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Prospero Homeobox 1 and Doublecortin Correlate with Neural Damage after Ischemic Stroke

  • Dong-Hun Lee (Department of Neurosurgery Soonchunhyang University Cheonan Hospital, College of Medicine, Soonchunhyang University) ;
  • Eun Chae Lee (Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea) ;
  • Sang-Won Park (Department of Neurosurgery Soonchunhyang University Cheonan Hospital, College of Medicine, Soonchunhyang University) ;
  • Ji young Lee (Department of Neurosurgery, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Kee-Pyo Kim (Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea) ;
  • Jae Sang Oh (Department of Neurosurgery, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea)
  • Received : 2023.07.20
  • Accepted : 2023.10.16
  • Published : 2024.05.01

Abstract

Objective : Markers of neuroinflammation during ischemic stroke are well characterized, but additional markers of neural damage are lacking. The study identified associations of behavioral disorders after stroke with histologic neural damage and molecular biological change. Methods : Eight-week-old, 25 g male mice of the C57BL/6J strain were subjected to middle cerebral artery occlusion (MCAO) to induce ischemic stroke. The control group was a healthy wild type (WT), and the experimental group were designed as a low severity MCAO1 and a high severity MCAO2 based on post-stroke neurological scoring. All groups underwent behavioral tests, realtime polymerase chain reaction, triphenyltetrazolium chloride (TTC) staining and Hematoxylin and Eosin staining. One-way analysis of variance was used to analyze statistical significance between groups. Results : In TTC staining, MCAO1 showed 29.02% and MCAO2 showed 38.94% infarct volume (p<0.0001). The pro-inflammatory cytokine interleukin (IL)-1β was most highly expressed in MCAO2 (WT 0.44 vs. MCAO1 2.69 vs. MCAO2 5.02, p<0.0001). From the distance to target in the Barnes maze test, WT had a distance of 178 cm, MCAO1 had a distance of 276 cm, and MCAO2 had a distance of 1051 (p=0.0015). The latency to target was 13.3 seconds for WT, 27.9 seconds for MCAO1, and 87.9 seconds for MCAO2 (p=0.0007). Prospero homeobox 1 (Prox1) was most highly expressed in MCAO2 (p=0.0004). Doublecortin (Dcx) was most highly expressed in MCAO2 (p<0.0001). Conclusion : The study demonstrated that histological damage to neural cells and changes in brain mRNA expression were associated with behavioral impairment after ischemic stroke. Prox1 and Dcx may be biomarkers of neural damage associated with long-term cognitive decline, and increased expression at the mRNA level was consistent with neural damage and long-term cognitive dysfunction.

Keywords

Acknowledgement

This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation funded by the Korean government (2023RA1A2C100531), by the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, Republic of Korea, the Ministry of Food and Drug Safety) (HC22C0043). The author(s) wish(es) to ac - knowledge the f inancial support of The Catholic University of Korea Uijeongbu St. Mary's Hospital Clinical Research Laboratory Foundation made in the program year of 2023.

