Skip to main content

Advertisement

SpringerLink
Log in

A new approach to sepsis treatment by rasagiline: a molecular, biochemical and histopathological study

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Aim

We aimed to investigate the effects of rasagiline on acute lung injury that develops in the sepsis model induced with the cecal ligation and puncture in rats.

Main Methods

The rats were separated into the following six groups, Group 1: Sham, Group 2: Sham + Rasagiline 4 mg/kg, Group 3: Sepsis, Group 4: Sepsis + Rasagiline 1 mg/kg, Group 5: Sepsis + Rasagiline 2 mg/kg, Group 6: Sepsis + Rasagiline 4 mg/kg. A total of four holes were opened with a 16-gauge needle through the cecum distal to the point of ligation.

Key Findings

Rasagiline treatment increased glutathione level and superoxide dismutase activity while decreased the malondialdehyde level after the sepsis. There was a statistically significant improvement in the doses of 2 mg/kg and 4 mg/kg. Rasagiline also increased Tnf-α, IL1β, IL6, NF-κβand HMGB1 gene expressions in dose-dependent at 2 mg/kg and 4 mg/kg doses. In increased doses, rasagiline prevent the development of edema, the formation of inflammation, and hemorrhage.

Significance

Rasagiline exerts both antioxidant and anti-inflammatory effects on the cecal ligation and puncture induced acute lung injury in rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Availability of data and materials

Yes.

References

  1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC (2016) The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315:801–810. https://doi.org/10.1001/jama.2016.0287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Deutschman CS, Tracey KJ (2014) Sepsis: current dogma and new perspectives. Immunity 40:463–475. https://doi.org/10.1016/j.immuni.2014.04.001

    Article  CAS  PubMed  Google Scholar 

  3. Carlton EF, McHugh WM, McDonough K, Sturza J, Desch K, Cornell TT (2020) Markers of Endothelial Dysfunction and Cytokines in High-Risk Pediatric Patients with Severe Sepsis. Am J Respir Crit Care Med 201:380–384. https://doi.org/10.1164/rccm.201904-0910LE

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cao C, Yu M, Chai Y (2019) Pathological alteration and therapeutic implications of sepsis-induced immune cell apoptosis. Cell Death Dis 10:782. https://doi.org/10.1038/s41419-019-2015-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Schulte W, Bernhagen J, Bucala R (2013) Cytokines in sepsis: potent immunoregulators and potential therapeutic targets--an updated view. Mediators Inflamm 2013:165974. https://doi.org/10.1155/2013/165974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Movat HZ, Cybulsky MI, Colditz IG, Chan MK, Dinarello CA (1987) Acute inflammation in gram-negative infection: endotoxin, interleukin 1, tumor necrosis factor, and neutrophils. Fed Proc 46:97–104

    CAS  PubMed  Google Scholar 

  7. Levy MM, Evans LE, Rhodes A (2018) The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Med 44:925–928. https://doi.org/10.1007/s00134-018-5085-0

    Article  CAS  PubMed  Google Scholar 

  8. Oldfield V, Keating GM, Perry CM (2007) Rasagiline: a review of its use in the management of Parkinson’s disease. Drugs 67:1725–1747. https://doi.org/10.2165/00003495-200767120-00006

    Article  CAS  PubMed  Google Scholar 

  9. Levkovitch-Verbin H, Vander S, Melamed S (2011) Rasagiline-induced delay of retinal ganglion cell death in experimental glaucoma in rats. J Glaucoma 20:273–277. https://doi.org/10.1097/IJG.0b013e3181e3d101

    Article  PubMed  Google Scholar 

  10. Eigeldinger-Berthou S, Meier C, Zulliger R, Lecaude S, Enzmann V, Sarra GM (2012) Rasagiline interferes with neurodegeneration in the Prph2/rds mouse. Retina 32:617–628. https://doi.org/10.1097/IAE.0b013e31821e2070

    Article  CAS  PubMed  Google Scholar 

  11. Jenner P, Langston JW (2011) Explaining ADAGIO: a critical review of the biological basis for the clinical effects of rasagiline. Mov Disord 26:2316–2323. https://doi.org/10.1002/mds.23926

    Article  PubMed  Google Scholar 

  12. Naoi M, Maruyama W (2009) Functional mechanism of neuroprotection by inhibitors of type B monoamine oxidase in Parkinson’s disease. Expert Rev Neurother 9:1233–1250. https://doi.org/10.1586/ern.09.68

