Effects of conivaptan and mannitol on serum cytokine levels (TNF-α, IL-15 and IL-35) following bilateral carotid artery occlusion

Abstract

This study was aimed to investigate the post-ischemic effects of aquaretic conivaptan and diuretic mannitol on serum tumor necrosis factor-α (TNF-α), interleukin-15 (IL-15) and interleukin-35 (IL-35) levels in an experimental cerebral ischemia-reperfusion (I/R) rat model. Healty male Sprague-Dawley rats were randomly divided into five groups: Control (Sham), I/R (I/R+Saline), MAN (I/R+mannitol), CON10 (I/R+conivaptan 10 mg/ml), and CON20 (I/R+conivaptan 20 mg/ml). Cerebral ischemia was conducted using bilateral common carotid artery occlusion technique. At the onset of reperfusion, saline, conivaptan or mannitol were administrated intravenously. The blood samples were taken at 6th hours of reperfusion. Rat serum TNF-α, IL-15 and IL-35 levels were measured by using commercial ELISA Kits. The biochemical analyses showed that I/R method led to an increase in serum TNF-α and IL-15 levels when compared with the control. Conivaptan treatments decreased TNF-α and IL-15 levels significantly compared to the I/R group (p<0.001). IL-35 levels were high in all ischemia groups, but 10 mg/ml conivaptan brought its levels close to the control (p<0.001). The results of Spearman’s correlation analyses showed that serum TNF-α levels were positively correlated with IL-15 levels (p<0.001, r=0.596) and IL-35 levels (p<0.05, r=0.319). According to our findings on pro-inflammatory and anti-inflammatory cytokine levels, conivaptan was dose-dependently more effective than mannitol in balancing inflammatory response. This study may provide useful information in the development of treatment/follow-up strategies for ischemia and inflammation related diseases such as stroke and brain edema.

Keywords

• brain edema,conivaptan,interleukin,mannitol,serum cytokines

Bilateral Karotis Arter Oklüzyonu Sonrasında Conivaptan ve Mannitol’ün Serum Sitokin (TNF-α, IL-15 ve IL-35) Düzeyleri Üzerine Etkileri

Abstract

Bu çalışmada, deneysel serebral iskemi-reperfüzyon hayvan modelinde akuaretik Conivaptan ve diüretik Mannitol tedavilerinin serum tümör nekroz faktör-α (TNF-α), interlökin-15 (IL-15) ve interlökin-35 (IL-35) düzeylerine post-iskemik etkilerinin araştırılması amaçlanmıştır. Sağlıklı erkek Sprague-Dawley sıçanlar rastgele 5 gruba ayrılmıştır: Kontrol (Sham), I/R (I/R+Salin), MAN (I/R+Mannitol), CON10 (I/R+Conivaptan 10 mg/ml), and CON20 (I/R+Conivaptan 20 mg/ml). Serebral iskemi, bilateral kommon karotis arter oklüzyonu tekniği kullanılarak gerçekleştirilmiştir. Reperfüzyonun başlangıcında salin, conivaptan veya mannitol intravenöz yolla uygulanmıştır. Kan örnekleri reperfüzyonun 6. saatinde alınmıştır. Sıçan TNF-α, IL-15 ve IL-35 serum düzeyleri ticari ELISA kitleri kullanılarak ölçülmüştür. Biyokimyasal analizler, I/R uygulamasının TNF-α ve IL-15 düzeylerinde kontrole göre artışa yol açtığını göstermiştir. Conivaptan tedavileri TNF-α ve IL-15 düzeylerini I/R grubuna göre anlamlı düzeyde azaltmıştır (p<0.001). IL-35 düzeyleri tüm iskemi gruplarında yüksek bulunurken, 10 mg/ml Conivaptan tedavisi IL-35 düzeylerini kontrol grubu düzeylerine yaklaştırmıştır (p<0.001). Yapılan Spearman korelasyon analizleri, serum TNF-α düzeylerinin IL-15 (p<0.001, r=0.596) ve IL-35 (p<0.05, r=0.319) düzeyleri ile pozitif yönde ilişkili olduğunu göstermiştir. Sonuç olarak pro-inflamatuar ve anti-inflamatuar bu sitokin düzeylerine dair bulgularımız, Conivaptan’ın doza bağlı olarak inflamatuar yanıtın dengelenmesinde Mannitol’den daha etkili olduğunu göstermektedir. Bu çalışma, inme ve beyin ödemi gibi iskemi ve inflamasyon ile ilişkili hastalıkların tedavi ve takibine yönelik stratejilerin geliştirilmesinde yararlı bilgiler sağlayabilir.

