Colchicine as an Adjunctive Therapy to Improve Ischemic Stroke Reperfusion Outcomes in Mice

Mechanical thrombectomy (MT) has become a cornerstone therapy for acute ischemic stroke (AIS) caused by large-vessel occlusion; however, incomplete microvascular reperfusion and blood-brain barrier (BBB) disruption frequently limit its clinical benefit. Emerging evidence implicates neutrophil-driven thrombo-inflammation, particularly neutrophil extracellular trap (NET)-mediated microvascular obstruction, as a key mechanism underlying post-reperfusion hypoperfusion and secondary neurovascular injury. Colchicine, an FDA-approved microtubule inhibitor, potently suppresses neutrophil effector functions with a favorable safety profile, making it a promising adjunct to ischemia-reperfusion.

Using a transient middle cerebral artery occlusion (tMCAO) mouse model of ischemia-reperfusion, colchicine (0.8 mg/kg, intraperitoneal) was administered at reperfusion. We assessed circulating neutrophil response and activation, neutrophil F-actin polymerization, NET formation, microvascular fibrin(ogen) deposition, cerebral blood flow, leukocyte brain infiltration, BBB integrity, and neuroinflammation at acute and subacute time points. Whole-blood phagocytosis and bone marrow cellularity were examined at Day 3 after tMCAO. Neutrophil depletion was achieved using an anti-Ly6G antibody. Long-term neurological outcomes and brain tissue loss were evaluated up to 14 days after tMCAO.

Colchicine administration at reperfusion significantly blunted early neutrophil increase and activation, inhibited neutrophil F-actin polymerization, and suppressed intravascular NET formation and microvascular fibrin(ogen) deposition in tMCAO mice. It also improved cerebral blood flow, reduced leukocyte brain infiltration, attenuated BBB disruption, and decreased infarct size. Importantly, colchicine-treated mice exhibited sustained improvements in sensorimotor and cognitive function and reduced chronic brain tissue loss. Notably, colchicine did not exacerbate post-stroke immunosuppression, and its neuroprotective effects were abolished by neutrophil depletion.

Colchicine administered at reperfusion suppresses neutrophil-driven thrombo-inflammation, preserves BBB integrity, and improves cerebral blood flow, resulting in reduced ischemic brain injury and long-term neurological deficits after ischemic stroke. These findings suggest colchicine might be developed as a potential adjunctive therapy to limit reperfusion-associated microvascular dysfunction and neurovascular injury.