Cerebral small vessel disease’s impact on the development of chronic cerebral ischemia: paradigms of treatment

The article is dedicated to the issues of treatment of cerebral small vessel disease (CSVD), one of the most common pathological processes that is a leading cause of different types of cerebrovascular disorders and cognitive impairment. It also discusses the reasons for the development of small vessel pathology, which is usually referred to as the “chronic cerebral ischemia” in the Russian neurology. Emphasis is made on the etiopathogenetic factors affecting small calibre vessels, in which the metabolic-angiogenic mechanisms, in particular endothelial dysfunction and oxidative stress, are dominant.

Difficulties in studying CSVD are explained by the disease course features and the insufficient introduction of unified approaches to the terminology and diagnosis. The article presents new data on the pathogenesis of small vessel disease based on the clinical and pathological findings and achievements of neuroimaging. A modern classification is provided, the clinical manifestations of vascular cognitive disorders associated with chronic cerebrovascular insufficiency are described in detail.

The authors consider the issue of choosing and using drugs for the treatment of cerebrovascular diseases through the lens of understanding their own clinical experience and scientific research findings. They provide data of their own research on the antioxidant status and changes in the phospholipid composition of blood plasma in patients with chronic cerebral ischemia during separate and combined administration of 2-ethyl-6-methyl-3-hydroxypyridine-succinate (Neurox) and citicoline (Neupilept), which are natural metabolites and are involved in biochemical processes throughout the body. Based on the literature review and their own data, the authors conclude that complex pharmacological therapy can be effectively used in patients with CSVD, which is due to various points of “application” of pharmacological activity in the pathogenetic processes chain.

1. Blinder P., Tsai P.S., Kaufhold J.P., Knutsen P.M., Suhl H., Kleinfeld D. The cortical angiome: an interconnected vascular network with noncolumnar patterns of blood flow. Nat Neurosci. 2013;16:889–897. doi: 10.1038/nn.3426.

2. Gulevskaya T.S., Morgunov V.A. Pathological anatomy of cerebrovascular accidents with ath¬ erosclerosis and arterial hypertension. Moscow: Meditsina; 2009. 296 p. (In Russ.)

3. Nishimura N., Rosidi N.L, Iadecola C., Schaffer C.B. Limitations of collateral flow after occlusion of a single cortical penetrating arteriole. J Cereb Blood Flow Metab. 2010;30(12):1914– 1927. doi: 10.1038/jcbfm.2010.157.

4. Iadecola C. The pathobiology of vascular dementia. Neuron. 2013;80(4):844–866. doi: 10.1016/j.neuron.2013.10.008.

5. Lozano R., Naghavi M., Kassebaum N.J., Jasrasaria R., Johns N., Wulf S., Chou D., Murray C.J.L. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095–2128. doi: 10.1016/S0140-6736(12)61728-0.

6. Vermeer S.E., Longstreth W.T., Koudstaal P.J. Silent Brain Infarcts: A Systematic Review. Lancet Neurology. 2007;6(7):611–619. doi: 10.1016/S1474-4422(07)70170-9.

7. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurology. 2010;9(7):689–701. doi: 10.1016/S14744422(10)70104-6.

8. Wardlaw J.M., Smith C., Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurology. 2013;12(5):483–497. doi: 10.1016/S1474-4422(13)70060-7.

9. Charidimou A., Pantoni L., Love S. The concept of sporadic cerebral small vessel disease: A road map on key definitions and current concepts. Int J Stroke. 2016;11(1):6–18. doi: 10.1177/1747493015607485.

10. Dunayevskaya S.S., Vinnik Y.S. Development of endothelial dysfunction at an obliterating atherosclerosis of vessels of the lower extremities and markers of prediction the a course of a disease. Byulleten’ sibirskoy medit¬ siny = Bulletin of Siberian Medicine. 2017;16(1):108–118. (In Russ.) doi: 10.20538/1682-0363-2017-1-108-118.

11. Suchkov I.A., Pshennikov A.S., Gerasimov A.A., Agapov A.B., Kamaev A.A. Prophylaxis of restenosis in reconstructive surgery of main arteries. Nauka molodykh (Eruditio Juvenium) = Science of the Young (Eruditio Juvenium). 2013;(2):12–19. (In Russ.) Available at: http://naukamolod.rzgmu.ru/uploads/art/art22_ e8a088.pdf.

12. Nakayama M., Yamamuro M., Takashio S., Uemura T., Nakayama N., Hirakawa K. et al. Late gadolinium enhancement on cardiac magnetic resonance imaging is associated with coronary endothelial dysfunction in patients with dilated cardiomyopathy. Heart Vessels. 2018;33(4):393–402. doi: 10.1007/s00380-017-1069-1.

13. Bryushkov A.I., Ershov P.V., Sergeeva N.A., Bogachev V.Yu. On the possible role of endothelial dysfunction in the development of acute venous thrombosis. Angiologiya i sosudistaya khirurgiya = Angiology and Vascular Surgery. 2016;22(1):91–95. (In Russ.) Available at: http://www.angiolsurgery.org/magazine/2016/1/11.htm.

