Патогенетические сценарии развития ишемии головного мозга и основные элементы ишемического каскада

   Ишемический инсульт занимает одно из лидирующих мест среди всех причин инвалидизации и смертности. Ключевыми подходами к лечению этой патологии являются тромболитическая терапия и тромбоаспирация. Несмотря на доказанную эффективность, применение этих методов ограничено сравнительно узким терапевтическим окном. Учитывая это, сохраняется большая актуальность в дальнейшем изучении молекулярных механизмов ишемического-реперфузионного повреждения головного мозга в рамках концепции ишемического каскада. Воздействие на механизмы индукции и реализации различных видов программируемой клеточной гибели с помощью фармакологических агентов представляет собой перспективный подход к ослаблению повреждения головного мозга при ишемическом инсульте. В настоящем обзоре рассмотрены ключевые процессы, ведущие к необратимому повреждению нейронов и их гибели. Детально рассмотрены механизмы формирования и роль эксайтотоксичности, кальциевой перегрузки, оксидативного и нитрозильного стресса, дисфункции митохондрий, а также запуск сигнальных путей апоптоза и асептического воспаления. Обсужден вопрос различных вариантов клеточной гибели на фоне этих патологических процессов. Наряду с рассмотрением сигнальных путей, способствующих прогрессии повреждения головного мозга, отдельное внимание уделено активации при ишемии протективных сигнальных механизмов, обеспечивающих повышение резистентности клетки к гибели.

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

2. Lo Eng H, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 2003; 4(5):399–415. DOI: 10.1038/nrn1106.

3. Moskowitz MA, Lo Eng H, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010; 67(2):181–198. DOI: 10.1016/j.neuron.2010.07.002.

4. Markus HS, de Leeuw FE. Cerebral small vessel disease: Recent advances and future directions. Int J Stroke. 2023; 18(1):4–14. DOI: 10.1177/17474930221144911.

5. Faraco G, Iadecola C. Hypertension: a harbinger of stroke and dementia. Hypertension. 2013; 62(5):810–817. DOI: 10.1161/HYPERTENSIONAHA.113.01063.

6. Ungvari Z, Toth P, Tarantini S, et al. Hypertension-induced cognitive impairment: from pathophysiology to public health. Nat Rev Nephrol. 2021; 17(10):639–654. doi: 10.1038/s41581-021-00430-6.

7. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010; 9(7):689–701. DOI: 10.1016/S1474-4422(10)70104-6.

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

9. Ntaios G, Lambrou D, Michel P. Blood pressure changes in acute ischemic stroke and outcome with respect to stroke etiology. Neurology. 2012; 79(14):1440–1448. DOI: 10.1212/WNL.0b013e31826d5ed6.

10. Weaver NA, Kuijf HJ, Aben HP. Strategic infarct locations for post-stroke cognitive impairment: a pooled analysis of individual patient data from 12 acute ischaemic stroke cohorts. Lancet Neurol. 2021; 20(6):448–459. DOI: 10.1016/S1474-4422(21)00060-0.

11. Diener HC, Easton JD, Hart RG. Review and update of the concept of embolic stroke of undetermined source. Nat Rev Neurol. 2022; 18(8):455–465. DOI: 10.1038/s41582-022-00663-4.

12. Lipton P. Ischemic cell death in brain neurons. Physiol Rev. 1999; 79(4):1431–1568. DOI: 10.1152/physrev.1999.79.4.1431.

13. Markus HS. Cerebral perfusion and stroke. J Neurol Neurosurg Psychiatry. 2004; 75(3):353–361.

14. Shen Z, Xiang M, Chen C, et al. Glutamate excitotoxicity: Potential therapeutic target for ischemic stroke. Biomed Pharmacother. 2022; 151:113125. DOI: 10.1016/j.biopha.2022.113125.

15. Choi DW. Excitotoxic cell death. J Neurobiol. 1992; 23(9):1261–1276. DOI: 10.1002/neu.480230915.

16. Choi DW, Rothman SM. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci. 1990; 13:171–182. DOI: 10.1146/annurev.ne.13.030190.001131.

17. Ankarcrona M, Dypbukt JM, Bonfoco E, et al. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron. 1995; 15(4):961–973. DOI: 10.1016/0896-6273(95)90186-8.

18. Yamamoto Y, Henrich M, Snipes RL, et al. Altered production of nitric oxide and reactive oxygen species in rat nodose ganglion neurons during acute hypoxia. Brain Res. 2003; 961(1):1–9. DOI: 10.1016/s0006-8993(02)03826-x.