References

  1. Aggleton JP, Pralus A, Nelson AJ, Hornberger M : Thalamic pathology and memory loss in early Alzheimer's disease: moving the focus from the medial temporal lobe to Papez circuit. Brain 139(Pt 7) : 1877-1890, 2016 https://doi.org/10.1093/brain/aww083
  2. Brown JP, Couillard-Despres S, Cooper-Kuhn CM, Winkler J, Aigner L, Kuhn HG : Transient expression of doublecortin during adult neurogenesis. J Comp Neurol 467 : 1-10, 2003 https://doi.org/10.1002/cne.10874
  3. Bustamante A, Simats A, Vilar-Bergua A, Garcia-Berrocoso T, Montaner J : Blood/brain biomarkers of inflammation after stroke and their association with outcome: from C-reactive protein to damage-associated molecular patterns. Neurotherapeutics 13 : 671-684, 2016 https://doi.org/10.1007/s13311-016-0470-2
  4. Carr MW, Roth SJ, Luther E, Rose SS, Springer TA : Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci U S A 91 : 3652-3656, 1994 https://doi.org/10.1073/pnas.91.9.3652
  5. Cramer SC : Repairing the human brain after stroke: I. Mechanisms of spontaneous recovery. Ann Neurol 63 : 272-287, 2008 https://doi.org/10.1002/ana.21393
  6. Deb P, Sharma S, Hassan KM : Pathophysiologic mechanisms of acute ischemic stroke: an overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology 17 : 197-218, 2010 https://doi.org/10.1016/j.pathophys.2009.12.001
  7. Eichenbaum H : A cortical-hippocampal system for declarative memory. Nat Rev Neurosci 1 : 41-50, 2000 https://doi.org/10.1038/35036213
  8. Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, et al. : Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 387 : 1723-1731, 2016 https://doi.org/10.1016/S0140-6736(16)00163-X
  9. Huo Y, Ley K : Adhesion molecules and atherogenesis. Acta Physiol Scand 173 : 35-43, 2001 https://doi.org/10.1046/j.1365-201X.2001.00882.x
  10. Iwano T, Masuda A, Kiyonari H, Enomoto H, Matsuzaki F : Prox1 post-mitotically defines dentate gyrus cells by specifying granule cell identity over CA3 pyramidal cell fate in the hippocampus. Development 139 : 3051-3062, 2012 https://doi.org/10.1242/dev.080002
  11. Jokinen H, Melkas S, Ylikoski R, Pohjasvaara T, Kaste M, Erkinjuntti T, et al. : Post-stroke cognitive impairment is common even after successful clinical recovery. Eur J Neurol 22 : 1288-1294, 2015 https://doi.org/10.1111/ene.12743
  12. Karalay O, Doberauer K, Vadodaria KC, Knobloch M, Berti L, Miquelajauregui A, et al. : Prospero-related homeobox 1 gene (Prox1) is regulated by canonical Wnt signaling and has a stage-specific role in adult hippocampal neurogenesis. Proc Natl Acad Sci U S A 108 : 5807-5812, 2011 https://doi.org/10.1073/pnas.1013456108
  13. Koton S, Pike JR, Johansen M, Knopman DS, Lakshminarayan K, Mosley T, et al. : Association of ischemic stroke incidence, severity, and recurrence with dementia in the atherosclerosis risk in communities cohort study. JAMA Neurol 79 : 271-280, 2022 https://doi.org/10.1001/jamaneurol.2021.5080
  14. Lackland DT, Roccella EJ, Deutsch AF, Fornage M, George MG, Howard G, et al. : Factors influencing the decline in stroke mortality: a statement from the American Heart Association/American Stroke Association. Stroke 45 : 315-353, 2014 https://doi.org/10.1161/01.str.0000437068.30550.cf
  15. Langhorne P, Coupar F, Pollock A : Motor recovery after stroke: a systematic review. Lancet Neurol 8 : 741-754, 2009 https://doi.org/10.1016/S1474-4422(09)70150-4
  16. Lavado A, Lagutin OV, Chow LM, Baker SJ, Oliver G : Prox1 is required for granule cell maturation and intermediate progenitor maintenance during brain neurogenesis. PLoS Biol 8 : e1000460, 2010
  17. Liu T, McDonnell PC, Young PR, White RF, Siren AL, Hallenbeck JM, et al. : Interleukin-1 beta mRNA expression in ischemic rat cortex. Stroke 24 : 1746-1750; discussion 1750-1751, 1993
  18. Lo EH, Dalkara T, Moskowitz MA : Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4 : 399-415, 2003 https://doi.org/10.1038/nrn1106
  19. Lo JW, Crawford JD, Desmond DW, Godefroy O, Jokinen H, Mahinrad S, et al. : Profile of and risk factors for poststroke cognitive impairment in diverse ethnoregional groups. Neurology 93 : e2257-e2271, 2019
  20. Longa EZ, Weinstein PR, Carlson S, Cummins R : Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20 : 84-91, 1989 https://doi.org/10.1161/01.STR.20.1.84
  21. Lv ZM, Zhao RJ, Zhi XS, Huang Y, Chen JY, Song NN, et al. : Expression of DCX and transcription factor profiling in photothrombosis-induced focal ischemia in mice. Front Cell Neurosci 12 : 455, 2018
  22. Mergenthaler P, Lindauer U, Dienel GA, Meisel A : Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci 36 : 587-597, 2013 https://doi.org/10.1016/j.tins.2013.07.001
  23. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. : Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380 : 2197-2223, 2012 https://doi.org/10.1016/S0140-6736(12)61689-4
  24. Nawabi H, Belin S, Cartoni R, Williams PR, Wang C, Latremoliere A, et al. : Doublecortin-like kinases promote neuronal survival and induce growth cone reformation via distinct mechanisms. Neuron 88 : 704-719, 2015 https://doi.org/10.1016/j.neuron.2015.10.005
  25. Olmez I, Ozyurt H : Reactive oxygen species and ischemic cerebrovascular disease. Neurochem Int 60 : 208-212, 2012 https://doi.org/10.1016/j.neuint.2011.11.009
  26. Pendlebury ST, Rothwell PM : Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet Neurol 8 : 1006-1018, 2009 https://doi.org/10.1016/S1474-4422(09)70236-4
  27. Pendlebury ST, Rothwell PM; Oxford Vascular Study : Incidence and prevalence of dementia associated with transient ischaemic attack and stroke: analysis of the population-based Oxford Vascular Study. Lancet Neurol 18 : 248-258, 2019 https://doi.org/10.1016/S1474-4422(18)30442-3
  28. Rost NS, Brodtmann A, Pase MP, van Veluw SJ, Biffi A, Duering M, et al. : Post-stroke cognitive impairment and dementia. Circ Res 130 : 1252-1271, 2022 https://doi.org/10.1161/CIRCRESAHA.122.319951
  29. Toyoda K, Yoshimura S, Nakai M, Koga M, Sasahara Y, Sonoda K, et al. : Twenty-year change in severity and outcome of ischemic and hemorrhagic strokes. JAMA Neurol 79 : 61-69, 2022 https://doi.org/10.1001/jamaneurol.2021.4346
  30. Ullman MT : Contributions of memory circuits to language: the declarative/procedural model. Cognition 92 : 231-270, 2004 https://doi.org/10.1016/j.cognition.2003.10.008
  31. Zarei M, Patenaude B, Damoiseaux J, Morgese C, Smith S, Matthews PM, et al. : Combining shape and connectivity analysis: an MRI study of thalamic degeneration in Alzheimer's disease. Neuroimage 49 : 1-8, 2010 https://doi.org/10.1016/j.neuroimage.2009.09.001