Salvinorin A pretreatment preserves cerebrovascular autoregulation after brain hypoxic/ischemic injury via extracellular signal-regulated kinase/mitogen-activated protein kinase in piglets.
Salvinorin A pretreatment preserves cerebrovascular autoregulation after brain hypoxic/ischemic injury via extracellular signal-regulated kinase/mitogen-activated protein kinase in piglets.
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DOI：
10.1213/ane.0b013e31823a5d36
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发表时间：
2012-01
影响因子：
5.7
通讯作者：
Liu R
中科院分区：
文献类型：
--
作者：
Su D;Riley J;Armstead WM;Liu R
婴儿先天性心脏病手术期间的脑缺氧/缺血并不少见，并可能导致终生持续的破坏性神经功能障碍。缺氧/缺血所致的脑血管功能障碍被认为是神经损伤的重要因素。目前还没有发现可以预防这种情况的药理制剂。丝裂原活化蛋白激酶(MAPK)包括细胞外信号调节激酶(ERK)、c-Jun-N末端激酶(JNK)和p38，被认为与缺血预适应有关。我们研究了唯一的天然非阿片类kappa受体激动剂salvinorin A预处理是否能通过MAPK保护软脑膜动脉的自我调节。在有或没有ERK上游的蛋白激酶抑制剂U0126、c-JNK的抑制剂sp600125或p38的抑制剂sb203580的存在或不存在的情况下，在配备了关闭的颅窗的仔猪的缺氧和缺血前后，监测了软脑膜动脉对低血压和高二氧化碳的反应。在缺氧/缺血前30分钟静脉注射丹参素A(10μg/kg)。分别于给药前和给药后30min采集脑脊液标本，测定MAPK的含量。采用重复测量方差分析方法对5例数据进行分析。低氧/缺血后对高碳酸血症和低血压的软脑膜动脉扩张被钝化，但预先给予丹参甲素U0126保存良好，而不是sp600125或sb203580，取消了丹参甲素对低血压和高碳酸血症的脑血管自我调节的保护作用。Salvinorin组动物脑脊液中PERK/ERK比值显著升高，U0126可抑制其升高。Salvinorin A通过ERK在仔猪模型中保护软脑膜动脉对缺氧/缺血后低血压和高碳酸血症的自动调节。
Cerebral hypoxia/ischemia during infant congenital heart surgery is not uncommon, and may induce devastating neurologic disabilities persistent over the lifespan. Hypoxia/ischemia-induced cerebrovascular dysfunction is thought to be an important contributor to neurological damage. No pharmacological agents have been found to prevent this. Mitogen activated protein kinase (MAPK), including extracellular signal regulated kinase (ERK), c-Jun-N-terminal kinase (JNK) and p38, is thought to contribute to ischemic preconditioning. We investigated whether pretreatment with salvinorin A, the only natural non-opioid kappa receptor agonist, could preserve autoregulation of the pial artery via MAPK. The response of the pial artery to hypotension and hypercapnia was monitored in piglets equipped with a closed cranial window before and after hypoxia and ischemia in the presence or absence of U0126, an inhibitor for the protein kinase upstream of ERK, sp600125, an inhibitor of c-JNK or sb203580, an inhibitor of p38. Salvinorin A (10 μg/kg IV) was administered 30 minutes before hypoxia/ischemia in salvinorin-treated animals. Cerebrospinal fluid samples were collected before and 30 minutes after salvinorin A administration for the measurement of MAPK. Data (n=5) were analyzed by repeated-measures analysis of variance. Pial artery dilation to hypercapnia and hypotension was blunted after hypoxia/ischemia, but preserved well by pretreatment with salvinorin A. U0126, but not sp600125 or sb203580, abolished the preservative effects of salvinorin A on cerebral vascular autoregulation to hypotension and hypercapnia. The ratio of pERK/ERK in cerebrospinal fluid increased significantly in salvinorin-treated animals, which was inhibited by U0126. Salvinorin A pretreatment preserves autoregulation of the pial artery to hypotension and hypercapnia after hypoxia/ischemia via ERK in a piglet model.