MRI EVALUATION OF BBB DISRUPTION AFTER ADJUVANT AcSDKP TREATMENT OF STROKE WITH tPA IN RAT

作者：Ding G; Zhang Z; Chopp M; Li L; Zhang L; Li Q; Wei M; Jiang Q^*

来源：Neuroscience, 2014, 271: 1-8.

DOI：10.1016/j.neuroscience.2014.04.025

• BBB
• stroke
• tPA
• AcSDKP
• MRI
• rat

The primary limitation of thrombolytic treatment of ischemic stroke with tissue plasminogen activator (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 4 h after ischemia. Magnetic resonance imaging (MRI) measurements were performed before and after the treatments. Immunohistochemical staining and measurements were performed to confirm MRI findings. Longitudinal MRI permeability measurements with gadolinium-diethylenetriamine penta-acetic acid (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 +/- 9.8 mm(3) vs 65.0 +/- 21.0 mm(3), p %26lt; 0.001) after the onset of stroke, although BBB leakage was comparable between the two groups prior to the treatments (6.8 +/- 4.4 mm(3) vs 4.3 +/- 3.3 mm(3), p %26gt; 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 +/- 24.9 mm(3) vs 188.1 +/- 60.8 mm(3), p %26lt; 0.04 at 6 days). Histopathological analysis of the same population of rats showed that the combination treatment significantly reduced parenchymal fibrin deposition (0.063 +/- 0.059 mm(2) vs 0.172 +/- 0.103 mm(2), p %26lt; 0.03) and infarct volume (146.7 +/- 35.9 mm(3) vs 199.3 +/- 60.4 mm(3), p %26lt; 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 h after onset, and demonstrates significantly improved cerebrovascular integrity with neuroprotective effects compared with tPA monotherapy.

• 出版日期2014-6-20