Therapeutic time window and dose dependence of neuroprotective effects of sodium orthovanadate following transient middle cerebral artery occlusion in rats
Therapeutic time window and dose dependence of neuroprotective effects of sodium orthovanadate following transient middle cerebral artery occlusion in rats
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DOI：
10.1124/jpet.105.096677
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发表时间：
2006-05-01
影响因子：
3.5
通讯作者：
Kuratsu, JI
中科院分区：
文献类型：
--
作者：
Hasegawa, Y;Morioka, M;Kuratsu, JI
钒广泛分布于环境中，在人体内具有多种生物和生理效应。我们先前记录了原钒酸钠(SOV)对啮齿动物静脉注射的神经保护作用。大脑中动脉闭塞(MCAO)后即刻注射50 mM SOV 2ml/kg，MCAO后0min。为了评估其潜在的临床应用，我们确定了大鼠大脑中动脉阻塞后的治疗时间窗(0、45和90min)和SOV的神经保护剂量(2ml/kg、12.5、25、37.5和50 mm)。在MCAO后0min或45min单次注射50 mM SOV也有相似的神经保护作用，即使在MCAO后90min注射50 mM SOV也具有显著的神经保护作用。尽管在50 mM SOV时保护作用最强，但在MCAO后0和45min一次性注射25 mM和12.5 mM可显著缩小脑梗塞体积。我们还发现，SOV治疗通过激活蛋白激酶B(Akt)和细胞外信号调节激酶(ERK)来减轻大鼠脑缺血后神经细胞的损伤，抑制血糖，并诱导局部脑血流量(RCBF)在短暂的MCAO后逐渐恢复。为了阐明SOV参与神经元保护的重要因素(S)，我们测定了不同SOV处理后的Akt和ERK活性、生理参数、血糖水平和局部脑血流量。总之，Akt的激活是SOV诱导的神经保护中最重要的因素，ERK的激活、rCBF的逐渐恢复和血糖的下降是微弱的贡献因素。
Vanadium is widely distributed in the environment and exhibits various biological and physiological effects in the human body. We previously documented the neuroprotective effect of sodium orthovanadate (SOV) against in rodents i.v. injected with 2 ml/kg 50 mM SOV just after the induction of middle cerebral artery occlusion (MCAO; 0 min post-MCAO). To evaluate its potential clinical use, we determined here therapeutic time window (0, 45, and 90 min post-MCAO) and the neuroprotective dose (2 ml/kg, 12.5, 25, 37.5, and 50 mM) of SOV in rats. A single injection of 50 mM SOV at 0 or 45 min post-MCAO produced similar neuroprotective effects, and even 50 mM delivered 90 min post-MCAO exerted significant neuroprotection. Although the maximal neuroprotective effect was obtained at 50 mM SOV, 25 mM injected once and 12.5 mM delivered at 0 and 45 min post-MCAO significantly reduced the infarct volume. We also documented that SOV treatment ameliorates ischemic neuronal cell injury via the activation of both protein kinase B (Akt) and extracellular signal-regulated kinase (ERK), inhibits serum glucose, and elicits the gradual recovery of regional cerebral blood flow (rCBF) after transient MCAO in rats. To elucidate the important factor(s) involved in the neuronal protection afforded by SOV, we measured Akt and ERK activity, physiological parameters, blood glucose levels, and rCBF following various SOV treatments. In conclusion, Akt activation was the most important factor in SOV-induced neuroprotection; ERK activation, the gradual recovery of rCBF, and decreased blood glucose were weak contributors.