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Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Research Article

Pregabalin Ameliorates Lipopolysaccharide-Induced Pancreatic Inflammation in Aged Rats

Author(s): Ozlem Ozmen* and Senay Topsakal

Volume 19, Issue 8, 2019

Page: [1141 - 1147] Pages: 7

DOI: 10.2174/1871530319666190306095532

Price: $65

Abstract

Objective: The aim of this study was to examine pancreatic pathology and the prophylactic effects of pregabalin in lipopolysaccharide (LPS) induced sepsis model in aged rats.

Methods: Twenty-four female, one-year-old, Wistar Albino rats were assigned to three groups; Group I (control), Group II (study group: 5mg/kg LPS intraperitoneal, single dose) and Group III(treatment group: 5mg/kg LPS+30 mg/kg oral pregabalin one hour before LPS). Animals were sacrificed by exsanguination 6 hours after LPS administration. Blood and pancreatic tissue samples were collected for biochemical, pathological, and immunohistochemical analyses.

Results: LPS caused increases in serum amylase and lipase level but led to a reduction in glucose levels. Following histopathological analysis, numerous neutrophil leucocyte infiltrations were observed in vessels and pancreatic tissues. Increased caspase-3 expression was observed in both the endocrine and exocrine pancreas in the LPS group. Similarly, IL-6, caspase-3 (Cas-3), inducible nitric oxide synthase (iNOS), granulocyte colony-stimulating factor (G-CSF) and serum amyloid-A (SAA) expressions were increased by LPS. Pregabalin improved biochemical, histopathological, and immunohistochemical findings.

Conclusion: This study showed that LPS causes pathological findings in the pancreas, but pregabalin has ameliorative effects in aged rats with sepsis. Cas-3, IL-6, iNOS, G-CSF, and SAA all play pivotal roles in the pathogenesis of LPS-induced pancreatic damage.

Keywords: Lipopolysaccharide, pregabalin, pancreas, pathology, immunohistochemistry, rat.

