Biochemical markers of cerebral ischemia
Keywords:
cerebral ischemia, biochemical markers, predictorsAbstract
This review summarizes and systemizes the findings of studies published over the past 25 years focusing on biochemical markers of cerebral ischemia and their role in the pathogenesis of ischemic injury. Throughout this period, the understanding of the molecular mechanisms underlying ischemic damage has significantly deepened, enabling the identification of a broad spectrum of markers that reflect energy deficit, oxidative and nitrosative stress, inflammatory activation, structural impairment of neurons and glia, as well as blood-brain barrier dysfunction. These biomolecules are considered key indicators of the severity of ischemic injury, the dynamics of secondary damaging cascades, and the recovery potential of neuronal networks.
Particular attention is paid to markers associated with mitochondrial dysfunction, nitric oxide (NO)-ergic system activation, disrupted ion homeostasis, and enhanced inflammatory responses, as these specific indicators demonstrate high prognostic value regarding clinical outcomes. Systematizing the data on cerebral ischemia biomarkers gathered between 2002 and 2025 provides deeper insights into pathogenic mechanisms, increases the accuracy of early diagnosis, improves patient stratification, and optimizes the monitoring of therapeutic intervention efficacy. The presented data confirm that biochemical markers serve as an essential tool for evaluating the progression of the ischemic process and developing personalized treatment strategies aimed at improving long-term neurological outcomes.
References
Girnar, G.A. Cerebral ischemic stroke and different approaches for treatment of stroke / G.A. Girnar, H.S. Mahajan // Future Journal of Pharmaceutical Sciences. – 2021. – Vol. 7, № 134 – P. 1–10. DOI: https://doi.org/10.1186/s43094-021-00289-1.
Maksimovich, N. Ye. Changes in the pool of amino acids during cerebral ischemia. Review. / N. Ye. Maksimovich, E.I Bon // Clinical Trials and Clinical Research. – 2024. – Vol. 3., №2 – P.1–17. DOI:10.31661/gmj.v12i.2993.
Sun, B. Short review on advances in early diagnosis and treatment of ischemic stroke / B. Sun, Z. Wang // Galen Medical Journal. – 2023. – Vol. 12. – P.1–13. DOI: 10.31661/gmj.v12i0.2993.
Saini, V. Global epidemiology of stroke and access to acute ischemic stroke interventions / V. Saini, L. Guada, D.R. Yavagal // Neurology. – 2021. – Vol. 16, № 97. – P.6–16. DOI: 10.1212/WNL.0000000000012781.
Белок S100β, мозговой натрийуретический пептид и интерлейкины как биомаркеры прогноза исходов при черепно-мозговой травме. / Л.М. Ценципер, Н.В. Дрягина, М.В Румянцева [и др.] // Анестезиология и реаниматология. – 2019. – № 4. – С. 50–54.
Post-mortem serum concentrations of GFAP correlate with agony time but do not indicate a primary cerebral cause of death / B. Breitling, R. Brunkhorst, M. Verhoff, C. Foerch // PLOS ONE. – 2018. – Vol. 13, No. 10. – P. 1–11. DOI: 10.1371/journal.pone.0205323.
Peng, J.-J. Peripheral blood mirnas as a potential biomarker for ischemic stroke / J.-J. Peng, X.-J. Luo, J. Peng // Austin Journal of Pharmacology and Therapeutics. – 2014. – Vol. 2, No. 9. – P. 2–3.
Baranovicova, E. Glutamate/GABA/glutamine ratios in intact and ischemia reperfusion challenged rat brain subregions, the effect of ischemic preconditioning / E. Baranovicova, D. Kalenska, J. Lehotsky // Metabolic Brain Disease. – 2025. – Vol. 40.– P. 1–11. DOI: 10.1007/s11011-024-01511-8.
Wierońska, J.M. Nitric oxide-dependent pathways as critical factors in the consequences and recovery after brain ischemic hypoxia / J.M. Wierońska, P. Cieślik, L. Kalinowski // Biomolecules. – 2021. – Vol. 11, No. 8. – P. 1–10. DOI: 10.3390/biom11081097.
Baidya, O.P. Role of serum neuron specific enolase in differentiating the side of brain lesion in acute ischemic stroke / O.P. Baidya, S. Tiwari, K. Usman // International Journal of Biomedical Research. – 2015. – Vol. 6, No. 8. – P. 570–573. DOI:10.7439/ijbr.v6i8.2389.
Прогностическое значение исследования нейронспецифической енолазы у пациентов с ишемическим инсультом. / А.С. Куракина, Т.Н. Семенова, Е.В. Гузанова [и др.] // Современные технологии в медицине. – 2021. – Т. 13, № 2. – С. 68–73.
The Neuroprotective effect of picroside II and its best therapeutic dose and time window in cerebral ischemic injury in rats / L. Zhao, X. Li, Y. Guo [et al.] // Journal of Behavioral and Brain Science. – 2013. – Vol. 3, No. 5. – P. 385–392. DOI: 10.1186/1471-2202-15-25.
