Introduction: Mechanical thrombectomy (MT) effectively restores large-vessel patency in acute ischemic stroke (AIS), yet incomplete reperfusion and blood–brain barrier (BBB) disruption with hemorrhagic transformation often limit its clinical benefit. Growing evidence implicates thrombo-inflammation, particularly neutrophil extracellular trap (NET)-driven microvascular obstruction, as a key barrier to microcirculatory reperfusion. Ischemia–reperfusion rapidly activates circulating neutrophils, triggering NET release and brain infiltration that promote microvascular thrombosis, impede capillary flow, and disrupt the BBB. Colchicine, an FDA-approved microtubule inhibitor, suppresses neutrophil effector functions in inflammatory diseases. We hypothesized that colchicine administration at reperfusion would attenuate neutrophil-driven thrombo-inflammation and improve MT outcomes. Methods: A transient middle cerebral artery occlusion (tMCAO) model was established in male C57BL/6J mice to mimic MT. Colchicine (0.4, 0.8, or 1.6 mg/kg, i.p.) was administered immediately before reperfusion; the optimal dose was determined by infarct volume reduction on 2,3,5-triphenyltetrazolium chloride (TTC) staining at day 3. Using this dose, we assessed leukocyte counts and phenotypes, neutrophil F-actin polymerization (flow cytometry, phalloidin staining), and cerebral blood flow (laser speckle imaging) at 4–24 h post-tMCAO. Brain tissue was analyzed for leukocyte infiltration, neutrophil activation, NET formation, fibrin deposition, and BBB integrity (flow cytometry, immunohistochemistry). Sensorimotor and cognitive outcomes were evaluated up to 14 days. Results: Colchicine significantly reduced infarct volume at day 3 and inhibited neutrophil F-actin polymerization. At 4 h post-tMCAO, colchicine reduced circulating neutrophil recruitment and activation. At 24 h, colchicine markedly decreased NET formation and fibrin deposition in cerebral microvessels, improved regional cerebral blood flow, and attenuated leukocyte brain infiltration, neutrophil pro-inflammatory activation, and BBB disruption. Colchicine-treated mice exhibited better sensorimotor and cognitive performance and reduced brain tissue loss up to 14 days. Conclusions: Colchicine administered at reperfusion attenuates neutrophil-driven thrombo-inflammation, improving neurovascular outcomes in a murine MT-mimicking stroke model. These findings support colchicine as a potential adjunct to reperfusion therapy for AIS.
Wang et al. (Thu,) studied this question.