Effect of Thrombolysis on the Dynamics of Infarct Evolution After Clot Embolism of Middle Cerebral Artery in Mice

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Abstract
Reversible focal ischemia may lead to delayed tissue injury despite primary restoration of blood flow and metabolism. The authors investigated whether such delayed changes also occur after thrombolytic treatment of thromboembolic stroke. Clot embolism of the middle cerebral artery (MCA) was produced in C57/B16J mice by intracarotid injection of heterologous clots. One hour after embolism, one group was treated with intracarotid infusion of rt-PA (10 mg/kg). The untreated control group received an equal amount of vehicle. Just before onset of treatment and after 1, 3, 6, and 24 hours, animals were frozen in situ and cerebral blood flow (CBF), cerebral protein synthesis (CPS), ATP content, and DNA fragmentations (TUNEL) were imaged on cryostat sections using double tracer autoradiography, bioluminescence, and immunohistochemical techniques, respectively. In untreated animals (n = 20), CPS was suppressed in approximately 68% of hemispheric transsection at 1 hour after embolization. The ATP depleted area was smaller (approximately 58%), but between 6 and 24 hours it merged with that of CPS suppression. TUNEL-positive neurons became visible between 6 and 24 hours exclusively in regions with ATP depletion. rt-PA-induced thrombolysis (n = 20) led to the gradual improvement of blood flow. At 24 hours, ATP depletion was fully reversed and the CPS suppression area declined to approximately 16% of hemispheric transsection. Despite progressive metabolic recovery, large numbers of neurons became TUNEL-positive and animals died between 24 and 48 hours. Thrombolysis after clot embolism restores metabolic activity including protein synthesis, but the therapeutic benefit is limited by secondary injury that requires additional treatment to improve final outcome.