    Article  CAS  PubMed  Google Scholar 

  13. Kranthi K, Punnagai VVMAPK, Chellathai D David (2019) A Comparative free Radical Scavenging Evaluation of Amantadine and Rasagiline. Biomedical and Pharmacology Journal. https://doi.org/10.13005/bpj/1746

  14. Varela A, Mavroidis M, Katsimpoulas M, Sfiroera I, Kappa N, Mesa A, Kostomitsopoulos NG, Cokkinos DV (2017) The neuroprotective agent Rasagiline mesylate attenuates cardiac remodeling after experimental myocardial infarction. ESC Heart Fail 4:331–340. https://doi.org/10.1002/ehf2.12140

    Article  PubMed  PubMed Central  Google Scholar 

  15. Sanchez-Rodriguez R, Munari F, Angioni R, Venegas F, Agnellini A, Castro-Gil MP, Castegna A, Luisetto R, Viola A, Canton M (2020) Targeting monoamine oxidase to dampen NLRP3 inflammasome activation in inflammation. Cell Mol Immunol. https://doi.org/10.1038/s41423-020-0441-8

    Article  PubMed  PubMed Central  Google Scholar 

  16. Polat G, Ugan RA, Cadirci E, Halici Z (2017) Sepsis and Septic Shock: Current Treatment Strategies and New Approaches. Eurasian J Med 49:53–58. https://doi.org/10.5152/eurasianjmed.2017.17062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Eliash S, Dror V, Cohen S, Rehavi M (2009) Neuroprotection by rasagiline in thiamine deficient rats. Brain Res 1256:138–148. https://doi.org/10.1016/j.brainres.2008.11.097

    Article  CAS  PubMed  Google Scholar 

  18. Ugan RA, Cadirci E, Halici Z, Toktay E, Cinar I (2018) The role of urotensin-II and its receptors in sepsis-induced lung injury under diabetic conditions. Eur J Pharmacol 818:457–469. https://doi.org/10.1016/j.ejphar.2017.11.011

    Article  CAS  PubMed  Google Scholar 

  19. Akpinar E, Halici Z, Cadirci E, Bayir Y, Karakus E, Calik M, Topcu A, Polat B (2014) What is the role of renin inhibition during rat septic conditions: preventive effect of aliskiren on sepsis-induced lung injury. Naunyn Schmiedebergs Arch Pharmacol 387:969–978. https://doi.org/10.1007/s00210-014-1014-0

    Article  CAS  PubMed  Google Scholar 

  20. Uyanik A, Unal D, Uyanik MH, Halici Z, Odabasoglu F, Altunkaynak ZB, Cadirci E, Keles M, Gundogdu C, Suleyman H, Bayir Y, Albayrak M, Unal B (2010) The effects of polymicrobial sepsis with diabetes mellitus on kidney tissues in ovariectomized rats. Ren Fail 32:592–602. https://doi.org/10.3109/08860221003759478

    Article  CAS  PubMed  Google Scholar 

  21. Sun Y, Oberley LW, Li Y (1988) A simple method for clinical assay of superoxide dismutase. Clin Chem 34:497–500

    Article  CAS  PubMed  Google Scholar 

  22. Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 25:192–205. https://doi.org/10.1016/0003-2697(68)90092-4

    Article  CAS  PubMed  Google Scholar 

  23. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358. https://doi.org/10.1016/0003-2697(79)90738-3

    Article  CAS  PubMed  Google Scholar 

  24. Bayir Y, Un H, Cadirci E, Akpinar E, Diyarbakir B, Calik I, Halici Z (2019) Effects of Aliskiren, an RAAS inhibitor, on a carrageenan-induced pleurisy model of rats. Anais da Academia Brasileira de Ciências 91

  25. Demir R, Cadirci E, Akpinar E, Cayir Y, Atmaca HT, Un H, Kunak CS, Yayla M, Bayraktutan Z, Demir I (2015) Does bosentan protect diabetic brain alterations in rats? The role of endothelin-1 in the diabetic brain. Basic Clin Pharmacol Toxicol 116:236–243

    Article  CAS  PubMed  Google Scholar 

  26. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2 – ∆∆CT method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  27. Yayla M, Cetin D, Adali Y, Kilicle PA, Toktay E (2018) Potential therapeutic effect of pomegranate seed oil on ovarian ischemia/reperfusion injury in rats. Iran J basic Med Sci 21:1262

    PubMed  PubMed Central  Google Scholar 

  28. Un H, Ugan RA, Kose D, Bayir Y, Cadirci E, Selli J, Halici Z (2020) A novel effect of Aprepitant: Protection for cisplatin-induced nephrotoxicity and hepatotoxicity. Eur J Pharmacol 880:173168

