Preview

General Reanimatology

Advanced search

Morphological Сlassification of Neuronal Damage

https://doi.org/10.15360/1813-9779-2025-5-2580

Abstract

Objectives. To develop a morphological classification of neuronal damage for use in practical activities by researchers, pathologists, and forensic experts.

Material and methods. The neurons of the cerebral cortex of 30 experimental animals (Wistar rats) were studied. Of these: with circulatory arrest N=10, with clozapine poisoning in combination with alcohol N=20 (clozapine dose 150 mg/kg, alcohol dose 5 ml/kg); morphological material of the human cerebral cortex was studied in subarachnoid hemorrhages (SAH) N=23, sudden cardiac death N=10, coronavirus infection N=18. Histological preparations were stained with hematoxylin and eosin, according to Nissl, according to Feulgen (for DNA), according to Brachet (for RNA and RNP), caspase-3 was detected by immunohistochemistry.

Results. A morphological classification of neuronal damage was proposed, including: decentralization of the nucleus within a neuron, morphological changes in the nucleolus, dark neurons, chromatin remodeling, lipofuscinosis, neuronal edema, Nissl substance lysis, neuronal calcification, neuronophagia, necrosis, and neuronal apoptosis. Functional disorders that occur in the studied variants of neuronal alteration were considered. As a result of developing neuronal damage, the function of the neuronal cytoskeleton, synthesis of ribosome subunits, synthesis of ribonucleoproteins, and DNA reparation are impaired, apoptosis is activated, lysosomes are damaged, the formation of reactive oxygen species is activated, and irreversible forms of neuronal damage (neuronophagia, necrosis, apoptosis) are recorded.

Conclusion. The proposed morphological classification complements existing classifications based on the study of molecular markers of neuronal damage and can be used in experimental studies and in the practical work of pathologists and forensic experts.

About the Author

A. M. Golubev
V. A. Negovsky Research Institute of General Reanimatology, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology
Russian Federation

Arkady M. Golubev

25 Petrovka Str., Bldg. 2, 107031 Moscow



References

1. Yermokhin P. N. Histopathology of the central nervous system. Ed. by prof. A. P. Avtsyn, member of the USSR Academy of Medical Sciences. M.: Meditsina; 1969: 245. UDC 616.831/832-001.8 (084.4). (in Russ.).

2. Clarke G. D. Developmental cell death: morphological diverciti and multiple mechanisms. Anatomy Embryology (Berl). 1990; 181: 195–201. DOI: 10.1007/BF00174615. PMID: 2186664.

3. Kroemer G., El-Deiry W. S., Golstein P. Nomenclature Committee on Cell Death Classification of cell death: recommendations of the Nomenclature Committee on Cell Death. Cell Death Differentiation. 2005; 2: 1463–1467. DOI: 10.1038/sj.cdd.4401724. PMID: 16247491.

4. Galluzzi L., Vitale I., Abrams J. M., Alnemri E. S., Baehrecke E. H., Blagosklonny M. V., Dawson T. M., et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death. Cell Death & Differentiation. 2012; 19: 07–120. DOI: 10.1038/cdd.2011.96. PMID: 21760595.

5. Di Giaimo R., PennaE., Pizzella A., Cirillo R., Perrone-Capano C., Crispino M. Cross talk at the cytoskeleton–plasma membrane interface: impact on neuronal morphology and functions. Int J Mol Sci. 2020; 21 (23): 9133. DOI: 10.3390/ijms21239133. PMID: 33266269.

6. Kengaku M. Cytoskeletal control of nuclear migration in neurons and non-neuronal cells. Proc Jpn Acad Ser B Phys Biol Sci. 2018; 94 (9): 337–349. DOI: 10.2183/pjab.94.022. PMID: 30416174.

7. Wilson D. M., Cookson M. R., Van Den Bosch L., Zetterberg H., Holtzman D. M., Dewachter I. Hallmarks of neurodegenerative diseases. Cell. 2023; 186: 693–714. DOI: 10.1016/j.cell.2022.12.032. PMID: 36803602.