Keywords

• beyin ödemi,conivaptan,interlökin,mannitol,serum sitokinleri

References

1. Ali F, Raufi MA, Washington B, Ghali JK 2007. Conivaptan: A Dual Receptor Vasopressin V1a/V2 Antagonist. Cardiovasc Drug Rev 25(3): 261-79.
2. Amantea D, Tassorelli C, Petrelli F, Certo M, Bezzi P, Micieli G, Corasaniti MT, Bagetta G 2014. Understanding the multi-faceted role of inflammatory mediators in ischemic stroke. Curr Med Chem 21(18): 2098-2117.
3. Banchereau J, Pascual V, O’Garra A 2012. From IL-2 to IL-37: the expanding spectrum of anti-inflammatory cytokines. Nat Immunol 13(10): 925–931.
4. Barreca T, Gandolfo C, Corsini G, Del Sette M, Cataldi A, Rolandi E, Franceschini R 2001. Evaluation of the secretory pattern of plasma arginine vasopressin in stroke patients. Cerebrovasc Dis 11(2): 113-118.
5. Bonaventura A, Liberale L, Vecchie A, Casula M, Carbone F, Dallegri F, Montecucco F 2016. Update on Inflammatory Biomarkers and Treatments in Ischemic Stroke. Int J Mol Sci 25: 17(12).
6. Budagian V, Bulanova E, Paus R, Bulfone-Paus S 2006. IL-15/IL-15 receptor biology: a guided tour through an expanding universe. Cytokine Growth Factor Rev 17(4): 259-280.
7. Chen M, Xu H 2015. Parainflammation, chronic inflammation and age-related macular degeneration. J Leukoc Biol 98(5): 713–725.
8. Dawson DA., Martin D, Hallenbeck JM 1996. Inhibition of tumor necrosis factor-alpha reduces focal cerebral ischemic injury in the spontaneously hypertensive rat. Neurosci Lett 218(1): 41-44.