Biochemical changes in the injured brain / S. Sahu, D.S. Nag, A. Swain, D.P. Samaddar // World Journal of Biological Chemistry. – 2017. – Vol. 8, No. 1. – P. 21–31. DOI: 10.4331/wjbc.v8.i1.21.
Trafimovich, Y. Myelin basic protein: unlocking the key to brain function / Y. Trafimovich // World Journal of Neuroscience. – 2025. – Т. 15, № 4. – P. 1-6.
High phenylalanine concentrations induce demyelination and microglial activation in mouse cerebellar organotypic slices / O. Thau-Zuchman, P.N. Pallier, P.J.M. Savelkoul[et al.] // Frontiers in Neuroscience. – 2022. – Vol. 16. – P. 1–17. DOI: 10.3389/fnins.2022.926023.
Ишемия головного мозга на фоне подавления и активации иммунитета / И.Н. Тюренков, Б.Ю. Гумилевский, И.С. Филина [и др.] // Журнал неврологии и психиатрии им. С.С. Корсакова. – 2015. – Т. 115, № 9. – С. 23–29.
Chu, M. Focal cerebral ischemia activates neurovascular restorative dynamics in mouse brain / M. Chu, X. Hu, S. Lu [et al.] // Frontiers in Bioscience. – 2011. – №4. – P. 1926-1936. DOI: 10.2741/e513.
Cerebral white matter injury and damage to myelin sheath following whole-brain ischemia / Y. Chen, Q. Yi, G. Liu [et al.] // Brain Research. – 2013. – Vol. 1495. – P. 11–17. DOI: 10.1016/j.brainres.2012.12.006.
Can serum GFAP and UCH-L1 replace ct in assessing acute ischemic stroke severity? / I. Kraljević, M. Marinović Guić, K. Dolić [et al.] // Life. – 2025. – Vol. 15, No. 3. – P. 1–11. DOI: 10.3390/life15030495.
The importance of increased serum GFAP and UCH-L1 levels in distinguishing large vessel from small vessel occlusion in acute ischemic stroke / I. Kraljević, S. Sablić, M. Marinović Guić [et al.] // Biomedicines. – 2024. – Vol. 12. – P. 1–9. DOI: 10.3390/biomedicines12030608.
The association between serum S100β levels and prognosis in acute stroke patients after intravenous thrombolysis: a multicenter prospective cohort study / Y. Qu, H. Jin, R. Abuduxukuer, S. Qi [et al.] // BMC Medicine. – 2024. – Vol. 22. – P. 1–8. DOI: 10.1186/s12916-024-03517-6.
The S100B protein: a multifaceted pathogenic factor more than a biomarker / F. Michetti, M.E. Clementi, R. Di Liddo, F. Valeriani [et al.] // International Journal of Molecular Sciences. – 2023. – Vol. 24. – P. 1–12. DOI: 10.3390/ijms24119605.
Белок S100β, мозговой натрийуретический пептид и интерлейкины как биомаркеры прогноза исходов при черепно-мозговой травме. / Л.М. Ценципер, Н.В. Дрягина, М.В. Румянцева [и др.] // Анестезиология и реаниматология. – 2019. – № 4. – С. 50–54.
Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery / I. Badan, B. Buchhold, A. Hamm [et al.] // Journal of Cerebral Blood Flow and Metabolism. – 2003. – Vol. 23, No. 7. – P. 845–854. DOI: 10.1097/01.WCB.0000071883.63724.A7.
Mori, T. Targeting S100B in cerebral ischemia and in alzheimer's disease / T. Mori, T. Asano, T. Town // Cardiovascular Psychiatry and Neurology. – 2010. – Vol. 2010. – P. 1–11.
Serum GFAP levels correlate with astrocyte reactivity, post-mortem brain atrophy and neurofibrillary tangles / P. Sánchez-Juan, E. Valeriano-Lorenzo, A. Ruiz-González [et al.] // Brain. – 2024. – Vol. 147, No. 5. – P. 1667–1679. DOI: 10.1093/brain/awae035.
Amalia, L. Glial fibrillary acidic protein (gfap): neuroinflammation biomarker in acute ischemic stroke / L. Amalia // Journal of Inflammation Research. – 2021. – Vol. 14. – P. 7501–7506. DOI: 10.2147/JIR.S342097.
Гуманова, Н.Г. Оксид азота, его циркулирующие метаболиты NOx и их роль в функционировании человеческого организма и прогнозе риска сердечно-сосудистой смерти (часть I) / Н.Г. Гуманова // Профи-лактическая медицина. – 2021. – Т. 24, № 9. – С. 102–109.
Inhibiting sphingosine 1-phosphate receptor subtype 3 attenuates brain damage during ischemia-reperfusion injury by regulating nNOS/NO and oxidative stress / X. Fan, H. Chen, C. Xu [et al.] // Frontiers in Neuroscience. – 2022. – Vol. 16. – P. 1–10. DOI: 10.3389/fnins.2022.838621.
