Применение микрорибонуклеиновых кислот в терапии ишемического инсульта

Инсульт является одной из ведущих причин смерти и инвалидности во всем мире. Последствия инсульта проявляются глубокой и стойкой клинической симптоматикой, что в значительной степени ложится бременем, как на пациента, так и на общество. Текущие методы лечения ишемического инсульта оказались недостаточными, отчасти из-за неполного понимания клеточных и молекулярных изменений, происходящих при инсульте. Микрорибонуклеиновые кислоты (микроРНК) представляют собой эндогенно экспрессируемые молекулы рибонуклеиновой кислоты (РНК) длиной 18-22 нуклеотида, которые подавляют экспрессию гена на посттранскрипционном уровне путем связывания с 3'-нетранслируемой областью матричных рибонуклеиновых кислот-мишеней. МикроРНК участвуют практически во всех биологических процессах, включая клеточную пролиферацию, апоптоз и дифференцировку клеток, но и так же играют ключевую роль в патофизиологических процессах, способствующих ишемическому поражению. Более того, микроРНК могут представлять собой не только как потенциальные биомаркеры, но и стать новыми терапевтическими мишенями в клинической практике, что опять же подтверждает необходимость их изучения. Терапия, основанная на микроРНК, включает агонисты или мимики и ингибиторы (антагомиры), что соответственно уменьшает и увеличивает экспрессию генов-мишеней. В этом обзоре суммируются современные знания на текущий момент о фундаментальных исследованиях применения микроРНК в лечении инсульта. Обсуждаются методы лечения, временные окна и дозировки для эффективной доставки препаратов, основанных на микроРНК, в центральную нервную систему. Рассматриваются воздействия микроРНК-терапии на основные патологические механизмы инсульта, включая окислительный стресс, воспаление, апоптоз, ангиогенез, нейрогенез и сохранность гематоэнцефалического барьера.

1. Mendis S, Davis S, Norrving B. Organizational update: the world health organization global status report on noncommunicable diseases 2014; one more landmark step in the combat against stroke and vascular disease. Stroke. 2015;46:e121-2. doi:10.1161/STROKEAHA.115.008097.

2. Zhang R, Zhang Z, Chopp M. Function of neural stem cells in ischemic brain repair processes. J Cereb Blood Flow Metab. 2016;36:2034-43. doi:10.1177/0271678X16674487.

3. Stylli SS, Adamides AA, Koldej RM, et al. MiRNA expression profiling of cerebrospinal fluid in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg. 2017;126(4):1131-9. doi:10.3171/2016.1.JNS151454.

4. Powers CJ, Dickerson R, Zhang SW, et al. Human cerebrospinal fluid microRNA: temporal changes following subarachnoid hemorrhage. Physiol Genomics. 2016;48(5):361-6. doi:10.1152/physiolgenomics.00052.2015.

5. Hayes J, Peruzzi PP and Lawler S. MicroRNAs in cancer: biomarkers, functions and therapy. Trends Mol Med. 2014;20:460-9. doi:10.1016/j.molmed.2014.06.005.

6. Jickling GC, Ander BP, Zhan X, et al. MicroRNA expression in peripheral blood cells following acute ischemic stroke and their predicted gene targets. PLoS One. 2014;9:e99283. doi:10.1371/journal.pone.0099283.

7. Christopher AF, Kaur RP, Kaur G, et al. MicroRNA therapeutics: discovering novel targets and developing specific therapy. Perspect Clin Res. 2016;7:68-74. doi:10.4103/2229-3485.179431.

8. Rupaimoole R and Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16:203-22. doi:10.1038/nrd.2016.246.

9. Schmidt MF. Drug target miRNAs: chances and challenges. Trends Biotechnol. 2014;32:578-85. doi:10.1016/j.tibtech.2014.09.002.

10. Yin KJ, Deng Z, Huang H, et al. MiR-497 regulates neuronal death in mouse brain after transient focal cerebral ischemia. Neurobiol Dis. 2010;38:17-26. doi:101016/j.nbd.2009.12.021.

11. Selvamani A, Sathyan P, Miranda RC, et al. An antagomir to microRNA Let7f promotes neuroprotection in an ischemic stroke model. PLoS One. 2012;7:e32662. doi:10.1371/journal.pone.0032662.