19. Stanika RI, Pivovarova NB, Brantner CA, et al. Coupling diverse routes of calcium entry to mitochondrial dysfunction and glutamate excitotoxicity. Proc Natl Acad Sci U S A. 2009; 106(24):9854–9859. DOI: 10.1073/pnas.0903546106.

20. Qin C, Yang S, Chu YH, et al. Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2022; 7(1):215. DOI: 10.1038/s41392-022-01064-1.

21. Shu S, Pei L, Lu Y. Promising targets of cell death signaling of NR2B receptor subunit in stroke pathogenesis. Regen Med Res. 2014; 2(1):8. DOI: 10.1186/2050-490X-2-8.

22. Wang S, Shi X, Li H, et al. DAPK1 Signaling Pathways in Stroke: from Mechanisms to Therapies. Mol Neurobiol. 2017; 54(6):4716–4722. DOI: 10.1007/s12035-016-0008-y.

23. Swiatkowski P, Nikolaeva I, Kumar G, et al. Role of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival. Sci Rep. 2017; 7(1):1539. doi: 10.1038/s41598-017-01826-w.

24. Ginsberg MD. Current status of neuroprotection for cerebral ischemia: synoptic overview. Stroke. 2009; 40(3 Suppl): S111-S114. DOI: 10.1161/STROKEAHA.108.528877.

25. Sun JY, Zhao SJ, Wang HB, et al. Ifenprodil Improves Long-Term Neurologic Deficits Through Antagonizing Glutamate-Induced Excitotoxicity After Experimental Subarachnoid Hemorrhage. Transl Stroke Res. 2021; 12(6):1067–1080. DOI: 10.1007/s12975-021-00906-4.

26. Bano D, Munarriz E, Chen HL, et al. The plasma membrane Na+/Ca²⁺ exchanger is cleaved by distinct protease families in neuronal cell death. Ann N Y Acad Sci. 2007; 1099:451–455. DOI: 10.1196/annals.1387.006.

27. Xiong ZG, Zhu XM, Chu XP, et al. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell. 2004; 118(6):687–698. DOI: 10.1016/j.cell.2004.08.026.

28. Aarts MM, Tymianski M. TRPMs and neuronal cell death. Pflugers Arch. 2005; 451(1):243–249. DOI: 10.1007/s00424-005-1439-x.

29. Simon RP. Acidotoxicity trumps excitotoxicity in ischemic brain. Arch Neurol. 2006; 63(10):1368–1371. DOI: 10.1001/archneur.63.10.1368.

30. Abe T, Kunz A, Shimamura M, et al. The neuroprotective effect of prostaglandin E2 EP1 receptor inhibition has a wide therapeutic window, is sustained in time and is not sexually dimorphic. J Cereb Blood Flow Metab. 2009; 29(1):66–72. DOI: 10.1038/jcbfm.2008.88.

31. Adibhatla RM, Hatcher JF. Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2010; 12(1):125–169. DOI: 10.1089/ars.2009.2668.

32. Förstermann U. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch. 2010; 459(6):923–939. DOI: 10.1007/s00424-010-0808-2.

33. Brennan AM, Suh SW, Won SJ, et al. NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation. Nat Neurosci. 2009; 12(7):857–863. DOI: 10.1038/nn.2334.

34. Nicholls DG. Oxidative stress and energy crises in neuronal dysfunction. Ann N Y Acad Sci. 2008; 1147:53–60. DOI: 10.1196/annals.1427.002.

35. Abramov AY, Scorziello A, Duchen MR. Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci. 2007; 27(5):1129–1138. DOI: 10.1523/JNEUROSCI.4468-06.2007.

36. Oliver CN, Starke-Reed PE, Stadtman ER, et al. Oxidative damage to brain proteins, loss of glutamine synthetase activity, and production of free radicals during ischemia/reperfusion-induced injury to gerbil brain. Proc Natl Acad Sci U S A. 1990; 87(13):5144–5147. DOI: 10.1073/pnas.87.13.5144.

37. Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 1995; 80(2):293–299. DOI: 10.1016/0092-8674(95)90412-3.

38. Endo H, Kamada H, Nito C, et al. Mitochondrial translocation of p53 mediates release of cytochrome c and hippocampal CA1 neuronal death after transient global cerebral ischemia in rats. J Neurosci. 2006; 26(30):7974–7983. DOI: 10.1523/JNEUROSCI.0897-06.2006.

39. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007; 87(1):315–424. DOI: 10.1152/physrev.00029.2006.

40. Gu Z, Kaul M, Yan B, et al. S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science. 2002; 297(5584):1186–1190. DOI: 10.1126/science.1073634.

41. Nakamura T, Lipton SA. According to GOSPEL: filling in the GAP(DH) of NO-mediated neurotoxicity. Neuron. 2009; 63(1):3–6. DOI: 10.1016/j.neuron.2009.06.013.

42. Jurcau A, Ardelean AI. Oxidative Stress in Ischemia/Reperfusion Injuries following Acute Ischemic Stroke. Biomedicines. 2022; 10(3):574. DOI: 10.3390/biomedicines10030574.

43. Петрищев Н.Н., Шляхто Е.В., Цырлин В.А. и др. Роль свободных радикалов кислорода в механизмах локального и дистантного ишемического прекондиционирования миокарда. Вестник РАМН. 2006; 8:10–15.

44. Faraci FM. Reactive oxygen species: influence on cerebral vascular tone. J Appl Physiol (1985). 2006; 100(2):739–743. DOI: 10.1152/japplphysiol.01044.2005.

45. Lipton SA. Pathologically activated therapeutics for neuroprotection. Nat Rev Neurosci. 2007; 8(10):803–808. DOI: 10.1038/nrn2229.

46. Jo H, Mondal S, Tan D, et al. Small molecule-induced cytosolic activation of protein kinase Akt rescues ischemia-elicited neuronal death. Proc Natl Acad Sci U S A. 2012; 109(26):10581–10586. DOI: 10.1073/pnas.1202810109.

47. Zhang Y, Qiao L, Xu W, et al. Paeoniflorin Attenuates Cerebral Ischemia-Induced Injury by Regulating Ca²⁺/CaMKII/CREB Signaling Pathway. Molecules. 2017; 22(3):359. DOI: 10.3390/molecules22030359.

48. Ning K, Pei L, Liao M, et al. Dual neuroprotective signaling mediated by downregulating two distinct phosphatase activities of PTEN. J Neurosci. 2004; 24(16):4052–4060. DOI: 10.1523/JNEUROSCI.5449-03.2004.

49. Shamloo M, Soriano L, Wieloch T, et al. Death-associated protein kinase is activated by dephosphorylation in response to cerebral ischemia. J Biol Chem. 2005; 280(51):42290–42299. DOI: 10.1074/jbc.M505804200.

50. Zhou L, Li F, Xu HB, et al. Treatment of cerebral ischemia by disrupting ischemia-induced interaction of nNOS with PSD-95. Nat Med. 2010; 16(12):1439–1443. DOI: 10.1038/nm.2245.

51. Kim JW, Tchernyshyov I, Semenza GL, et al. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006; 3(3):177–185. DOI: 10.1016/j.cmet.2006.02.002.

52. Dinkova-Kostova AT, Abramov AY. The emerging role of Nrf2 in mitochondrial function. Free Radic Biol Med. 2015; 88(Pt B):179–188. DOI: 10.1016/j.freeradbiomed.2015.04.036.

53. Kim GS, Jung JE, Narasimhan P, et al. Release of mitochondrial apoptogenic factors and cell death are mediated by CK2 and NADPH oxidase. J Cereb Blood Flow Metab. 2012; 32(4):720–730. DOI: 10.1038/jcbfm.2011.176.

54. Kim YC, Guan KL. mTOR: a pharmacologic target for autophagy regulation. J Clin Invest. 2015; 125(1):25-32. DOI: 10.1172/JCI73939

55. Rami A. Upregulation of Beclin 1 in the ischemic penumbra. Autophagy. 2008; 4(2):227-229. DOI: 10.4161/auto.5339

56. Datta A, Sarmah D, Mounica L, et al. Cell Death Pathways in Ischemic Stroke and Targeted Pharmacotherapy. Transl Stroke Res. 2020; 11(6):1185–1202. DOI: 10.1007/s12975-020-00806-z.

57. Balaganapathy P, Baik SH, Mallilankaraman K, et al. Interplay between Notch and p53 promotes neuronal cell death in ischemic stroke. J Cereb Blood Flow Metab. 2018; 38(10):1781–1795. DOI: 10.1177/0271678X17715956.

