Abstract TP253: Adjuvant Treatment with N-acetyl-seryl-aspartyl-lysyl-proline Extends the Therapeutic Window of Tissue Plasminogen Activator in a Rat Model of Embolic Stroke
N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is a peptide normally found in human plasma, which has been shown to exert anti-inflammatory and pro-angiogenic activities in the experimental cardiovascular diseases. The present study evaluated the neuroprotective effect of AcSDKP alone and in combination with delayed thrombolytic therapy on focal cerebral ischemia. Rats subjected to embolic middle cerebral artery occlusion were treated with: 1) AcSDKP (2.4mg/kg for 3 days) starting at 1 (n=6), or 4h (n=5) after stroke; 2) combination treatment of tissue plasminogen activator (tPA, 10mg/kg) and AcSDKP (n=12) starting at 4h after stroke; 3) tPA at 4 h after stroke (n=10); 4) saline (n=10). Plasma and cerebrospinal fluid (CSF) samples were taken 24h post stroke to assess the AcSDKP activity by EIA assay. Infarct volume and the incidence of hemorrhage were measured at 7 days after stroke. Monotherapy with AcSDKP starting 1h after stroke onset significantly (p<0.05) reduced lesion volume (20±4% vs 37±4%) and neurological deficits compared with saline treated rats. In addition, while monotherapy with AcSDKP or tPA at 4h failed to reduce lesion volume (34±8% and 38±1%, respectively), combination treatment with tPA and AcSDKP starting 4h after stroke onset significantly reduced volume (15±2%) and exhibited a robust improvement in neurological outcome compared with monotherapy of AcSDKP or tPA. Combination of AcSDKP and tPA did not increase brain hemorrhage measured 7 days after stroke. Concurrently, the combination treatment significantly reduced the density of transforming growth factor β (TGFβ) positive vessels (30±3/mm2) compared with monotherapy of tPA (54±5/mm2) or saline (47±4/mm2), and completely blocked tPA-induced increase in the density of nuclear transcription factor-κB (NF-κB) positive vessels (9±1/mm2 vs 13±2/mm2 in tPA monotherapy group). Treatment with AcSDKP significantly increased AcSDKP levels in plasma (9±3nM vs 3±1nM in control) and CSF (6±2nM vs 3±1nM in control). Our data indicate that: 1) AcSDKP passes the BBB and reduces ischemic cell damage, 2) Combination treatment with AcSDKP and tPA extends the therapeutic window for thrombolysis, and 3) NF-κB and TGFβ signaling are likely involved in the neuroprotective effect of AcSDKP.
- © 2012 by American Heart Association, Inc.