12. Ouyang YB, Lu Y, Yue S, et al. miR-181 regulates GRP78 and influences outcome from cerebral ischemia in vitro and in vivo. Neurobiol Dis. 2012;45:555-63. doi:10.1016/j.nbd.2011.09.012.

13. Yang X, Tang X, Sun P, et al. MicroRNA-15a/16-1 antagomir ameliorates ischemic brain injury in experimental stroke. Stroke. 2017;48:1941-7. doi:10.1161/STROKEAHA.117.017284.

14. Zhao H, Tao Z, Wang R, et al. MicroRNA-23a-3p attenuates oxidative stress injury in a mouse model of focal cerebral ischemia-reperfusion. Brain Res. 2014;1592:65-72. doi:10.1016/j.brainres.2014.09.055.

15. Liu P, Zhao H, Wang R, et al. MicroRNA-424 protects against focal cerebral ischemia and reperfusion injury in mice by suppressing oxidative stress. Stroke. 2015 ;46:513-9. doi:10.1161/STROKEAHA.114.007482.

16. Sun Y, Gui H, Li Q, et al. MicroRNA-124 protects neurons against apoptosis in cerebral ischemic stroke. CNS Neurosci Ther. 2013;19:813-9. doi:10.1111/cns.12142.

17. Liu DZ, Jickling GC, Ander BP, et al. Elevating microRNA-122 in blood improves outcomes after temporary middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab. 2016;36:1374-83. doi:10.1177/0271678X15610786.

18. Krdtzfeldt J. Strategies to use microRNAs as therapeutic targets. Best Pract Res Clin Endocrinol Metab. 2016 Oct;30(5):551-61. doi:10.1016/j.beem.2016.07.004.

19. Zhang Y, Wang Z and Gemeinhart RA. Progress in microRNA delivery. J Control Release. 2013;172:962-74. doi:10.1016/j.jconrel.2013.09.015.

20. Ni J, Wang X, Chen S, et al. MicroRNA let-7c-5p protects against cerebral ischemia injury via mechanisms involving the inhibition of microglia activation. Brain Behav Immun. 2015;49:75-85. doi:10.1016/j.bbi.2015.04.014.

21. Tao Z, Zhao H, Wang R, et al. Neuroprotective effect of microRNA-99a against focal cerebral ischemia-reperfusion injury in mice. J Neurol Sci. 2015;355:113-9. doi:10.1016/j.jns.2015.05.036.

22. Li Y, Mao L, Gao Y, et al. MicroRNA-107 contributes to post-stroke angiogenesis by targeting Dicer-1. Sci Rep. 2015;5:13316. doi:10.1038/srep13316.

23. Tao J, Liu W, Shang G, et al. MiR-207/352 regulate lysosomal-associated membrane proteins and enzymes following ischemic stroke. Neuroscience. 2015;305:1-14. doi:10.1016/j.neuroscience.2015.07.064.

24. Liu FJ, Kaur P, Karolina DS, et al. MiR-335 regulates hif-1alpha to reduce cell death in both mouse cell line and rat ischemic models. PLoS One. 2015;10:e0128432. doi:10.1371/journal.pone.0128432.

25. Zhang N, Zhong J, Han S, et al. MicroRNA-378 alleviates cerebral ischemic injury by negatively regulating apoptosis executioner caspase-3. Int J Mol Sci. 2016;17:1427 doi:10.3390/ijms17091427.

26. Liu W, Chen X, Zhang Y. Effects of microRNA-21 and microRNA-24 inhibitors on neuronal apoptosis in ischemic stroke. Am J Transl Res. 2016;8:3179-87.

27. Stary CM, Xu L, Sun X, et al. MicroRNA-200c contributes to injury from transient focal cerebral ischemia by targeting reelin. Stroke. 2015;46:551-6. doi:10.1161/STROKEAHA.114.007041.

28. Xing G, Luo Z, Zhong C, et al. Influence of miR-155 on cell apoptosis in rats with ischemic stroke: role of the ras homolog enriched in brain (Rheb)/mTOR pathway. Med Sci Monit. 2016;22:5141-53. doi:10.12659/MSM.898980.