8. Parlato R., Kreiner G. Nucleolar activity in neurodegenerative diseases: a missing piece of the puzzle? J Mol Med (Berl). 2013; 91 (5): 541–547. DOI: 10.1007/s00109-012-0981-1. PMID: 23179684.

9. Dubois M.-L., Boisvert F.-M. The nucleolus: structure and function. In the book: The Functional Nucleus. David P. Bazett-Jones, Graham Dellaire. (eds.). Springer Nature Link; 2016: 29–49. DOI: 10.1007/978-3-319-38882-3_2.

10. Schцfer C., Weipoltshammer K. Nucleolus and chromatin. Histochem Cell Biol. 2018; 150 (3): 209–225. DOI: 10.1007/s00418-018-1696-3. PMID: 30046888.

11. Slomnicki L. P., Hallgren J., Vashishta A., Smith S. C., Ellis S. R., Hetman M. Proapoptotic requirement of ribosomal protein L11 in ribosomal stress-challenged cortical neurons. Mol Neurobiol. 2018; 55 (1): 538–553. DOI: 10.1007/s12035-016-0336-y. 14. PMID: 27975169.

12. Regier M., Liang J., Choi A., Verma K., Libien J., Hernández A. I. Evidence for decreased nucleolar PARP-1 as an early marker of cognitive impairment. Neural Plast. 2019; 2019: 4383258. DOI: 10.1155/2019/4383258. PMID: 31827497.

13. Wang X., Zhang X. Y., Liao N. Q., He Z.H., Chen Q. F. Identification of ribosome biogenesis genes and subgroups in ischaemic stroke. Front Immunol. 2024; 15: 1449158. DOI: 10.3389/fimmu.2024.1449158. PMID: 39290696.

14. Chen Q. M. The Odds of protein translation control under stress. Antioxid Redox Signal. 2024; 40 (16-18): 943–947. DOI: 10.1089/ars.2023.0478. PMID: 38573012.

15. Hellas J. A., Andrew R. D. Neuronal swelling: a non-osmotic consequence of spreading depolarization. Neurocrit Care. 2021; 35 (Suppl 2): 112–134. DOI: 10.1007/s12028-021-01326-w. PMID: 34498208.

16. Murphy T. R., Davila D., Cuvelier N., Young L.R, Lauderdale K., Binder D. K., Fiacco T. A. Hippocampal and cortical pyramidal neurons swell in parallel with astrocytes during acute hypoosmolar stres. Front Cell Neurosci. 2017; 11: 275. DOI: 10.3389/fncel.2017.00275. PMID: 28979186.

17. Chen S., Shao L., Ma L. Cerebral edema formation after stroke: emphasis on blood–brain barrier and the lymphatic drainage system of the brain. Front Cell Neurosci. 2021; 15: 716825. DOI: 10.3389/fncel.2021.716825. PMID: 34483842.

18. Stokum J. A., Gerzanich V., Simard J. M. Molecular pathophysiology of cerebral edema. J Cereb Blood Flow Metab. 2016; 36 (3): 513–538. DOI: 10.1177/0271678X15617172. PMID: 26661240.

19. Zimatkin S. M., Bon E. I. Dark neurons of the brain. Morphollogy = Morfologiya. 2017; 152 (6): 81–86. (in Russ.). DOI: 10.17816/morph.398200.

20. Avdeev D. B., Stepanov S. S., Gorbunova A. V., Shoronova A.Yu., Makar’eva L.M., Akulinin V. A., Korzhuk M. S., Zabolotnykh M. V. Dark Neurons of the Sensorimotor Cortex of White Rats after Acute Incomplete Ischemia in Terms of Artifacts Fixation and Neuroglial Relationships. Journal of Anatomy and Histopathology = Zhurnal Anatomii i Gistopatologii. 2021; 10 (2): 9–22. (In Russ.). DOI: 10 18499/2225-7357-2021-10-2-9-22.

21. Gallias F., CsordasA., Schwartz A., Mazlo M. «Dark» (compacted) neurons may not die in a necrotic manner. Exp Brain Res. 2005; 160 (4): 473–86. DOI: 10.1007/s00221-004-2037-4 PMID: 15480602. PMID: 15480602.

