L-Arginine-induced acute pancreatitis and its associated lung injury in rats: Down-regulation of TLR-4/MAPK-p38/JNK signaling pathway via Ginkgo biloba extract EGb 761

Document Type : Original Article

Authors

1 Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Centre (ID: 60014618), Cairo, Egypt

2 Pathology Department, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt

10.22038/ijbms.2024.76162.16480

Abstract

Objective(s): Acute pancreatitis (AP) is an abrupt inflammatory condition characterized by a storm of inflammatory cytokines leading to high morbidity and mortality. The current study aimed to examine the efficacy of Ginkgo biloba extract EGb 761 (GBE) in the treatment of L-arginine-induced AP and its associated lung injury. 
Materials and Methods: Forty rats were randomly assigned into four groups. The normal group received only saline intraperitoneally while the other groups received two intraperitoneal L-arginine injections (250 mg/100 g b.wt) separated by a 1-hour interval to provoke AP. GBE (200 and 400 mg/kg/day, PO) was administered for 2 weeks post-induction of pancreatitis. Sera and pancreatic tissues were isolated.
Results: The outcome of the present study revealed that GBE ameliorated the elevated levels of serum amylase, lipase, and pancreatic inflammatory mediators viz., tumor necrosis factor-alpha (TNF-α), mitogen-activated protein kinase P38 (MAPK-P38), c-Jun N-terminal kinase 1 (JNK1), and nuclear factor-kappa B (NF-κB). Moreover, GBE restored the pancreatic gene expression of Toll-like receptor 4 (TLR4) and prostatic acid phosphatase-2 (PAP-2). Pancreatic and lung histopathological examinations confirmed the aforementioned parameters. 
Conclusion: GBE interfered with the mechanistic pathway of L-arginine-induced acute pancreatic and its associated lung injury. Due to its anti-inflammatory properties, GBE can be used as a novel therapeutic candidate for the treatment of AP through down-regulating TLR-4/MAPK-p38/JNK and MAPK- p38/NF-κB signaling cascades.

