Combination treatment with N-acetyl-seryl-aspartyl-lysyl-proline and tissue plasminogen activator provides potent neuroprotection in rats after stroke.
Combination treatment with N-acetyl-seryl-aspartyl-lysyl-proline and tissue plasminogen activator provides potent neuroprotection in rats after stroke.
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DOI：
10.1161/strokeaha.113.004399
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发表时间：
2014-04
期刊：
影响因子：
8.3
通讯作者：
Zhang ZG
中科院分区：
文献类型：
--
作者：
Zhang L;Chopp M;Teng H;Ding G;Jiang Q;Yang XP;Rhaleb NE;Zhang ZG
N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), an endogenously produced circulating peptide in humans and rodents, exerts anti-inflammatory and cardioprotective activities in various cardiovascular diseases. The present study evaluated the neuroprotective effect of AcSDKP alone and in combination with thrombolytic therapy in a rat model of embolic focal cerebral ischemia. We found that treatment with AcSDKP alone at 1h or the combination treatment with AcSDKP and tissue plasminogen activator (tPA) at 4h after stroke onset substantially increased AcSDKP levels in plasma and cerebrospinal fluid (CSF) and robustly reduced infarct volume and neurological deficits, without increasing the incidence of brain hemorrhage compared with ischemic rats treated with saline, AcSDKP alone at 4h, and tPA alone at 4h. Moreover, the combination treatment considerably reduced the density of nuclear transcription factor-κB (NF-κB), transforming growth factorβ (TGFβ), and plasminogen activator inhibitor-1 (PAI-1) positive cerebral blood vessels in the ischemic brain, all of which were associated with reduced microvascular fibrin extravasation and platelet accumulation compared to tPA monotherapy. In vitro, AcSDKP blocked fibrin-elevated TGFβ1, PAI-1, and NF-κB proteins in primary human brain microvascular endothelial cells. Our data indicate that AcSDKP passes the blood brain barrier (BBB) and that treatment of acute stroke with AcSDKP either alone at 1h or in combination with tPA at 4h of the onset of stroke is effective to reduce ischemic cell damage in a rat model of embolic stroke. Inactivation of TGFβ and NF-κB signaling by AcSDKP in the neurovascular unit may underlie the neuroprotective effect of AcSDKP.