Matsui, T. Role of nitric oxide in ischemic brain damage / T. Matsui, T. Asano // Molecular Biology and Brain Ischemia. – 2002. – P. 129–150.
Targeting reactive nitrogen species: a promising therapeutic strategy for cerebral ischemia-reperfusion injury / X.-M. Chen, H.-S. Chen, M.-J. Xu, J.-G. Shen // Acta Pharmacologica Sinica. – 2013. – Vol. 34. – P. 67–77. DOI: 10.1038/aps.2012.82.
Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection / H. Chen, H. Yoshioka, G.S. Kim [et al.] // Antioxidants & Redox Signaling. – 2011. – Vol. 14, No. 8. – P. 1505–1517. DOI: 10.1089/ars.2010.3576.
Cu, Zn-superoxide dismutase increases the therapeutic potential of adipose-derived mesenchymal stem cells by maintaining antioxidant enzyme levels / D.Y. Yoo, D.W. Kim, J.Y. Chung [et al.] // Neurochemical Research. – 2016. – Vol. 41. – P. 3300–3307. DOI: 10.1007/s11064-016-2062-2.
SOD1 aggregation in astrocytes following ischemia/reperfusion injury: a role of NO-mediated S-nitrosylation of protein disulfide isomerase (PDI) / X. Chen, T. Guan, C. Li [et al.] // Journal of Neuroinflammation. – 2012. – Vol. 9. – P. 1–10. DOI: 10.1186/1742-2094-9-237.
Younus, H. Therapeutic potentials of superoxide dismutase / H. Younus // International Journal of Health Sciences. – 2018. – Vol. 12, No. 3. – P. 88–93.
Manganese superoxide dismutase deficiency exacerbates ischemic brain damage under hyperglycemic conditions by altering autophagy / S.L. Mehta, Y. Lin, W. Chen [et al.] // Translational Stroke Research. – 2011. – Vol. 2, No. 1. – P. 42–50. DOI: 10.1007/s12975-010-0027-3.
Protective role of glutathione in the hippocampus after brain ischemia / Y. Higashi, T. Aratake, T. Shimizu, S. Shimizu // International Journal of Molecular Sciences. – 2021. – Vol. 22, No. 15. – P. 1–10. DOI: 10.3390/ijms22157765.
Differential changes of glutathione levels in astrocytes and neurons in ischemic brains by two-photon imaging / D.E. Bragin, B. Zhou, P. Ramamoorthy [et al.] // Journal of Cerebral Blood Flow & Metabolism. – 2010. – Vol. 30, No. 4. – P. 1–10. DOI: 10.1038/jcbfm.2010.9.
The role of glutamate receptors in ischemic stroke / L. Qi, C. Wu, H. Sun, H. Liao // Biocell. – 2025. – Vol. 49, No. 2. – P. 167–180. DOI:10.32604/biocell.2025.059159
Kostandy, B.B. The role of glutamate in neuronal ischemic injury: the role of spark in fire / B.B. Kostandy // Neurological Sciences. – 2012. – Vol. 33, № 2. – P. 223–237. DOI: 10.1007/s10072-011-0828-5.
Glutamate-mediated excitotoxicity in the pathogenesis and treatment of neurodevelopmental and adult mental disorders / N. Nicosia, M. Giovenzana, P. Misztak [et al.] // International Journal of Molecular Sciences. – 2024. – Vol. 25, No. 12.– P. 1–10. DOI: 10.3390/ijms25126521.
Baranovicova, E. Gluta-mate/GABA/glutamine ratios in intact and ischemia reperfusion challenged rat brain subregions, the effect of ischemic preconditioning / E. Baranovicova, D. Kalenska, J. Lehotsky // Metabolic Brain Disease. – 2025. – Vol. 40.– P. 1–11. DOI: 10.1007/s11011-024-01511-8.
Blood and brain metabolites after cerebral ischemia / E. Baranovicova, D. Kalenska, P. Kaplan [et al.] // International Journal of Molecular Sciences. – 2023. – Vol. 24, No. 24.– P. 1–25.
Gan, C.S. Circulatory microRNA-145 expression is increased in cerebral ischemia / C.S. Gan, C.W. Wang, K.S. Tan // Genetics and Molecular Research. – 2012. – Vol. 11, No. 1. – P. 147–152. DOI: 10.4238/2012.January.27.1.
microRNAs: innovative targets for cerebral ischemia and stroke / Y. B. Ouyang, C.M. Stary, G.-Y. Yang, R. Giffard // Current Drug Targets. – 2013. – Vol. 14, No. 1. – P. 90–101. DOI: 10.2174/138945013804806424.
Up-regulation of brain-enriched miR-107 promotes excitatory neurotoxicity through down-regulation of glutamate transporter-1 expression following ischaemic stroke / Z.-B. Yang, Z. Zhang, T.-B. Li [et al.] // Clinical Science (London). – 2014. – Vol. 127, No. 12. – P. 679–689. DOI: 10.1042/CS20140084.