Keywords

Main Subjects


Komara N L, Paragomi P, Greer P J, Wilson A S, Breze C, Papachristou G I, et al. Severe acute pancreatitis: capillary permeability model linking systemic inflammation to multiorgan failure. Am J Physiol Gastrointest Liver Physiol 2020; 319:573-583.
2. Yadav D, Lowenfels A B. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology 2013; 144:1252-1261.
3. Gómez-Cambronero L G, Sabater L, Pereda J, Cassinello N, Camps B, Viña J, et al. Role of cytokines and oxidative stress in the pathophysiology of acute pancreatitis: therapeutical implications. Curr Drug Targets Inflamm Allergy 2002; 1:393-403.
4. Meher S, Mishra T S, Sasmal P K, Rath S, Sharma R, Rout B, et al. Role of biomarkers in diagnosis and prognostic evaluation of acute pancreatitis. J Biomark 2015; 2015:519534-519547.
5. Escobar J, Pereda J, Arduini A, Sandoval J, Sabater L, Aparisi L, et al. Cross-talk between oxidative stress and pro-inflammatory cytokines in acute pancreatitis: a key role for protein phosphatases. Curr Pharm Des 2009; 15:3027-3042.
6. Manohar M, Verma A K, Venkateshaiah S U, Sanders N L, Mishra A. Pathogenic mechanisms of pancreatitis. World J Gastrointest Pharmacol Ther 2017; 8:10-25.
7. Bhatia M. Apoptosis versus necrosis in acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 2004; 286:189-196.
8. Yu J H, Kim H. Oxidative stress and inflammatory signaling in cerulein pancreatitis. World J Gastroenterol 2014; 20:17324-17329.
9. Kany S, Vollrath J T, Relja B. Cytokines in inflammatory disease. Int J Mol Sci 2019; 20:6008-6039.
10. Garg P K, Singh V P. Organ failure due to systemic injury in acute pancreatitis. Gastroenterology 2019; 156:2008-2023.
11. Wang Y, Zhang L, Xi X, Zhou J X. The association between etiologies and mortality in acute respiratory distress syndrome: a multicenter observational cohort study. Front Med (Lausanne) 2021; 8:739596-739605.
12. Gonzales J, Lucas R, Verin A. The acute respiratory distress syndrome: mechanisms and perspective therapeutic approaches. Austin J Vasc Med 2015; 2:1009-1022.
13. Mostafa R E, Ibrahim BM, Jaleel GAA. Neuro-protective effects of Ginkgo biloba leaves extract on cerebral ischemia-reperfusion injury induced experimentally in ovariectomized rats. Int J Pharm Pharm Sci 2016; 8:237-242.
14. Noor E T, Das R. Ginkgo biloba: A treasure of functional phytochemicals with multimedicinal applications. Evid Based Complement Alternat Med 2022; 2022:1-30.
15. Mansour D F, Saleh D O, Ahmed-Farid O A, Rady M, Bakeer R M, Hashad I M. Ginkgo biloba extract (EGb 761) mitigates methotrexate-induced testicular insult in rats: targeting oxidative stress, energy deficit and spermatogenesis. Biomed Pharmacother 2021; 143:112201.
16. Hegyi P, Rakonczay Jr Z, Sári R, Góg C, Lonovics J, Takács T, et al. L-arginine-induced experimental pancreatitis. World J Gastroenterol 2004; 10:2003-2009.
17. Moon B, Kim W, Park C H, Oh S M. Ginkgo biloba extract (EGb761) did not express estrogenic activity in an immature rat uterotrophic assay. Environ Anal Health Toxicol 2018; 33:1-9.
18. Yuzer H, Yuzbasioglu M F, Ciralik H, Kurutas E B, Ozkan O V, Bulbuloglu E, et al. Effects of intravenous anesthetics on renal ischemia/reperfusion injury. Ren Fail 2009; 31:290-296.
19. Bradford M. Bradford protein assay (determination of protein concentrations). Anal Biochem 1976; 72:248-254.
20. Iannuzzi J P, King J A, Leong J H, Quan J, Windsor J W, Tanyingoh D, et al. Global incidence of acute pancreatitis is increasing over time: a systematic review and meta-analysis. Gastroenterology 2022; 162:122-134.
21. Dawra R, Sharif R, Phillips P, Dudeja V, Dhaulakhandi D, Saluja A K. Development of a new mouse model of acute pancreatitis induced by administration of L-arginine. Am J Physiol Gastrointest Liver Physiol 2007; 292:1009-1018.
22. Tran Q T, Sendler M, Wiese M L, Doller J, Zierke L, Gischke M, et al. Systemic bile acids affect the severity of acute pancreatitis in mice depending on their hydrophobicity and the disease pathogenesis. Int J Mol Sci 2022; 23:13592-13610.
23. El Morsy E M, Ahmed M A E. Carvedilol attenuates l-arginine induced acute pancreatitis in rats through modulation of oxidative stress and inflammatory mediators. Chem Biol Interact 2020; 327:109181-109222.
24. Pérez S, Pereda J, Sabater L, Sastre J. Redox signaling in acute pancreatitis. Redox Biol 2015; 5:1-14.
25. Mostafa R E, Salama A A. Eplerenone modulates the inflammatory response in monosodium iodoacetate-induced knee osteoarthritis in rats: involvement of RANKL/OPG axis. Life Sci 2023; 316:121405.
26. Abdelzaher W Y, Ahmed S M, Welson N N, Marraiki N, El-Saber Batiha G, Kamel M Y. Vinpocetine ameliorates L-arginine induced acute pancreatitis via Sirt1/Nrf2/TNF pathway and inhibition of oxidative stress, inflammation, and apoptosis. Biomed Pharmacother 2021; 133:110976-110976.
