Abstract WP249: Effect Of Acute Hyperglycemia On Stroke Outcome And Immune Response

Abstract

Background: Acute hyperglycemia occurs in over 40% of ischemic stroke patients, increases hemorrhagic transformation (HT) and worsens stroke outcome. Previous rodent studies reported deleterious effects of hyperglycemia on stroke outcome during acute stroke (within hours to days), however, its impact during subacute stroke period (days to weeks) remains unclear. Moreover, the mechanisms underlying hyperglycemia’s worsening of stroke outcomes remains elusive. In this study, we investigated the effect of acute hyperglycemia on immune responses and stroke outcome in acute and subacute phases. Method: Male C57/BL6 mice were subjected to middle cerebral artery occlusion (MCAO) for 30 min, followed by reperfusion to mimic ischemic stroke. Acute hyperglycemia was induced by glucose injection 10 min before MCAO. For the acute phase study, mice were sacrificed at 4.5 hrs to assess blood-brain barrier leakage (Evans blue) and brain immune cell populations (flow cytometry), and at 24 hrs to evaluate brain infarct, swelling and HT. In the sub-acute phase, mice were allowed to survive 14 days after stroke to evaluate mortality rate, neurological deficit, and motor-sensory dysfunction using a rotating beam test. Result: In the acute phase, hyperglycemia rapidly increased BBB leakage by 4.5 hrs after stroke, when compared to the normoglycemia group (p<0.0001). At this early timepoint, hyperglycemic mice brains showed more Ly6C hi microglia and infiltrating myeloid cells, including neutrophils and Ly6C hi monocytes, than normoglycemic mice. By 24 hrs after stroke, hyperglycemic mice showed increased HT and larger brain edema; brain infarct volume however, was not affected. In the subacute-phase, hyperglycemic mice exhibited a higher mortality rate than normoglycemic mice (100% VS 25%, p=0.0008), with greater body weight loss, and worsened neurological deficit and rotating beam performance. Conclusion: Acute hyperglycemia adversely impacts stroke outcomes in acute and subacute phases, with HT and brain edema as the key pathological events associated with higher mortality, as well as more severe neurological and motor-sensory deficits. Rapid modulation of immune responses may play an important role in mediating the detrimental effect of hyperglycemia.