29. Yi H, Huang Y, Yang F, et al. MicroRNA-182 aggravates cerebral ischemia injury by targeting inhibitory member of the ASPP family (iASPP). Arch Biochem Biophys. 2017;620:52-8. doi:10.1016/j.abb.2016.05.002.

30. Li Q, He Q, Baral S, et al. MicroRNA-493 regulates angiogenesis in a rat model of ischemic stroke by targeting MIF. FEBS J 2016;283:1720-33. doi:10.1111/febs.13697.

31. Wang P, Liang X, Lu Y, et al. MicroRNA-93 downregulation ameliorates cerebral ischemic injury through the Nrf2/HO-1 defense pathway. Neurochem Res. 2016;41:2627-35. doi:10.1007/s11064-016-1975-0.

32. Fang Z, He QW, Li Q, et al. MicroRNA-150 regulates blood-brain barrier permeability via Tie-2 after permanent middle cerebral artery occlusion in rats. FASEB J. 2016;30:2097-107. doi:10.1096/fj.201500126.

33. Ma Q, Dasgupta C, Li Y, et al. Inhibition of microRNA-210 provides neuroprotection in hypoxicischemic brain injury in neonatal rats. Neurobiol Dis. 2016;89:202-12. doi:10.1016/j.nbd.2016.02.011.

34. Zhao F, Qu Y, Zhu J, et al. miR-30d-5p plays an important role in autophagy and apoptosis in developing rat brains after hypoxic-ischemic injury. J Neuropathol Exp Neurol. 2017;76:709-19. doi:10.1093/jnen/nlx052.

35. Li XQ, Lv HW, Wang ZL, et al. MiR-27a ameliorates inflammatory damage to the blood-spinal cord barrier after spinal cord ischemia: reperfusion injury in rats by downregulating TICAM-2 of the TLR4 signaling pathway. J Neuroinflammation. 2015;12:25. doi:10.1186/s12974-015-0246-3.

36. Li XQ, Fang B, Tan WF, et al. MiR-320a affects spinal cord edema through negatively regulating aquaporin-1 of blood-spinal cord barrier during bimodal stage after ischemia reperfusion injury in rats. BMC Neurosci. 2016;17:10. doi:101186/s12868-016-0243-1.

37. He F, Ren Y, Shi E, et al. Overexpression of microRNA-21 protects spinal cords against transient ischemia. J Thorac Cardiovasc Surg. 2016;152:1602-8. doi: 10.1016/j.jtcvs.2016.07.065.

38. Xu M, Wang HF, Zhang YY, et al. Protection of rats spinal cord ischemia-reperfusion injury by inhibition of MiR-497 on inflammation and apoptosis: possible role in pediatrics. Biomed Pharmacother. 2016;81:337-44. doi:10.1016/j.biopha.2016.04.028.

39. Caballero-Garrido E, Pena-Philippides JC, Lordkipanidze T, et al. In vivo inhibition of miR-155 promotes recovery after experimental mouse stroke. J Neurosci. 2015;35:12446-64. doi:10.1186/s12974-016-0753-x.

40. Li P, Shen M, Gao F, et al. An antagomir to microRNA-106b-5p ameliorates cerebral ischemia and reperfusion injury in rats via inhibiting apoptosis and oxidative stress. Mol Neurobiol. 2017;54:2901-21. doi:10.1007/s12035-016-9842-1.

41. Wang X, Suofu Y, Akpinar B, et al. Systemic antimiR-337-3p delivery inhibits cerebral ischemia-mediated injury. Neurobiol Dis. 2017;105:156-63. doi:101016/j.nbd.2017.04.018.

42. Wei N, Xiao L, Xue R, et al. MicroRNA-9 mediates the cell apoptosis by targeting Bcl2l11 in ischemic stroke. Mol Neurobiol. 2016;53:6809-17. doi:101007/s12035-015-9605-4.

43. Liu da Z, Jickling GC, Ander BP, et al. Elevating microRNA-122 in blood improves outcomes after temporary middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab. 2016;36:1374-83. doi:10.1177/0271678X15610786.