    Article  CAS  PubMed  Google Scholar 

  29. Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA (1987) A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 317:653–658. https://doi.org/10.1056/NEJM198709103171101

    Article  CAS  PubMed  Google Scholar 

  30. Ziegler EJ, Fisher CJ Jr, Sprung CL, Straube RC, Sadoff JC, Foulke GE, Wortel CH, Fink MP, Dellinger RP, Teng NN et al (1991) Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. N Engl J Med 324:429–436. https://doi.org/10.1056/NEJM199102143240701

    Article  CAS  PubMed  Google Scholar 

  31. Fisher CJ Jr, Agosti JM, Opal SM, Lowry SF, Balk RA, Sadoff JC, Abraham E, Schein RM, Benjamin E (1996) Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med 334:1697–1702. https://doi.org/10.1056/NEJM199606273342603

    Article  CAS  PubMed  Google Scholar 

  32. Fisher CJ Jr, Slotman GJ, Opal SM, Pribble JP, Bone RC, Emmanuel G, Ng D, Bloedow DC, Catalano MA, I.-R, .S.S.S. Group (1994) Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. Crit Care Med 22:12–21. https://doi.org/10.1097/00003246-199401000-00008

    Article  PubMed  Google Scholar 

  33. Gao M, Ha T, Zhang X, Liu L, Wang X, Kelley J, Singh K, Kao R, Gao X, Williams D, Li C (2012) Toll-like receptor 3 plays a central role in cardiac dysfunction during polymicrobial sepsis. Crit Care Med 40:2390–2399. https://doi.org/10.1097/CCM.0b013e3182535aeb

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511. https://doi.org/10.1038/nri1391

    Article  CAS  PubMed  Google Scholar 

  35. Maruyama W, Nitta A, Shamoto-Nagai M, Hirata Y, Akao Y, Yodim M, Furukawa S, Nabeshima T, Naoi M (2004) N-Propargyl-1 (R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-kappaB transcription factor. Neurochem Int 44:393–400. https://doi.org/10.1016/j.neuint.2003.08.005

    Article  CAS  PubMed  Google Scholar 

  36. Patel RT, Deen KI, Youngs D, Warwick J, Keighley MR (1994) Interleukin 6 is a prognostic indicator of outcome in severe intra-abdominal sepsis. Br J Surg 81:1306–1308. https://doi.org/10.1002/bjs.1800810914

    Article  CAS  PubMed  Google Scholar 

  37. Casey LC, Balk RA, Bone RC (1993) Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med 119:771–778. https://doi.org/10.7326/0003-4819-119-8-199310150-00001

    Article  CAS  PubMed  Google Scholar 

  38. Trudler D, Weinreb O, Mandel SA, Youdim MB, Frenkel D (2014) DJ-1 deficiency triggers microglia sensitivity to dopamine toward a pro-inflammatory phenotype that is attenuated by rasagiline. J Neurochem 129:434–447. https://doi.org/10.1111/jnc.12633

    Article  CAS  PubMed  Google Scholar 

  39. Wang H, Ward MF, Sama AE (2014) Targeting HMGB1 in the treatment of sepsis. Expert Opin Ther Targets 18:257–268. https://doi.org/10.1517/14728222.2014.863876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chan ED, Riches DW (2001) IFN-gamma + LPS induction of iNOS is modulated by ERK, JNK/SAPK, and p38(mapk) in a mouse macrophage cell line. Am J Physiol Cell Physiol 280:C441–C450. https://doi.org/10.1152/ajpcell.2001.280.3.C441

    Article  CAS  PubMed  Google Scholar 

  41. Degryse B, de Virgilio M (2003) The nuclear protein HMGB1, a new kind of chemokine? FEBS Lett 553:11–17. https://doi.org/10.1016/s0014-5793(03)01027-5

    Article  CAS  PubMed  Google Scholar 

  42. Swanson KV, Deng M, Ting JP (2019) The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 19:477–489. https://doi.org/10.1038/s41577-019-0165-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Galley HF, Davies MJ, Webster NR (1996) Xanthine oxidase activity and free radical generation in patients with sepsis syndrome. Crit Care Med 24:1649–1653. https://doi.org/10.1097/00003246-199610000-00008

    Article  CAS  PubMed  Google Scholar 

  44. Borrelli E, Roux-Lombard P, Grau GE, Girardin E, Ricou B, Dayer J, Suter PM (1996) Plasma concentrations of cytokines, their soluble receptors, and antioxidant vitamins can predict the development of multiple organ failure in patients at risk. Crit Care Med 24:392–397. https://doi.org/10.1097/00003246-199603000-00006

