Enhancing the efficacy of thrombolysis by AMPA receptor blockade with NBQX in a rat embolic stroke model

Abstract

Efficacy and safety of combined α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor blockade and thrombolytic therapy with human recombinant tissue plasminogen activator (TPA) was tested in a rat embolic stroke model. Sixty-three rats were embolized in the right internal carotid territory with a 200 μl suspension of microclots formed by alternate moving of 150 μl whole blood and 50 μl of thrombin between two interconnected syringes for 4 min. Sixteen embolized rats served as controls, and 16 rats were treated with NBQX immediately after embolization. Thirty-one rats were treated with TPA 2 h following embolization, and in 16 of these rats additional NBQX treatments were initiated 90 min following embolization. Hemispheric cerebral blood flow (CBF) was measured by an intraarterial 133Xenon injection method before and after embolization. Carotid angiography displayed the rate of occlusion of the cerebral arterial supply before and after treatment. Brains were fixed after 2 days, evaluated neuropathologically, and infarct volumes were measured. Median CBF was reduced by 70–77% in the affected hemispheres following embolization. Significant recanalization occurred in all groups except those treated with NBQX. TPA-treated rats had significantly better reperfusion compared to controls judged by angiography 3 h following embolization ( P = 0.04). NBQX alone and TPA alone caused insignificant reduction in infarct volume but, when combined, total infarct volume was reduced by 77% compared to controls ( P = 0.02). Separate measurement of cortical infarct revealed significantly smaller infarcts ( P = 0.05) in the combined treatment group compared to the TPA treatment group. Mortality rate was 19% among controls, 31% among NBQX alone, and 25% among the combined treatment group. Rats treated with TPA alone had a significantly lower mortality rate (0%; P = 0.05, treated vs. controls). The combination of NBQX administered prior to delayed TPA treatment (120 min) significantly reduced cerebral infarct size in rats. The combined therapy was superior to either therapy alone.