58. Shi S, Yang W, Tu X, et al. Ischemic preconditioning reduces ischemic brain injury by suppressing nuclear factor kappa B expression and neuronal apoptosis. Neural Regen Res. 2013; 8(7):633–638. URL: https://www.semanticscholar.org/paper/Ischemic-preconditioning-reduces-ischemic-brain-by-Shi-Yang/b865b50ef29ed7f713a4adc8b29ebf471f9888ea.

59. Qin C, Fan WH, Liu Q, et al. Fingolimod Protects Against Ischemic White Matter Damage by Modulating Microglia Toward M2 Polarization via STAT3 Pathway. Stroke. 2017; 48(12):3336–3346. DOI: 10.1161/STROKEAHA.117.018505.

60. Fann DY, Lee SY, Manzanero S, et al. Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis. 2013; 4(9):e790. DOI: 10.1038/cddis.2013.326.

61. Maddahi A, Edvinsson L. Cerebral ischemia induces microvascular pro-inflammatory cytokine expression via the MEK/ERK pathway. J Neuroinflammation. 2010; 7:14. DOI: 10.1186/1742-2094-7-14.

62. Di Lisa F, Canton M, Menabò R, et al. Mitochondria and reperfusion injury. The role of permeability transition. Basic Res Cardiol. 2003; 98(4):235–241. DOI: 10.1007/s00395-003-0415-x.

63. Tian H, Chen X, Liao J, et al. Mitochondrial quality control in stroke: From the mechanisms to therapeutic potentials. J Cell Mol Med. 2022; 26(4):1000–1012. DOI: 10.1111/jcmm.17189.

64. An H, Zhou B, Ji X. Mitochondrial quality control in acute ischemic stroke. J Cereb Blood Flow Metab. 2021; 41(12):3157–3170. DOI: 10.1177/0271678X211046992.

65. Xu B, Zhu L, Chu J, et al. Esculetin improves cognitive impairments induced by transient cerebral ischaemia and reperfusion in mice via regulation of mitochondrial fragmentation and mitophagy. Behav Brain Res. 2019; 372:112007. DOI: 10.1016/j.bbr.2019.112007.

66. Bonfoco E, Krainc D, Ankarcrona M, et al. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci U S A. 1995; 92(16):7162–7166. DOI: 10.1073/pnas.92.16.7162.

67. Mao R, Zong N, Hu Y, et al. Neuronal Death Mechanisms and Therapeutic Strategy in Ischemic Stroke. Neurosci Bull. 2022; 38(10):1229–1247. DOI: 10.1007/s12264-022-00859-0.

68. Tuo QZ, Zhang ST, Lei P. Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications. Med Res Rev. 2022; 42(1):259–305. DOI: 10.1002/med.21817.

69. Tedeschi V, Vinciguerra A, Sisalli MJ, et al. Pharmacological inhibition of lysosomal two-pore channel 2 (TPC2) confers neuroprotection in stroke via autophagy regulation. Neurobiol Dis. 2023; 178:106020. DOI: 10.1016/j.nbd.2023.106020.

70. Дмитриев Ю.В., Минасян С.М., Галагудза М.М. Прямое сравнение инфаркт-лимитирующих и гемодинамических эффектов различных ингибиторов некроптоза на модели длительной холодовой консервации донорского сердца крысы. Артериальная гипертензия. 2018; 24(5):581–585. DOI: 10.18705/1607-419X-2018-24-5-581-585.

71. Deng XX, Li SS, Sun FY. Necrostatin-1 Prevents Necroptosis in Brains after Ischemic Stroke via Inhibition of RIPK1-Mediated RIPK3/MLKL Signaling. Aging Dis. 2019; 10(4):807–817. DOI: 10.14336/AD.2018.0728.

72. Gou X, Xu D, Li F, et al. Pyroptosis in stroke-new insights into disease mechanisms and therapeutic strategies. J Physiol Biochem. 2021; 77(4):511–529. DOI: 10.1007/s13105-021-00817-w.

73. Wei Z, Xie Y, Wei M, et al. New insights in ferroptosis: Potential therapeutic targets for the treatment of ischemic stroke. Front Pharmacol. 2022; 13:1020918. DOI: 10.3389/fphar.2022.1020918.

74. Liu S, Luo W, Wang Y. Emerging role of PARP-1 and PARthanatos in ischemic stroke. J Neurochem. 2022; 160(1):74–87. DOI: 10.1111/jnc.15464.