22. Ahmadpour S., Behrad A., Fernández-Vega I. Dark neurons: a protective mechanism or a mode of death. Journal of Medical Histology. 2019; 3 (2): 125–131. DOI: 10.21608/jmh.2020.40221.1081.

23. Kockelkoren R., De Vis J. B., Stavenga M., Mali W. P. Th. M., Hendrikse J., Rozemuller A. M., Koek H. L., et al, the DUST study group. Hippocampal calcification on brain CT: prevalence and risk factors in a cerebrovascular cohort. Eur Radiol. 2018; 28 (9): 3811–3818. DOI: 10.1007/s00330-018-5372-8. PMID: 29619516.

24. Dzreyan V. A., Khaitin A. M., Demyanenko S. V. Disruption of calcium homeostasis and following changes in calcium signaling in neurons and glial cells in response to photodynamic treatment. Biological Membranes: Journal of Membrane and Cell Biology = Biologicheskiye Membrany: Zhurnal Membrannoy i Kletochnoy Biologii. 2022; 39 (4): 283–291. (in Russ.). DOI: 10.31857/S0233475522040041.

25. Casas A. I., Kleikers P.Wm., Geuss E., Langhauser F., Adler T., Busch D. H., Gailus-Durner V., et al. Calcium-dependent bloodbrain barrier breakdown by NOX5 limits postreperfusion benefit in stroke. J Clin Invest. 2019; 129 (4): 1772–1778. DOI: 10.1172/JCI124283. PMID: 30882367.

26. Winick-Ng W., Kukalev A., Harabula I., Zea-Redondo L., Szabó D., Meijer M., SerebreniL., et al. Cell-type specialization is encoded by specific chromatin topologies. Nature. 2021; 599 (7886): 684–691. DOI: 10.1038/s41586-021-04081-2. PMID: 34789882.

27. Mirabella A. C., Foster B. M., Bartke T. Chromatin deregulation in disease. Chromosoma. 2016; 125: 75–93. DOI: 10.1007/s00412-015-0530-0. PMID: 26188466.

28. Aleksandrov R., Hristova R., Stoynov S., Gospodinov A. The chromatin response to double-strand DNA breaks and their repair. Cells. 2020; 9 (8): 1853. DOI: 10.3390/cells9081853. PMID: 32784607.

29. Su Y., Shin J., Zhong C., Wang S., Roychowdhury P., Lim J., Kim D., et al. Neuronal activity modifies the chromatin accessibility landscape in the adult brain. Nat Neurosci. 2017; 20 (3): 476–483. DOI: 10.1038/nn.4494. PMID: 28166220.

30. Kirmes I., Szczurek A., Prakash K., Charapitsa I., Heiser C., Musheev M., Schock F., et al. A transient ischemic environment induces reversible compaction of chromatin. Genome Biol. 2015; 16: 246. DOI: 10.1186/ s13059-015-0802-2. PMID: 26541514.

31. Fullard J. F., Hauberg M. E., Bendl J., Egervari G., Cirnaru M.-D., Reach S. M., Motl J., et al. An atlas of chromatin accessibility in the adult human brain. Genome Res. 2018; 28 (8): 1243–1252. DOI: 10.1101/gr.232488.117. PMID: 29945882.

32. Li X., Egervari G., Wang Y., Berger S. L., Nat Z. L. Regulation of chromatin and gene expression by metabolic enzymes and metabolites. Nat Rev Mol Cell Biol. 2018; 19 (9): 563–578. DOI: 10.1038/s41580-018-0029-7. PMID: 29930302.

33. Falk M., Feodorova Y., Naumova N., Imakaev M., Lajoie B. R., Leonhardt H., Joffe B., et al. Heterochromatin drives compartmentalization of inverted and conventional nuclei. Nature. 2019; 570 (7761): 395–399. DOI: 10.1038/s41586-019-1275-3. PMID: 31168090.

