Abstract DP167: Brain Maturational Step Affects the Magnitude of the Inflammatory Response and Hemorrhagic Transformation after Late Reperfusion in Perinatal and Childhood Arterial Ischemic Stroke Mouse Models

Brain development at the stroke onset plays a key role in the pathophysiology of perinatal arterial ischemic stroke (PAIS) and childhood arterial ischemic stroke (CAIS). Mechanical thrombectomy has revolutionized care in adult stroke whereas the safety profile for thrombectomy in infants and children with AIS is not defined and the mechanistic understanding of beneficial and harmful thresholds of late recanalization in PAIS and CAIS is lacking. Aim: Determine the magnitude and the patterns of adverse effects of late reperfusion in PAIS and CAIS mouse models. Methods: Models: 8h transient middle cerebral artery occlusion (tMCAO) as mimic of late reperfusion in CAIS (in postnatal day 21 mice; P21) and PAIS (P9 mice). Outcomes: cytokine multiplex, the presence of hemorrhages, endothelial activation, neuroinflammation, histological and functional outcomes. Results: The incidence of injury was similar in P9 (n=35) and P21 (n=18) mice, ~74%, whereas brain edema was markedly higher and hemorrhages of various sizes were apparent in injured cortex in P9 mice (57%) but not in P21 mice 18h after reperfusion. Clots at the occluder insertion site, in turn, were apparent in 5% of P9 and 52% P21 mice. Behavior tests showed distinct responses after PAIS and CAIS. At 48h, no hemorrhages observed in the cortex of P9. Clots at occluder insertion site were present in 31% of P21. By 7 days, remaining tissue was ~56% of injured hemisphere in P9 (n=12) and ~77% in P21 (n=15). The magnitude of increase of inducible endothelial molecules in injured Vs. contralateral regions 18h after reperfusion was markedly higher in P9 than in P21 mice, including ICAM-1 (48-fold), PAI-1 (172-fold), and MMP-9 (>1000-fold) (n=8). In P21 the levels increased 10-fold for ICAM-1, 37-fold for PAI-1, and 65-fold for MMP-9 (n=8). The magnitude of the inflammatory response was also vastly distinct for chemokines MCP-1 and KC and IL6, eotaxin and IL1b, but not for MIP1b. Conclusions: Cerebral hemorrhages upon late reperfusion/recanalization after ischemic stroke are apparent in PAIS and CAIS mouse models, raising safety concerns about adverse effects after extended ischemic periods, but the patterns of adverse effects, such as neuroinflammation and hemorrhagic transformation, are maturation-dependent. Funding: R21NS131837, R56NS103483, R01NS044025