44. Tian F, Yuan C, Hu L, et al. MicroRNA-93 inhibits inflammatory responses and cell apoptosis after cerebral ischemia reperfusion by targeting interleukin-1 receptorassociated kinase 4. Exp Ther Med. 2017;14:2903-10. doi:10.3892/etm.2017.4874.

45. Selvamani A, Sohrabji F. Mir363-3p improves ischemic stroke outcomes in female but not male rats. Neurochem Int. 2017;107:168-81. doi:10.1016/j.neuint.2016.10.008.

46. Wang Y, Huang J, Ma Y, et al. MicroRNA-29b is a therapeutic target in cerebral ischemia associated with aquaporin 4. J Cereb Blood Flow Metab. 2015;35:1977-84. doi :10.1038/jcbfm.2015.156.

47. Yu H, Wu M, Zhao P, et al. Neuroprotective effects of viral overexpression of microRNA-22 in rat and cell models of cerebral ischemia-reperfusion injury. J Cell Biochem. 2015;116:233-41. doi:10.1002/jcb.24960.

48. Zeng LL, He XS, Liu JR, et al. Lentivirus-Mediated overexpression of microRNA-210 improves long-term outcomes after focal cerebral ischemia in mice. CNS Neurosci Ther. 2016;22:961-9. doi:10.1111/cns.12589.

49. Wang P, Liang J, Li Y, et al. Down-regulation of miRNA-30a alleviates cerebral ischemic injury through enhancing beclin 1-mediated autophagy. Neurochem Res. 2014;39:1279-91. doi:10.1007/s11064-014-1310-6.

50. Chi W, Meng F, Li Y, et al. Impact of microRNA-134 on neural cell survival against ischemic injury in primary cultured neuronal cells and mouse brain with ischemic stroke by targeting HSPA12B. Brain Res. 2014;1592:22-33. doi: 10.1016/j.brainres.2014.09.072.

51. He F, Shi E, Yan L, et al. Inhibition of micro-ribonucleic acid-320 attenuates neurologic injuries after spinal cord ischemia. J Thorac Cardiovasc Surg. 2015;150:398-406. doi:10.1016/j.jtcvs.2015.03.066.

52. Liu K, Yan L, Jiang X, et al. Acquired inhibition of microRNA-124 protects against spinal cord ischemiareperfusion injury partially through a mitophagy-dependent pathway. J Thorac Cardiovasc Surg. 2017;154:1498-508. doi:10.1016/j.jtcvs.2017.05.046.

53. Javeed N, Mukhopadhyay D. Exosomes and their role in the micro-/macro-environment: a comprehensive review. J Biomed Res. 2017;31:386-94. doi:10.7555/JBR.30.20150162.

54. Luarte A, Batiz LF, Wyneken U, Lafourcade C. Potential therapies by stem cell-derived exosomes in CNS diseases: focusing on the neurogenic niche. Stem Cells Int. 2016;2016:5736059. doi:10.1155/2016/5736059.

55. Phinney DG, Di Giuseppe M, Njah J, et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015;6:8472. doi:10.1038/ncomms9472.

56. Zhang Y, Chopp M, Liu XS, et al. Exosomes derived from mesenchymal stromal cells promote axonal growth of cortical neurons. Mol Neurobiol. 2017;54:2659-73. doi:10.1007/s12035-016-9851-0.

57. Xin H, Li Y, Buller B, et al. Exosomemediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells. 2012;30:1556-64. doi:10.1002/stem.1129.

58. Xin H, Katakowski M, Wang F, et al. MicroRNA cluster miR-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke. 2017;48:747-53. doi:10.1161/STROKEAHA.116.015204.

59. Zhang Y, Ueno Y, Liu XS, et al. The microRNA-17-92 cluster enhances axonal outgrowth in embryonic cortical neurons. J Neurosci. 2013;33:6885-94. doi:10.1523/JNEUROSCI.5180-12.2013.

60. Xin H, Wang F, Li Y, et al. Secondary release of exosomes from astrocytes contributes to the increase in neural plasticity and improvement of functional recovery after stroke in rats treated with exosomes harvested from microRNA 133b-overexpressing multipotent mesenchymal stromal cells. Cell Transplant. 2017;26:243-57. doi:10.3727/096368916X693031.