27. Sproston N R, Ashworth J J. Role of C-reactive protein at sites of inflammation and infection. Front Immunol 2018; 9:754-765.
28. Chen C C. Serum markers in the early assessment of severity of acute pancreatitis: which is the most useful? J Chin Med Ass 2004; 67:439-441.
29. Fawzy H, Fikry E, Fawzy H, Mohammed A, et al. Mito-TEMPO improved L-Arginine- induced acute pancreatitis in rats via TLR-4/ NF-кB/ NLRP3 inflammasome downregulation and antioxidant properties. Azhar Int J Pharmaceut Med Sci 2021; 1:54-65.
30. Wang Z, Ni X, Zhang L, Sun L, Zhu X, Zhou Q, et al. Toll-like receptor 4 and inflammatory micro-environment of pancreatic islets in type-2 diabetes mellitus: a therapeutic perspective. Diabetes Metab Syndr Obes 2020; 13:4261-4272.
31. Li G, Xuejun Wu, Le Yang , Yuxiang He, Yang Liu, Xing Jin, et al. TLR4-mediated NF-κB signaling pathway mediates HMGB1-induced pancreatic injury in mice with severe acute pancreatitis. Int J Mol Med 2016; 37:99-107.
32. Lucas K, Maes M. Role of the toll like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. Mol Neurobiol 2013; 48:190-204.
33. Grendell J H. Idiopathic acute pancreatitis. Gastroenterol Clin North Am 1990; 19:843-848.
34. Mostafa R E, Shaffie N M, Allam R M. Panax ginseng alleviates thioacetamide-induced liver injury in ovariectomized rats: crosstalk between inflammation and oxidative stress. PloS One 2021; 16:1-17.
35. Liu T, Zhang L, Joo D, Sun S C. NF-κB signaling in inflammation. Signal Transduct Target Ther 2017; 2:17023-17032.
36. Schett G,  Zwerina J, Firestein G. The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis. Ann Rheum Dis 2008; 67:909-916.
37. Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 2018; 9:7204-7218.
38. Irrera N, Bitto A, Interdonato M, Squadrito F, Altavilla D, et al. Evidence for a role of mitogen-activated protein kinases in the treatment of experimental acute pancreatitis. World J Gastroenterol 2014; 20:16535-16543.
39. Bennett B L, Sasaki D T, Murray B W, O’Leary E C, Sakata S T, Xu W, et al. SP600125, an anthrapyrazolone inhibitor of jun N-terminal kinase. Proc Natl Acad Sci U S A 2001; 98:13681-13686.
40. Barbalho S M, Direito R, Laurindo L F, Marton L T, Guiguer E L, Goulart R A, et al. Ginkgo biloba in the aging process: a narrative review. Antioxidants 2022; 11:525-552.
41. Li C, Liu K, Liu S, Aerqin Q, Wu X. Role of ginkgolides in the inflammatory immune response of neurological diseases: a review of current literatures. Front Syst Neurosci 2020; 14:45-56.
42. Lee C Y, Yang J J, Lee S S, Chen S J, Huang Y C, Huang K H, et al. Protective effect of Ginkgo biloba leaves extract, EGb761, on endotoxin-induced acute lung Iinjury via a JNK- and Akt-dependent NFκB pathway. J Agric Food Chem 2014; 62:6337-6344.
43. Viterbo D, Bluth M H, Lin Y Y, Mueller C M, Wadgaonkar R, Zenilman M E. Pancreatitis-associated protein 2 modulates inflammatory responses in macrophages. J Immunol 2008; 181:1948-1958.
44. King C C, Sastri M, Chang P, Pennypacker J, Taylor S S. The rate of NF-κB nuclear translocation is regulated by PKA and A kinase interacting protein 1. PLoS One 2011; 6:1-15.
45. Kylänpää L, Rakonczay Z, O’Reilly D A. The clinical course of acute pancreatitis and the inflammatory mediators that drive it. Int J Inflam 2012; 2012:1-10.
46. Su X, Xia Y, Jiang W, Shen G, Pang Y. GbMYBR1 from Ginkgo biloba represses phenylpropanoid biosynthesis and trichome development in arabidopsis. Planta 2020; 252:68-86.
47. Xu X W, Yang X M, Bai Y H, Zhao Y R, Shi G S, Zhang J G, et al. Treatment with Ginkgo biloba extract protects rats against acute pancreatitis-associated lung injury by modulating alveolar macrophage. Prz Gastroenterol 2014; 9:43-48.
48. Liu D, Wen L, Wang Z, Hai Y, Yang D, Zhang Y, et al. The mechanism of lung and intestinal injury in acute pancreatitis: a review. Front Med (Lausanne) 2022; 9:904078-904091.
49. Ge P, Luo Y, Okoye C S, Chen H, Liu J, Zhang G, et al. Intestinal barrier damage, systemic inflammatory response syndrome, and acute lung injury: a troublesome trio for acute pancreatitis. Biomed Pharmacother 2020; 132:110770.
50. Zhu C J, Yang W G, Li D J, Song Y D, Chen S Y, Wang Q F, et al. Calycosin attenuates severe acute pancreatitis-associated acute lung injury by curtailing high mobility group box 1 - induced inflammation. World J Gastroenterol 2021; 27:7669-7686.
51. Ali A A, El-Zaitony A, Al-Haleem E. Evaluation of therapeutic efficacy of vinpocetine in adjuvant induced arthritis model in rats. J Pain Manage Med 2016; 2:1-10.
52. Mirmalek S A, Boushehrinejad A G, Yavari H, Kardeh b, Parsa Y, Salimi-Tabatabaee S a, et al. Antioxidant and anti-inflammatory effects of coenzyme Q10 on l-arginine-induced acute pancreatitis in rat. Oxid Med Cell Longev 2016; 2016:5818479-5818487.