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Cytokine profile in the peripheral blood and the brain in patients with focal drug-resistant epilepsy


Aim. To study markers of blood-brain barrier dysfunction (BBB) in patients with pharmacoresistant epilepsy (PhRE) – the amount of VEGF in endotheliocytes of brain capillaries, TNF-α in brain tissue and cytokine profile in blood serum.
Materials and methods. The study included 30 patients with PhRE who underwent anterior temporal bloc resection. Histological samples of the brain were examined to assess the amount of VEGF and TNF-α; the concentration of cytokines in the blood serum was determined.
Results. In the PhRE group, the densitometric density of cells expressing VEGF and the amount of TNF-α in the epileptogenic focus were higher than in the control groups (p < 0.001; p < 0.05). Compared with the control, the serum concentrations of IL-2 (0.98 ± 0.28 pg/ml vs. 2.80 ± 0.71 pg/ml; p < 0.001), IL-8 (14.04 ± 1.46 pg/ml vs. 26.13 ± 3.80 pg/ml; p < 0.001) and EGF (43.72 ± 5.63 pg/ml vs. 83.62 ± 24.06 pg/ml; p < 0.05) were statistically significantly lower in the PhRE group, and the amount of TNF-α (33.09 ± 1.23 pg/ml vs. 24.85 ± 1.32 pg/ml, p < 0.05), IL-4 (43.73 ± 2.57 pg/ml vs. 32.37 ± 5.80 pg/ml, p < 0.05), IL-5 (43.73 ± 2.57 pg/ml vs. 32.37 ± 5.80 pg/ml; p < 0.05), IL-7 (16.65 ± 3.07 pg/ml vs. 8.13 ± 1.67 pg/ml; p < 0.05), GRO (growth-regulated protein) (3054.0 ± 200.8 pg/ml vs. 1367.0 ± 187.3 pg/ml; p < 0.001), VEGF (316.10 ± 55.28 pg/ml vs. 95.22 ± 15.78 pg/ml; p < 0.01) are statistically significantly higher. There were no significant differences in the concentration of IL-1β, IL-1RA, IL-10 and IFN-γ between the PhRE group and the control.
Conclusion. Based on the studied cytokine profile, there is no systemic inflammation in patients with PhRE. The established overexpression of VEGF in the brain and an increase in its concentration in the blood, combined with a decrease in serum EGF concentrations and an increase in GRO, as well as pro-inflammatory factors, indicates damage to the BBB. A high amount of TNF-α in the epileptic focus indicates neuroinflammation, and an increased concentration of this marker can be found in the blood of patients with BBB dysfunction.

About the Authors

D. A. Sitovskaia
Polenov Neurosurgical Institute – Branch of Almazov National Medical Research Centre; Saint Petersburg State Pediatric Medical University
Russian Federation

 pathologist, researcher, Research Laboratory of Nervous System Pathomorphology; Assistant Professor, Department of Pathology 

 Tel.: +7 (981) 761-31-97 

12, Mayakovskogo str., Saint-Petersburg, 191014, Russia

2, Litovskaya str., Saint-Petersburg, 194100, Russia

A. V. Litovchenko
Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences
Russian Federation

post-graduate student, Laboratory of Comparative Biochemistry and Cellular Functions

44, Toreza av., Saint-Petersburg, 194223, Russia

E. D. Bazhanova
Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences; Golikov Research Clinical Center of Toxicology under the Federal Medical Biological Agency; Astrakhan State University
Russian Federation

 Dr. of Sci. (Med.), Leading Researcher, Laboratory of Comparative Biochemistry and Cellular Functions; Head of the Laboratory of Morphology and Electron Microscopy; Senior Researcher,  Department of Biochemistry

44, Toreza av., Saint-Petersburg, 194223, Russia

1, Bechtereva str., Saint-Petersburg, 192019, Russia 

 20a, Tatischeva str., Astrakhan, 414000, Russia 

E. N. Skiteva
Polenov Neurosurgical Institute – Branch of Almazov National Medical Research Centre
Russian Federation

 junior researcher, Research Laboratory of Nervous System Pathomorphology

 12, Mayakovskogo str., Saint-Petersburg, 191014, Russia 

Yu. M. Zabrodskaia
Polenov Neurosurgical Institute – Branch of Almazov National Medical Research Centre; Golikov Research Clinical Center of Toxicology under the Federal Medical Biological Agency; S.M. Kirov Military Medical Academy
Russian Federation

 Dr. of Sci. (Med.), Head of the Research Laboratory of Nervous System Pathomorphology; Leading Researcher, Laboratory of Morphology and Electron Microscopy; Associate Professor, Department of Pathology

 12, Mayakovskogo str., Saint-Petersburg, 191014, Russia 

1, Bechtereva str., Saint-Petersburg, 192019, Russia

6, Academician Lebedev str., Saint-Petersburg, 194044, Russia


1. Sheng J., Liu S., Qin H., et al. Drug-Resistant epilepsy and surgery. Curr Neuropharmacol. 2018; 16(1): 17–28. PMID: 28474565.