61. Hamzei Taj S, Kho W, Riou A, et al. MiRNA-124 induces neuroprotection and functional improvement after focal cerebral ischemia. Biomaterials. 2016;91:151-65. doi:10.1016/j.biomaterials.2016.03.025.

62. Qu Y, Wu J, Chen D, et al. MiR-139-5p inhibits HGTD-P and regulates neuronal apoptosis induced by hypoxia-ischemia in neonatal rats. Neurobiol Dis. 2014;63:184-93. doi:10.1016/j.nbd.2013.11.023.

63. Sepramaniam S, Armugam A, Lim KY, et al. MicroRNA 320a functions as a novel endogenous modulator of aquaporins 1 and 4 as well as a potential therapeutic target in cerebral ischemia. J Biol Chem. 2010;285:29223-30. doi: 10.1074/jbc.M110.144576.

64. Zhang L, Chopp M, Liu X, et al. Combination therapy with VELCADE and tissue plasminogen activator is neuroprotective in aged rats after stroke and targets microRNA-146a and the toll-like receptor signaling pathway. Arterioscler Thromb Vasc Biol. 2012;32:1856-64. doi:10.1161/ATVBAHA.112.252619/-/DC1.

65. Wen Y, Zhang X, Dong L, et al. Acetylbritannilactone modulates microRNA-155-mediated inflammatory response in ischemic cerebral tissues. Mol Med. 2015;21:197-209. doi:10.2119/molmed.2014.00199.

66. Dong YF, Chen ZZ, Zhao Z, et al. Potential role of microRNA-7 in the antineuroinflammation effects of nicorandil in astrocytes induced by oxygen-glucose deprivation. J Neuroinflammation. 2016;13:60. doi:10.1186/s12974-016-0527-5.

67. Li L, Jiang HK, Li YP, et al. Hydrogen sulfide protects spinal cord and induces autophagy via miR-30c in a rat model of spinal cord ischemia-reperfusion injury. J Biomed Sci. 2015;22:50. doi:10.1186/s12929-015-0135-1.

68. Yao S, Tang B, Li G, et al. miR-455 inhibits neuronal cell death by targeting TRAF3 in cerebral ischemic stroke. Neuropsychiatr Dis Treat. 2016;12:3083-92. doi:10.2147/NDT.S121183.

69. Xu LJ, Ouyang YB, Xiong X, et al. Post-stroke treatment with miR-181 antagomir reduces injury and improves long-term behavioral recovery in mice after focal cerebral ischemia. Exp Neurol. 2015;264:1-7. doi:10.1016/j.expneurol.2014.11.007.

70. Harraz MM, Eacker SM, Wang X, et al. MicroRNA-223 is neuroprotective by targeting glutamate receptors. Proc Natl Acad Sci USA. 2012;109:18962-7. doi: 101073/pnas.1121288109.

71. Moon JM, Xu L and Giffard RG. Inhibition of microRNA-181 reduces forebrain ischemia-induced neuronal loss. J Cereb Blood Flow Metab. 2013;33:1976-82. doi :101038/jcbfm.2013.157.

72. Liu X, Li F, Zhao S, et al. MicroRNA-124-mediated regulation of inhibitory member of apoptosis-stimulating protein of p53 family in experimental stroke. Stroke. 2013;44:1973-80. doi:10.1161/STROKEAHA.111.000613.

73. Zhao H, Wang J, Gao L, et al. MiRNA-424 protects against permanent focal cerebral ischemia injury in mice involving suppressing microglia activation. Stroke. 2013;44:1706-13. doi:10.1161/STROKEAHA.111.000504.

74. Sepramaniam S, Armugam A, Lim KY, et al. MicroRNA 320a functions as a novel endogenous modulator of aquaporins 1 and 4 as well as a potential therapeutic target in cerebral ischemia. J Biol Chem. 2010;285:29223-30. doi: 101074/jbc.M110144576.

75. Sepramaniam S, Ying LK, Armugam A, et al. MicroRNA-130a represses transcriptional activity of aquaporin 4 M1 promoter. J Biol Chem. 2012;287:12006-15. doi:101074/ jbc.M111.280701.

76. Xin H, Katakowski M, Wang F, et al. MicroRNA cluster miR-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke. 2017;48:747-53. doi:10.1161/STROKEAHA.116.015204.