14. Castro-Ferreira R., Cardoso R., Leite-Moreira A., Mansilha A. The Role of Endothelial Dysfunction and Inflammation in Chronic Venous Disease. Ann Vasc Surg. 2018;46:380– 393. doi: 10.1016/j.avsg.2017.06.131.

15. Frump A., Prewitt A., de Caestecker M. BMPR2 mutations and endothelial dysfunction in pulmonary arterial hypertension (2017 Grover Conference Series). Pulm Circ. 2018;8(2):2045894018765840. doi: 10.1177/2045894018765840.

16. Chong A.-Y., Blann A.D., Lip G.Y.H. Assessment of endothelial damage and dysfunction: observations in relation to heart failure. QJM. 2003;96(4):253–267. doi: 10.1093/qjmed/hcg037.

17. Peng H.Y., Li H.P., Li M.Q. High glucose induces dysfunction of human umbilical vein endothelial cells by upregulating miR-137 in gestational diabetes mellitus. Microvasc Res. 2018;118:90–100. doi: 10.1016/j. mvr.2018.03.002.

18. Wu K.K., Thiagarajan P. Role of endothelium in thrombosis and hemostasis. Annual review of medicine. 1996;47:315–331. doi: 10.1146/annurev.med.47.1.315.

19. Rajendran P., Rengarajan T., Thangavel J., Nishigaki Y., Sakthisekaran D., Sethi G., Nishigaki I. The vascular endothelium and human diseases. Int J Biol Sci. 2013;9(10):1057–1069. doi: 10.7150/ijbs.7502.

20. Chatzizisis Y.S., Coskun A.U., Jonas M., Edelman E.R., Feldman C.L., Stone P.H. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol.2007;49(25):2379–2393. doi: 10.1016/j.jacc.2007.02.059.

21. Papaioannou T.G., Stefanadis C. Vascular wall shear stress: basic principles and methods. Hellenic J Cardiol. 2005;46(1):9–15. Available at: https://www.hellenicjcardiol.org/archive/full_text/2005/1/2005_1_9.pdf.

22. Suchkov I.A. Correction of endothelial dysfunction: current state of the problem (literature review). Rossiyskiy mediko¬biologicheskiy vestnik im. akad. I.P. Pavlova = I.P. Pavlov Russian Medical Biological Herald. 2012;20(4):151–156. (In Russ.) doi: 10.17816/PAVLOVJ20124151-157.

23. Tabit C.E., Chung W.B., Hamburg N.M., Vita J.A. Endothelial dysfunction in diabetes mellitus: molecular mechanisms and clinical implications. Rev Endocr Metab Disord. 2010;11(1):61– 74. doi: 10.1007/s11154-010-9134-4.

24. Heitzer T., Schlinzig T., Krohn K., Meinertz T., Münzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular eventsin patients with coronary artery disease. Circulation. 2001;104(22):2673–2678. doi: 10.1161/hc4601.099485.

25. Neverov I.V. The place of antioxidants in the complex treatment of elderly patients with coronary heart disease. Russkiy meditsinskiy zhurnal = Russian Medical Journal. 2001;9(18):767–769. (In Russ.) Available at: https://www.rmj.ru/articles/kardiologiya/Mesto_antioksidantov_v_kompleksnoy_terapii_ poghilyh_bolynyh_IBS.

26. Nikonov V.V., Nud’ga A.N., Kovaleva E.A., Sidorenko O.A. The place of Actovegin in the treatment of patients with unstable angina pectoris. Meditsina neotlozhnykh sostoyaniy = Emergency Medicine. 2008;(1). (In Russ.) Available at: http://www.mif-ua.com/archive/article/4205.

27. Ushkalova Ye.A. Antioxidant and antihypoxic properties of Actovegin in cardiological patients. Trudnyy patsiyent = Difficult patient. 2005;(3):22–26. (In Russ.) Available at: http://t-pacient.ru/articles/6699/

28. Rumyantseva S.A., Oganov R.G., Silina E.V. Stupin V.A., Bolevich S.B., Svishcheva S.P. et al. Modern treatment strategies in patients with vascular comorbidity. Part 1. Correcting tissue energy deficiency. Kardiovaskulyarnaya terapiya i profilaktika = Cardiovascular Therapy and Preventation. 2012;11(6):44–49. (In Russ.) Available at: https://cardiovascular.elpub.ru/jour/article/viewFile/1965/1620.

29. Allen C.L., Bayraktutan U. Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int J Stroke. 2009;4(6):461–470. doi: 10.1111/j.1747-4949.2009.00387.x.

30. Orlova A.S. Somatic disorders and free radical processes in cerebrovascular disease. Fundamental’nye issledovaniya = Fundamental research. 2012;(8–1):220–224. (In Russ.) Available at: https://www.fundamentalresearch.ru/ru/article/view?id = 30300.