2. Sone D. Making the Invisible Visible: Advanced Neuroimaging Techniques in Focal Epilepsy. Front Neurosci. 2021 Jul 27; 15: 699176. PMID: 34385902.

3. Abbott N.J., Friedman A. Overview and introduction: the bloodbrain barrier in health and disease. Epilepsia. 2012 Nov; 53 Suppl 6(0 6): 1–6. PMID: 23134489.

4. Friedman A., Heinemann U. Role of blood-brain barrier dysfunction in epileptogenesis. In: Noebels J.L., Avoli M., Rogawski M.A., Olsen R.W., Delgado-Escueta A.V., editors. Jasper’s Basic Mechanisms of the epilepsies. 4th ed. Bethesda (MD): National Center for Biotechnology Information (US); 2012. PMID: 22787606.

5. Baruah J., Vasudevan A., Köhling R. Vascular Integrity and Signaling Determining Brain Development, Network Excitability, and Epileptogenesis. Front Physiol. 2020 Jan 22;10:1583. PMID: 32038280.

6. Commins S.P., Borish L., Steinke J.W. Immunologic messenger molecules: cytokines, interferons, and chemokines. J Allergy Clin Immunol. 2010 Feb; 125(2 Suppl 2): S53–72. Epub 2009 Nov 24. PMID: 19932918.

7. Geiseler S.J., Morland C. The Janus face of VEGF in stroke. Int J Mol Sci. 2018 May 4; 19(5): 1362. PMID: 29734653.

8. Sweeney M.D., Zhao Z., Montagne A., et al. Blood-brain barrier: from physiology to disease and back. Physiol Rev. 2019 Jan 1; 99(1): 21–78. PMID: 30280653.

9. Ureña-Guerrero M.E., Castañeda-Cabral J.L., Rivera-Cervantes MC, et al. Neuroprotective and neurorestorative effects of EPO and VEGF: perspectives for new therapeutic approaches to neurological diseases. Curr Pharm Des. 2020; 26(12): 1263–1276. PMID:31942853.

10. Castañeda-Cabral J.L., Beas-Zárate C., Rocha-Arrieta L.L., et al. Increased protein expression of VEGF-A, VEGF-B, VEGF-C and their receptors in the temporal neocortex of pharmacoresistant temporal lobe epilepsy patients. J Neuroimmunol. 2019 Mar 15; 328: 68–72. Epub 2018 Dec 21. PMID: 30597392.

11. Kan A.A., de Jager W., de Wit M., et al. Protein expression profiling of inflammatory mediators in human temporal lobe epilepsy reveals co-activation of multiple chemokines and cytokines. J Neuroinflammation. 2012 Aug 30; 9: 207. PMID: 22935090.

12. Aalbers M.W., Rijkers K., Majoie H.J., et al. The influence of neuropathology on brain inflammation in human and experimental temporal lobe epilepsy. J Neuroimmunol. 2014 Jun 15; 271(1–2): 36–42. Epub 2014 Mar 29. PMID: 24746448.

13. Fiala M., Avagyan H., Merino J.J., et al. Chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy. Pathophysiology. 2013 Feb; 20(1): 59–69. Epub 2012 Mar 22. PMID: 22444245.

14. Omran A., Peng J., Zhang C., et al. Interleukin-1β and microRNA-146a in an immature rat model and children with mesial temporal lobe epilepsy. Epilepsia. 2012 Jul; 53(7): 1215–1224. Epub 2012 Jun 18. PMID: 22708826.

15. Nowak M., Bauer S., Haag A., et al. Interictal alterations of cytokines and leukocytes in patients with active epilepsy. Brain Behav Immun. 2011 Mar; 25(3): 423–428. Epub 2010 Oct 25. PMID: 20977934.

