabetic rats. Eur J Pharmacol 2013;700:165-72.
16.	Azadbakht AA, Radahmadi M, Javanmard SH, Reisi P. The effects of doxepin on stress-induced learning, memory impairments, and TNF-α level in the rat hippocampus. Res Pharm Sci 2015;10:460-5.
17.	Marchant A, Bruyns C, Vandenabeele P, Ducarme M, Gérard C, Delvaux A, et al. Interleukin-10 controls interferon-gamma and tumor necrosis factor production during experimental endotoxemia. Eur J Immunol 1994;24:1167-71.
18.	Shen W, Ren X, Zhu J, Xu Y, Lin J, Li Y, et al. Discovery of a new structural class of competitive hDHODH inhibitors with in vitro and in vivo anti-inflammatory, immunosuppressive effects. Eur J Pharmacol 2016;791:205-12.
19.	Shimohama S. Apoptosis in Alzheimer's disease – An update. Apoptosis 2000;5:9-16.
20.	Frankola KA, Greig NH, Luo W, Tweedie D. Targeting TNF-a to elucidate and ameliorate neuroinflammation in neurodegenerative diseases. CNS Neurol Disord Drug Targets 2011;10:391-403.
21.	Quan N, Sundar SK, Weiss JM. Induction of interleukin-1 in various brain regions after peripheral and central injections of lipopolysaccharide. J Neuroimmunol 1994;49:125-34.
22.	Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA. Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology 2003;37:1043-55.
23.	Lauw FN, ten Hove T, Dekkers PE, de Jonge E, van Deventer SJ, van Der Poll T. Reduced Th1, but not Th2, cytokine production by lymphocytes after in vivo exposure of healthy subjects to endotoxin. Infect Immun 2000;68:1014-8.
24.	Ishii H, Kubo T, Kumanogoh A, Yamashita T. Th1 cells promote neurite outgrowth from cortical neurons via a mechanism dependent on semaphorins. Biochem Biophys Res Commun 2010;402:168-72.
25.	Joss A, Akdis M, Faith A, Blaser K, Akdis CA. IL-10 directly acts on T cells by specifically altering the CD28 co-stimulation pathway. Eur J Immunol 2000;30:1683-90.
26.	Daan de Boer J, Roelofs JJ, de Vos AF, de Beer R, Schouten M, Hommes TJ, et al. Lipopolysaccharide inhibits Th2 lung inflammation induced by house dust mite allergens in mice. Am J Respir Cell Mol Biol 2013;48:382-9.
27.	Andersson AC, Seppälä U, Rudin A. Activation of human neonatal monocyte-derived dendritic cells by lipopolysaccharide down-regulates birch allergen-induced Th2 differentiation. Eur J Immunol 2004;34:3516-24.
28.	Hang CH, Shi JX, Tian J, Li JS, Wu W, Yin HX. Effect of systemic LPS injection on cortical NF-kappaB activity and inflammatory response following traumatic brain injury in rats. Brain Res 2004;1026:23-32.
29.	Lee JW, Lee YK, Yuk DY, Choi DY, Ban SB, Oh KW, et al. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation 2008;5:37.
30.	Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 2011;25:181-213.
31.	Anaeigoudari A, Soukhtanloo M, Reisi P, Beheshti F, Hosseini M. Inducible nitric oxide inhibitor aminoguanidine, ameliorates deleterious effects of lipopolysaccharide on memory and long term potentiation in rat. Life Sci 2016;158:22-30.
32.	Valero J, Mastrella G, Neiva I, Sánchez S, Malva JO. Long-term effects of an acute and systemic administration of LPS on adult neurogenesis and spatial memory. Front Neurosci 2014;8:83.

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