Graphical Abstract

[1]
Cleave, O.; Melton, D.A. Development of the endocrine pancreas.Joslin’s Diabetes Mellitus; Kahn, C.R.; Weir, G.C.; King, G.L.; Jacobson, A.M.; Moses, A.C; Smith, R.J., Ed.; Lippincott Williams &Wilkins: Boston, 2005, pp. 21-23.
[2]
Raetz, C.R.H. Bacterial endotoxins: extraordinary lipids that activate eucaryotic signal transduction. J. Bacteriol., 1993, 175(18), 5745-5753.
[http://dx.doi.org/10.1128/jb.175.18.5745-5753.1993] [PMID: 8376321]
[3]
Morrison, D.C.; Dinarello, C.A.; Munford, R.S.; Natanson, C.; Danner, R.; Pollack, M.; Spitzer, J.J.; Ulevitch, R.J.; Vogel, S.N.; McSweegan, E. Current status of bacterial endotoxins. ASM News, 1994, 60, 479-484.
[4]
Kusske, A.M.; Rongione, A.J.; Reber, H.A. Cytokines and acute pancreatitis. Gastroenterology, 1996, 110(2), 639-642.
[http://dx.doi.org/10.1053/gast.1996.v110.agast960639] [PMID: 8566616]
[5]
Aslankoc, R.; Savran, M.; Ozmen, O.; Asci, S. Hippocampus and cerebellum damage in sepsis induced by lipopolysaccharide in aged rats - Pregabalin can prevent damage. Biomed. Pharmacother., 2018, 108, 1384-1392.
[http://dx.doi.org/10.1016/j.biopha.2018.09.162] [PMID: 30372841]
[6]
Exley, A.R.; Leese, T.; Holliday, M.P.; Swann, R.A.; Cohen, J. Endotoxaemia and serum tumour necrosis factor as prognostic markers in severe acute pancreatitis. Gut, 1992, 33(8), 1126-1128.
[http://dx.doi.org/10.1136/gut.33.8.1126] [PMID: 1398241]
[7]
Vaccaro, M.I.; Calvo, E.L.; Suburo, A.M.; Sordelli, D.O.; Lanosa, G.; Iovanna, J.L. Lipopolysaccharide directly affects pancreatic acinar cells: implications on acute pancreatitis pathophysiology. Dig. Dis. Sci., 2000, 45(5), 915-926.
[http://dx.doi.org/10.1023/A:1005521007609] [PMID: 10795755]
[8]
Lesser, H.; Sharma, U.; LaMoreaux, L.; Poole, R.M. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology, 2004, 63(11), 2104-2110.
[http://dx.doi.org/10.1212/01.WNL.0000145767.36287.A1] [PMID: 15596757]
[9]
Sabatowski, R.; Gálvez, R.; Cherry, D.A.; Jacquot, F.; Vincent, E.; Maisonobe, P.; Versavel, M. 1008-045 Study Group. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain, 2004, 109(1-2), 26-35.
[http://dx.doi.org/10.1016/j.pain.2004.01.001] [PMID: 15082123]
[10]
Arroyo, S.; Anhut, H.; Kugler, A.R.; Lee, C.M.; Knapp, L.E.; Garofalo, E.A.; Messmer, S. Pregabalin 1008-011 International Study Group. Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures. Epilepsia, 2004, 45(1), 20-27.
[http://dx.doi.org/10.1111/j.0013-9580.2004.31203.x] [PMID: 14692903]
[11]
Pande, A.C.; Crockatt, J.G.; Feltner, D.E.; Janney, C.A.; Smith, W.T.; Weisler, R.; Londborg, P.D.; Bielski, R.J.; Zimbroff, D.L.; Davidson, J.R.; Liu-Dumaw, M. Pregabalin in generalized anxiety disorder: a placebo-controlled trial. Am. J. Psychiatry, 2003, 160(3), 533-540.
[http://dx.doi.org/10.1176/appi.ajp.160.3.533] [PMID: 12611835]
[12]
Fink, K.; Dooley, D.J.; Meder, W.P.; Suman-Chauhan, N.; Duffy, S.; Clusmann, H.; Göthert, M. Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex. Neuropharmacology, 2002, 42(2), 229-236.
[http://dx.doi.org/10.1016/S0028-3908(01)00172-1] [PMID: 11804619]
[13]
Ben-Menachem, E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia, 2004, 45(6)(Suppl. 6), 13-18.
[http://dx.doi.org/10.1111/j.0013-9580.2004.455003.x] [PMID: 15315511]
[14]
Di Cesare Mannelli, L.; Maresca, M.; Micheli, L.; Farina, C.; Scherz, M.W.; Ghelardini, C. A rat model of FOLFOX-induced neuropathy: effects of oral dimiracetam in comparison with duloxetine and pregabalin. Cancer Chemother. Pharmacol., 2017, 80(6), 1091-1103.
[http://dx.doi.org/10.1007/s00280-017-3449-8] [PMID: 29026967]
[15]
Meymandi, M.S.; Sepehri, G.; Abdolsamadi, M.; Shaabani, M.; Heravi, G.; Yazdanpanah, O.; Aghtaei, M.M. The effects of co-administration of pregabalin and vitamin E on neuropathic pain induced by partial sciatic nerve ligation in male rats. Inflammopharmacology, 2017, 25(2), 237-246.
[http://dx.doi.org/10.1007/s10787-017-0325-4] [PMID: 28233159]
[16]
Creely, S.J.; McTernan, P.G.; Kusminski, C.M.; Fisher, M.; Da Silva, N.F.; Khanolkar, M.; Evans, M.; Harte, A.L.; Kumar, S. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am. J. Physiol. Endocrinol. Metab., 2007, 292(3), E740-E747.
[http://dx.doi.org/10.1152/ajpendo.00302.2006] [PMID: 17090751]
[17]
Devaraj, S.; Dasu, M.R.; Jialal, I. Diabetes is a proinflammatory state: a translational perspective. Expert Rev. Endocrinol. Metab., 2010, 5(1), 19-28.
[http://dx.doi.org/10.1586/eem.09.44] [PMID: 20204165]
[18]
Ruetten, H.; Southan, G.J.; Abate, A.; Thiemermann, C. Attenuation of endotoxin-induced multiple organ dysfunction by 1-amino-2-hydroxy-guanidine, a potent inhibitor of inducible nitric oxide synthase. Br. J. Pharmacol., 1996, 118(2), 261-270.
[http://dx.doi.org/10.1111/j.1476-5381.1996.tb15397.x] [PMID: 8735625]
[19]
Enari, M.; Sakahira, H.; Yokoyama, H.; Okawa, K.; Iwamatsu, A.; Nagata, S. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature, 1998, 391(6662), 43-50.
[http://dx.doi.org/10.1038/34112] [PMID: 9422506]
[20]
Green, D.R. Apoptotic pathways: paper wraps stone blunts scissors. Cell, 2000, 102(1), 1-4.
[http://dx.doi.org/10.1016/S0092-8674(00)00003-9] [PMID: 10929706]
[21]
Roilides, E.; Walsh, T.J.; Pizzo, P.A.; Rubin, M. Granulocyte colony-stimulating factor enhances the phagocytic and bactericidal activity of normal and defective human neutrophils. J. Infect. Dis., 1991, 163(3), 579-583.
[http://dx.doi.org/10.1093/infdis/163.3.579] [PMID: 1704903]
[22]
Sallerfors, B. Endogenous production and peripheral blood levels of granulocyte-macrophage (GM-) and granulocyte (G-) colony-stimulating factors. Leuk. Lymphoma, 1994, 13(3-4), 235-247.
[http://dx.doi.org/10.3109/10428199409056287] [PMID: 7519508]
[23]
Bozza, F.A.; Salluh, J.I.; Japiassu, A.M.; Soares, M.; Assis, E.F.; Gomes, R.N.; Bozza, M.T.; Castro-Faria-Neto, H.C.; Bozza, P.T. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit. Care, 2007, 11(2), R49.
[http://dx.doi.org/10.1186/cc5783] [PMID: 17448250]
[24]
Cetkovic-Cvrlje, M.; Eizirik, D.L. TNF-alpha and IFN-gamma potentiate the deleterious effects of IL-1 beta on mouse pancreatic islets mainly via generation of nitric oxide. Cytokine, 1994, 6(4), 399-406.
[http://dx.doi.org/10.1016/1043-4666(94)90064-7] [PMID: 7948748]
[25]
Darville, M.I.; Eizirik, D.L. Regulation by cytokines of the inducible nitric oxide synthase promoter in insulin-producing cells. Diabetologia, 1998, 41(9), 1101-1108.
[http://dx.doi.org/10.1007/s001250051036] [PMID: 9754830]
[26]
Eizirik, D.L.; Sandler, S.; Welsh, N.; Cetkovic-Cvrlje, M.; Nieman, A.; Geller, D.A.; Pipeleers, D.G.; Bendtzen, K.; Hellerström, C. Cytokines suppress human islet function irrespective of their effects on nitric oxide generation. J. Clin. Invest., 1994, 93(5), 1968-1974.
[http://dx.doi.org/10.1172/JCI117188] [PMID: 7514190]
[27]
Dong, Z.; Saikumar, P.; Weinberg, J.M.; Venkatachalam, M.A. Calcium in cell injury and death. Annu. Rev. Pathol., 2006, 1, 405-434.
[http://dx.doi.org/10.1146/annurev.pathol.1.110304.100218] [PMID: 18039121]

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