MRI evaluation of BBB disruption after adjuvant AcSDKP treatment of stroke with tPA in rat

摘要

The primary limitation of thrombolytic treatment of ischemic stroke with tPA is the hemorrhagic risk. We tested AcSDKP (N-acetyl-seryl-aspartyl-lysyl-proline), as an auxiliary therapeutic agent, to reduce blood-brain barrier (BBB) disruption in a combination tPA thrombolytic treatment of stroke. Wistar rats subjected to embolic stroke were randomly assigned to either the tPA monotherapy group (n=9) or combination of tPA and AcSDKP treatment group (n=9) initiated at 4h after ischemia. MRI measurements were performed before and after the treatments. Immunohistochemical staining and measurements were performed to confirm MRI findings. Longitudinal MRI permeability measurements with Gd-DTPA demonstrated that combination treatment of acute embolic stroke with AcSDKP and tPA significantly reduced BBB leakage, compared to tPA monotherapy, at 3 and 6 days (18.3±9.8mm³ vs 65.0±21.0mm³, p<0.001) after onset of stroke, although BBB leakage was comparable between the two groups prior to the treatments (6.8±4.4mm³ vs 4.3±3.3mm³, p>0.18). The substantial reduction of BBB leakage observed in the combination treatment group was closely associated with reduced ischemic lesions measured by T2 maps (113.6±24.9mm³ vs 188.1±60.8mm³, p<0.04 at 6d). Histopathological analysis of the same population rats showed that the combination treatment significantly reduced parenchymal fibrin deposition (0.063±0.059mm² vs 0.172±0.103mm², p<0.03) and infarct volume (146.7±35.9mm³ vs 199.3±60.4mm³, p<0.05) compared to the tPA monotherapy at 6 days after stroke. MRI provides biological insight into the therapeutic benefit of combination treatment of stroke with tPA and AcSDKP 4 hours after onset, and demonstrates significantly improved cerebrovascular integrity with neuroprotective effects compared with tPA monotherapy.