9. Embic Z 2015. The Cytokines of the Immune System The Role Of Cytokınes In Dısease Related To Immune Response. USA: Academic Press.
10. Gomez-Nicola D, Valle-Argos B, Pita-Thomas DW, Nieto-Sampedro M 2008. Interleukin 15 Expression in the CNS: Blockade of Its Activity Prevents Glial Activation After an Inflammatory Injury. GLIA 56: 494–505.
11. Grande PO, Romner B 2012. Osmotherapy in brain edema: a questionable therapy. J Neurosurg Anesthesiol 24(4): 407-412.
12. Hallenbeck JM 2002. The many faces of tumor necrosis factor in stroke. Nat Med 8(12): 1363-1368.
13. Iadecola C, Anrather J 2011. The immunology of stroke: from mechanisms to translation. Nat Med 17(7): 796-808.
14. Korenkov AI, Pahnke J, Frei K, Warzok R, Schroeder HW, Frick R, Muljana L, Piek J, Yonekawa Y, Gaab MR 2000. Treatment with nimodipine or mannitol reduces programmed cell death and infarct size following focal cerebral ischemia. Neurosurg Rev 23(3): 145-150.
15. Kumar V, Abbas AK, Aster JC 2012. Robbins Basic Pathology. (8rd Edition). Philadelphia: Saunders, pp 47-119.
16. Lambertsen KL, Biber K, Finsen B 2012. Inflammatory cytokines in experimental and human stroke. J Cereb Blood Flow Metab 32(9): 1677-1698.
17. Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, Feuerstein GZ 1994. Tumor necrosis factor-alpha expression in ischemic neurons. Stroke 25(7): 1481-1488.
18. Medzhitov R 2008. Origin and physiological roles of inflammation. Nature 454(7203): 428-435.
19. Mizuma A, Yenari MA 2017. Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke. Front Neurol 8: 467.
20. Murphy SJ, McCullough LD, Smith JM 2004. Stroke in the female: role of biological sex and estrogen. Ilar J 45(2): 147-159.
21. Nishioku T, Matsumoto J, Dohgu S, Sumi N, Miyao K, Takata F, Shuto H, Yamauchi A, Kataoka Y 2010. Tumor necrosis factor-alpha mediates the blood-brain barrier dysfunction induced by activated microglia in mouse brain microvascular endothelial cells. J Pharmacol Sci 112(2): 251-254.
22. Palmer BF 2015. Vasopressin Receptor Antagonists. Curr Hypertens Rep 17(1): 510.
23. Palmer BF, Rock AD, Woodward EJ 2016. Dose comparison of conivaptan (Vaprisol®) in patients with euvolemic or hypervolemic hyponatremia-efficacy, safety, and pharmacokinetics. Drug Des Devel and Ther 10: 339-351.
24. Pan W, Ding Y, Yu Y, Ohtaki H, Nakamachi T, Kastin AJ 2006. Stroke upregulates TNFalpha transport across the blood-brain barrier. Exp Neurol 198(1): 222-233.
25. Pan W, Wu X, He Y, Hsuchou H, Huang EYK, Mishra PK, Kastin AJ 2013. Brain interleukin-15 in neuroinflammation and behavior. Neurosci Biobehav Rev 37(2): 184–192.
26. Pan W, Yu C, Hsuchou H, Khan RS, Kastin AJ 2009. Cerebral microvascular IL15 is a novel mediator of TNF action. J Neurochem 111(3): 819–827.
27. Patidar M, Yadav N, Dalai SK 2016. Interleukin 15: A key cytokine for immunotherapy. Cytokine Growth Factor Rev 31: 49-59.
28. Peri A 2013. The Use of Vaptans in Clinical Endocrinology. The J Clin Endocrinol Metab 98: 1321–1332.
29. Rabinstein AA 2006. Treatment of cerebral edema. Neurologist 12(2): 59-73.
30. Ramesh G, MacLean AG, Philipp MT 2013. Cytokines and Chemokines at the Crossroads of Neuro-inflammation, Neurodegeneration, and Neuropathic Pain. Mediators Inflamm 2013: 480739.
31. Ransohoff RM, Benveniste EN 2006. CYTOKINES and the CNS (2rd Edition). Boca Raton: CRC Press.
32. Sokoloff L 1997. Anatomy of Cerebral Circulation. In: K.M.A., Caplan L.R., Reis D.J., Siesjo B.K., Weir B. (Eds.). San Diego: Academic Press.
33. Sun L, He C, Nair L, Yeung J, Egwuagu CE 2015. Interleukin 12 (IL-12) family cytokines: Role in immune pathogenesis and treatment of CNS autoimmune disease. Cytokine 75(2): 249-255.
34. Szmydynger-Chodobska J, Zink BJ, Chodobski A 2011. Multiple sites of vasopressin synthesis in the injured brain. J Cereb Blood Flow Metab 31(1): 47-51. Taya K, Gulsen S, Okuno K, Prieto R, Marmarou CR, Marmarou A 2008. Modulation of AQP4 expression by the selective V1a receptor antagonist, SR49059, decreases trauma-induced brain edema. Acta Neurochir Suppl 102: 425-429.
35. Thibonnier M, Coles P, Thibonnier A, Shoham M 2001. The Basic And Clinical Pharmacology of Nonpeptide Vasopressin Receptor Antagonists. Annu Rev Pharmacol Toxicol 41: 175-202.
36. Vignali DAA, Kuchroo VK 2014. IL-12 Family Cytokines: Immunological Playmakers. Nat Immunol 13(8): 722–728.
37. Wada K, Tahara A, Arai Y, Aoki M, Tomura Y, Tsukada J, Yatsu T 2002. Effect of the vasopressin receptor antagonist conivaptan in rats with heart failure following myocardial infarction. Eur J Pharmacol 450(2): 169-177.
38. Wang H, Czura CJ, Tracey KJ 2003. The Cytokine Handbook (4rd Edition). London: Elsevier Science Ltd.
39. Witt KA, Sandoval KE 2014. Steroids and the blood-brain barrier: therapeutic implications. Adv Pharmacol 71: 361-390.
40. Wykes V, Vindlacheruvu R. Intracranial pressure, cerebral blood flow and brain oedema. Surgery (Oxford) 33(8): 355-362.