    Article  CAS  PubMed  Google Scholar 

  45. Arnalich F, Garcia-Palomero E, Lopez J, Jimenez M, Madero R, Renart J, Vazquez JJ, Montiel C (2000) Predictive value of nuclear factor kappaB activity and plasma cytokine levels in patients with sepsis. Infect Immun 68:1942–1945. https://doi.org/10.1128/iai.68.4.1942-1945.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kazama H, Ricci JE, Herndon JM, Hoppe G, Green DR, Ferguson TA (2008) Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity 29:21–32. https://doi.org/10.1016/j.immuni.2008.05.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Carrillo MC, Minami C, Kitani K, Maruyama W, Ohashi K, Yamamoto T, Naoi M, Kanai S, Youdim MB (2000) Enhancing effect of rasagiline on superoxide dismutase and catalase activities in the dopaminergic system in the rat. Life Sci 67:577–585. https://doi.org/10.1016/s0024-3205(00)00643-3

    Article  CAS  PubMed  Google Scholar 

  48. Weiss M, Huber-Lang M, Taenzer M, Kron M, Hay B, Nass M, Huber M, Schneider M (2010) How many general and inflammatory variables need to be fulfilled when defining sepsis due to the 2003 SCCM/ESICM/ACCP/ATS/SIS definitions in critically ill surgical patients: a retrospective observational study. BMC Anesthesiol 10:22. https://doi.org/10.1186/1471-2253-10-22

    Article  PubMed  PubMed Central  Google Scholar 

  49. Sands KE, Bates DW, Lanken PN, Graman PS, Hibberd PL, Kahn KL, Parsonnet J, Panzer R, Orav EJ, Snydman DR, Black E, Schwartz JS, Moore R, Johnson BL Jr, Platt R, Academic Medical Center Consortium Sepsis Project Working (1997) Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA 278:234–240

    Article  CAS  PubMed  Google Scholar 

  50. Jude B, Tissier F, Dubourg A, Droguet M, Castel T, Leon K, Giroux-Metges MA, Pennec JP (2020) TGF-beta Pathway Inhibition Protects the Diaphragm From Sepsis-Induced Wasting and Weakness in Rat. Shock 53:772–778. https://doi.org/10.1097/SHK.0000000000001393

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not Applicable.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Faculty of Pharmacy, Department of Biochemistry, Agri Ibrahim Cecen University, Agri, Turkey

    Harun Un

  2. Faculty of Pharmacy, Department of Pharmacology, Ataturk University, Erzurum, Turkey

    Rustem Anil Ugan

  3. Faculty of Medicine, Department of Pharmacology, Ataturk University, Erzurum, Turkey

    Duygu Kose & Zekai Halici

  4. Faculty of Medicine, Department of Pharmacology, Kafkas University, Kars, Turkey

    Muhammed Yayla

  5. Faculty of Medicine, Department of Histology and Embryology, Erzincan Binali Yıldırım University, Erzincan, Turkey

    Tugba Bal Tastan

  6. Faculty of Pharmacy, Department of Biochemistry, Ataturk University, Erzurum, Turkey

    Yasin Bayir

  7. Clinical Research, Development and Design Application and Research Center, Ataturk University, Erzurum, Turkey

    Duygu Kose & Zekai Halici

Authors
  1. Harun Un
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rustem Anil Ugan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Duygu Kose
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Muhammed Yayla
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tugba Bal Tastan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yasin Bayir
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zekai Halici
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Design and Final Revisions: Harun Un, Zekai Halici, Methods and Animal Procedure: Harun Un, Rustem Anil Ugan, Duygu Kose, Muhammed Yayla, Molecular Analyses: Rustem Anil Ugan, Muhammed Yayla, Histological Analyses: Tugba Bal Tastan, Biochemical Analyses: Yasin Bayir.

Corresponding author

Correspondence to Harun Un.

Ethics declarations

Ethics approval and consent to participate

This study was approved by and performed in accordance with the institutional animal care and use ethics committee of Ataturk University with the protocol number 2019-6/98.

Consent for publication

Yes.

Conflict of interest

There is no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Un, H., Ugan, R.A., Kose, D. et al. A new approach to sepsis treatment by rasagiline: a molecular, biochemical and histopathological study. Mol Biol Rep 49, 3875–3883 (2022). https://doi.org/10.1007/s11033-022-07235-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-022-07235-1

Keywords

Search

Navigation