Abstract WP344: Inflammatory and Epigenetic Changes in the Human Ischemic Stroke Brain – Novel Insights for Therapeutic Targets

Introduction: Stroke remains one of the leading causes of death and disability worldwide. A major challenge in the field is the limited understanding of the molecular basis of stroke pathophysiology in the human brain, which hinders the development of effective novel therapies. Much of our current knowledge stems from preclinical rodent models, which do not fully capture the molecular and cellular complexity of the human condition—particularly at the inflammatory and epigenetic levels. Methods: In this study, we analyzed postmortem human brain tissue obtained from donors with a history of middle cerebral artery territory infarct, but stroke was not the cause of death. Specifically, we examined the cortex, the ischemic core/infarct area, and the hippocampus. The corresponding contralateral (non-stroke-affected) regions served as an internal control. Tissue samples were assessed for gene and protein expression of key inflammatory and epigenetic biomarkers. Results: A total of 13 donors were included in the study. Compared to the contralateral control regions, the stroke-affected (ipsilateral) regions showed a significant increase in inflammatory markers GFAP and Iba1, indicating heightened astrocyte and microglia activation. An increased trend for inflammatory markers like IL-1β, NLRP3, ASC, and Casp1 was also seen. Epigenetic markers like, histone deacetylases, HDAC2, which represents impaired memory formation and neuronal dysfunction, and HDAC9, which is implicated in stroke risk, were elevated in the ipsilateral side. DNA Methyltransferase 1 (DNMT1), an epigenetic marker that affects neuronal recovery, was also significantly upregulated in stroke-affected tissue. Correlation studies between biomarkers and patient demographics will be completed by the time of the presentation. Conclusion: These findings reveal inflammatory and epigenetic alterations in the human brain following stroke. The observed biomarker changes offer valuable insights into human stroke pathophysiology and may guide the development of future preclinical models and therapeutic targets aimed at modulating inflammation and epigenetic dysregulation in ischemic stroke.