31. Kampoli A.-M., Tousoulis D., Briasoulis A., Latsios G., Papageorgiou N., Stefanadis C. Potential pathogenic inflammatory mechanisms of endothelial dysfunction induced by type 2 diabetes mellitus. Curr Pharm Des. 2011;17(37):4147–4158. doi: 10.2174/138161211798764825.

32. Pantoni L., Gorelick P.B. (eds.) Cerebral Small Vessel Disease. Cambridge: Cambridge University Press, UK; 2014. 371 p. doi: 10.1017/CBO9781139382694.

33. O’Brien J., Ames D., Gustafson L., Folstein M., Chiu E. (eds.). Cerebrovascular Disease and Dementia. London: CRC Press; 2004. doi: 10.3109/9780203495803.

34. Parfenov V.A. Modern aspects of the diagnosis and treatment of chronic cerebral ischemia. Application of naftidrofuryl. Meditsinskiy sovet = Medical Council. 2015(18):11–17. (In Russ.) doi: 10.21518/2079-701X-2015-18-11-17.

35. Gorelick P.B., Scuteri A., Black S.E., Decarli C., Greenberg S.M., Iadecola C. et al. Vascular Contributions to Cognitive Impairment and Dementia: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2011;42(9):2672–2713. doi: 10.1161/STR.0b013e3182299496.

36. Baskys A., Hou A.C. Vascular dementia: Pharmacological treatment approaches and perspectives. Clin Interv Aging. 2007;2(3):327–335. Available at: https://www.ncbi.nlm.nih. gov/pmc/articles/PMC2685259.

37. Adibhatla R.M., Hatcher J.F. Cytidine 5’-diphosphocholine (CDP-choline) in stroke and other CNS disorders. Neurochem Res. 2005;30(1):15– 23. doi: 10.1007/s11064-004-9681-8.

38. Droge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002;82(l):47– 95. doi: 10.1152/physrev.00018.2001.

39. Klebanov G.I., Lyubitsky O.B., Vasiljeva O.V., Klimov Yu.A., Penzulaeva O.B., Teplyashin A.S. et al. Antioxidant properties of analogues of 3-oxypyridine: mexidol, emoxipin and proxypine. Voprosy meditsinskoy khimii =Problems of medical chemistry. 2001;47(3):288–300. (In Russ.) Available at: http://pbmc.ibmc. msk.ru/ru/article-ru/PBMC-2001-47-3-288.

40. Dávalos A., Secades J. Citicoline preclinical and clinical update 2009–2010. Stroke. 2010;42(1–1):36–39. doi: 10.1161/STROKEAHA.110.605568.

41. Dyumaev K.M., Voronina T.A., Smirnov L.D. Antioxidants in the prevention and treatment of CNS pathologies. Moscow: NII BMKH RAMN; 1995. 16 p. (In Russ.)

42. Burlakova E.B. Modification of lipids of the outer membrane of mitochondria of the liver of mice and kinetic parameters of membranebound monoamine oxidase in vivo and in vitro. Voprosy meditsinskoy khimii = Problems of medical chemistry. 1984;(1):66–71. (In Russ.)

43. Fedin A.I., Rumyantseva S.A., Mironova O.P., Yevseyev V.N. The use of the antioxidant Mexidol in patients with acute cerebrovascular accident. Moscow: Russian State Medical University; 2002. 16 p. (In Russ.)

44. Quinn P.J. The effect of tocopherol on the structure and permeability of phosphatidylcholine liposomes. J Control Release. 2012;160(2):158–163. doi: 10.1016/j.jconrel.2011.12.029.

45. Coyle J.T., Puttfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders. Science. 1993;262(5134):689–695. doi: 10.1126/science.7901908.

46. Gutiérrez-Fernández M., Rodríguez-Frutos B., Fuentes B., Vallejo-Cremades M.T., AlvarezGrech J., Expósito-Alcaide M., Díez-Tejedor E. CDP-choline treatment induces brain plasticity markers expression in experimental animal stroke. Neurochem Int. 2012;60(3):310–317. doi: 10.1016/j.neuint.2011.12.015.

47. Adibhatla R.M., Hatcher J.F., Dempsey R.J. Citicoline: neuroprotective mechanisms in cerebral ischemia. Neurochem J. 2002;80(1):12–23. doi: 10.1046/j.0022-3042.2001.00697.x.

48. Saver J.L. Target brain: neuroprotection and neurorestoration in ischemic stroke. Rev Neurol Dis. 2010;7(Suppl 1):14–21. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20410866.

49. Hall A.G. The role of glutathione in the regulation of apoptosis. Eur J Clin Invest 1999;29(3):238–245. doi: 10.1046/j.1365-2362.1999.00447.x.

50. Huang Y., He Q., Zhan L. The effects of CDPCholine on the improvement of the successful rate of cardiopulmonary resuscitation and post-resuscitation cardiac function. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2013;25(2):80–83. doi: 10.3760/cma.j.issn.2095-4352.2013.02.007.