16. Uludag I.F., Bilgin S., Zorlu Y., et al. Interleukin-6, interleukin-1 beta and interleukin-1 receptor antagonist levels in epileptic seizures. Seizure. 2013 Jul; 22(6): 457–461. Epub 2013 Apr 6. PMID: 23566695.

17. Curia G., Longo D., Biagini G., et al. The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods. 2008 Jul 30; 172(2): 143–157. Epub 2008 Apr 26. PMID: 18550176.

18. Gao F., Gao Y., Zhang S.J., et al. Alteration of plasma cytokines in patients with active epilepsy. Acta Neurol Scand. 2017 Jun; 135(6): 663–669. Epub 2016 Sep 4. PMID: 27593211.

19. Rahman M.T., Ghosh C., Hossain M., et al. IFN-γ, IL-17A, or zonulin rapidly increase the permeability of the blood-brain and small intestinal epithelial barriers: relevance for neuroinflammatory diseases. Biochem Biophys Res Commun. 2018 Dec 9; 507(1–4): 274–279. Epub 2018 Nov 16. PMID: 30449598.

20. Beattie E.C., Stellwagen D., Morishita W., et al. Control of synaptic strength by glial TNFalpha. Science. 2002 Mar 22; 295(5563): 2282–2285. PMID: 11910117.

21. Stellwagen D., Beattie E.C., Seo J.Y., Malenka R.C. Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci. 2005 Mar 23; 25(12): 3219–3228. Erratum in: J Neurosci. 2005 Jun 1; 25(22): 1 p following 5454. PMID: 15788779.

22. Bazhanova E.D., Kozlov A.A., Litovchenko A.V. Mechanisms of drug resistance in the pathogenesis of epilepsy: role of neuroinflammation. A literature review. Brain Sci. 2021 May 19; 11(5): 663. PMID: 34069567.

23. Matkar P.N., Ariyagunarajah R., Leong-Poi H., Singh K.K. Friends turned foes: angiogenic growth factors beyond angiogenesis. Biomolecules. 2017 Oct 2; 7(4): 74. PMID: 28974056.

24. Sladojevic N., Stamatovic S.M., Johnson A.M., et al. Claudin-1-dependent destabilization of the blood-brain barrier in chronic stroke. J Neurosci. 2019 Jan 23; 39(4): 743–757. Epub 2018 Nov 30. PMID: 30504279.

25. 25 Zhu H., Zhang Y., Zhong Y., et al. Inflammation-mediated angiogenesis in ischemic stroke. Front Cell Neurosci. 2021 Apr 21; 15: 652647. PMID: 33967696.

26. Mühleder S., Fernández-Chacón M., Garcia-Gonzalez I., Benedito R. Endothelial sprouting, proliferation, or senescence: tipping the balance from physiology to pathology. Cell Mol Life Sci. 2021 Feb; 78(4): 1329–1354. Epub 2020 Oct 19. PMID: 33078209.

27. Son D.S., Parl A.K., Rice V.M., Khabele D. Keratinocyte chemoattractant (KC)/human growth-regulated oncogene (GRO) chemokines and pro-inflammatory chemokine networks in mouse and human ovarian epithelial cancer cells. Cancer Biol Ther. 2007 Aug; 6(8): 1302–1312. Epub 2007 May 26. PMID: 17712227.

28. Øbro N.F., Grinfeld J., Belmonte M., et al. Longitudinal cytokine profiling identifies GRO-α and EGF as potential biomarkers of disease progression in essential thrombocythemia. Hemasphere. 2020 May 21; 4(3): e371. PMID: 32647796.

29. Nii T., Yumoto H., Hirota K., Miyake Y. Anti-inflammatory effects of olanexidine gluconate on oral epithelial cells. BMC Oral Health. 2019 Nov 8; 19(1): 239. PMID: 31703580.

30. Griffith J.W., Sokol C.L., Luster A.D. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev Immunol. 2014; 32: 659–702. PMID: 24655300.

31. Abbott N.J., Patabendige A.A., Dolman D.E., et al. Structure and function of the blood-brain barrier. Neurobiol Dis. 2010 Jan; 37(1): 13–25. Epub 2009 Aug 5. PMID: 19664713.

32. Pérez-Pérez D., Frías-Soria C.L., Rocha L. Drug-resistant epilepsy: From multiple hypotheses to an integral explanation using preclinical resources. Epilepsy Behav. 2021 Aug; 121(Pt B): 106430. Epub 2019 Aug 2. PMID: 31378558.

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