34. Hilbert L., Sato Y., Kuznetsova K., Bianucci T., Kimura H., Jülicher F., Honigmann A., et al. Transcription organizes euchromatin via microphase separation. Nat Commun. 2021; 12: 1360. DOI: 10.1038/s41467-021-21589-3. PMID: 33649325.

35. Di Guardo G. Lipofuscin, lipofuscin-like pigments and autofluorescence. Eur J Histochem. 2015; 59 (1): 2485. DOI: 10.4081/ejh.2015.2485. PMID: 25820564.

36. Riga D., Riga S., Halalau F., Schneider F. Brain lipopigment accumulation in normal and pathological aging. Ann N Y Acad Sci. 2006; 1067: 158–163. DOI: 10.1196/annals.1354.019. PMID: 16803981.

37. Glees P., Hasan M. Lipofuscin in neuronal aging and diseases. Norm Pathol Anat (Stuttg). 1976; 32: 1–68. PMID: 639413.

38. Snyder A. N., Crane J. S. Histology, lipofuscin. 2023. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. PMID: 30726043 Free Books & Documents.

39. Baldensperger T., Jung T., Heinze T., Schwerdtle T., Höhn A., Grune T. The age pigment lipofuscin causes oxidative stress, lysosomal dysfunction, and pyroptotic cell death. Free Radic Biol Med. 2024; 225: 871–880. DOI: 10.1016/j.freeradbiomed.2024.10.311. PMID: 39486751.

40. Liu K., Ding L., Li Y., Yang H., Zhao C., Lei Y., Han S., et al. Neuronal necrosis is regulated by a conserved chromatin-modifying cascade. Proc Natl Acad Sci U S A. 2014; 111 (38): 13960–13965. DOI: 10.1073/pnas.1413644111. PMID: 25201987.

41. Martin L. J., Chang Q. DNA damage response and repair, DNA methylation, and cell death in human neurons and experimental animal neurons are different. J Neuropathol Exp Neurol. 2018; 77 (7): 636–655. DOI: 10.1093/jnen/nly040. PMID: 29788379.

42. Nussbacher J. K., Tabet R., Yeo G. W., Lagier-Tourenne C. Disruption of RNA metabolism in neurological diseases and emerging therapeutic interventions. Neuron. 2019; 102 (2): 294–320. DOI: 10.1016/j.neuron.2019.03.014. PMID: 30998900.

43. Delgado-Martín S., Martínez-Ruiz A. The role of ferroptosis as a regulator of oxidative stress in the pathogenesis of ischemic stroke. FEBS Lett. 2024; 598 (17): 2160–2173. DOI: 10.1002/18733468.14894. PMID: 38676284.

44. Brown G. C. Neuronal loss after stroke due to microglial phagocytosis of stressed neurons. Int J Mol Sci. 2021; 22 (24): 13442. DOI: 10.3390/ijms222413442. PMID: 34948237.

45. Galloway D. A., Phillips A. E.M., Owen D. R.J., Moore C. S. Phagocytosis in the brain: homeostasis and disease. Front Immunol. 2019; 10: 790. DOI: 10.3389/fimmu.2019.00790. PMID: 31040847.

46. Wakida N. M., Cruz G. M. S., Ro C.C., Moncada E. G., KhatibzadehN., Flanagan L. A., Berns M. W. Phagocytic response of astrocytes to damaged neighboring cells. PLoS One. 2018; 13 (4): e0196153. DOI: 10.1371/journal.pone.019615.

47. Yanumula A., Cusick J. K. Biochemistry, extrinsic pathway of apoptosis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. PMID: 32809646 Free Books & Documents.

48. Glover H. L., Schreiner A., Dewson G., Tait S. W. G. Mitochondria and cell death. Nat Cell Biol. 2024, 26 (9): 1434–1446. DOI: 10.1038/s41556-024-01429-4. PMID: 38902422.


Review

For citations:


Golubev A.M. Morphological Сlassification of Neuronal Damage. General Reanimatology. (In Russ.) https://doi.org/10.15360/1813-9779-2025-5-2580

Views: 11


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.


ISSN 1813-9779 (Print)
ISSN 2411-7110 (Online)