Abstract WP279: Targeting GLUT5 in Ischemic Stroke: A New Metabolic Approach for Neuroprotection

Background: Current therapeutic options for ischemic stroke remain limited, necessitating novel therapeutic strategies. In ischemic stroke, glucose transport via glucose transporters (GLUT) is impaired, necessitating exploration of alternative anaerobic pathways such as fructose metabolism. The naked mole-rat has evolved fructose metabolism via GLUT5, enabling survival under anoxic conditions for up to 18 minutes, suggesting a hypoxia-adaptive mechanism. Conversely, GLUT5 is also upregulated in metabolic disorders (hypertension, diabetes, etc.) and cancers (breast, colon, lung, etc.), concerning worsening effects. However, the role of GLUT5 in ischemic stroke remains unclear. This study investigated the relationship between GLUT5 expression and oxidative stress in ischemic stroke. Methods: Distal middle cerebral artery occlusion (DMCAO) was performed in CB-17 mice and PBS, fructose or GLUT5 inhibitor were administered (N=10 per group). GLUT5 expression, oxidative stress markers and neurological function were evaluated. In vitro, primary cultured astrocytes were subjected to 3-hour oxygen glucose deprivation followed by fructose or GLUT5 inhibitor. Cell survival rates were compared, and GLUT5 expression and inflammatory markers were evaluated by Western blotting. Additionally, metabolomic analysis was performed using primary cultured astrocytes subjected to OGD to clarify the relationship between GLUT5 and fructose metabolism. Results: GLUT5 expression was increased in inflammatory microglia and reactive astrocytes following DMCAO. Fructose administration further enhanced GLUT5 expression and oxidative stress markers, whereas GLUT5 inhibition significantly reduced both. Fructose group showed increased infarct size and worsened neurological deficits, while GLUT5 inhibitor group showed improved outcomes. Similar patterns were observed in cell models, and correlations were observed between viability, GLUT5 expression, and inflammatory markers. Metabolomic analysis revealed elevated levels of glycolytic intermediates, lactate, and TCA cycle metabolites in fructose group. However, a lack of succinate-to-fumarate conversion indicated impaired Complex II activity. Conclusions: GLUT5 is closely associated with post-ischemic oxidative stress and tissue injury. While it may support anaerobic metabolism, its activity also contributes to mitochondrial dysfunction and inflammation. GLUT5 may represent a novel therapeutic target for limiting ischemic brain injury.