Attenuation of a delayed increase in the extracellular glutamate level in the peri-infarct area following focal cerebral ischemia by a novel agent ONO-2506
Attenuation of a delayed increase in the extracellular glutamate level in the peri-infarct area following focal cerebral ischemia by a novel agent ONO-2506
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DOI：
10.1016/j.neuint.2003.06.001
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发表时间：
2004-07-01
影响因子：
4.2
通讯作者：
Asano, T
中科院分区：
文献类型：
--
作者：
Mori, T;Tateishi, N;Asano, T
一种新型药物ONO-2506 [(R)-(-)-2-丙基辛酸，ONO制药有限公司]先前被证明可以通过抑制s -100 β的增强产生来减轻延迟性梗死扩张，同时在给药后24小时内诱导症状迅速改善，达到显著水平。为了阐明症状迅速改善的机制，本研究旨在研究ONO-2506是否调节短暂性大脑中动脉闭塞（tMCAO）大鼠的细胞外谷氨酸（[Glu]e）水平。在该模型中，研究表明ONO-2506可以减少梗死面积，改善神经功能缺损，并提高神经胶质谷氨酸转运体（GLT-1和GLAST）的mRNA表达。用脑内微透析连续测定缺血皮质[Glu]e水平。比较假手术组和假手术组在给药和不给药情况下[Glu]e水平的变化。在tMCAO组中，[Glu]e水平在tMCAO期间升高幅度相似，在再灌注时恢复正常，并在5 h左右再次升高。然而，在盐水处理组中，[Glu]e水平从15 h开始进一步升高，在24 h时达到正常水平的280%左右。ONO-2506阻止了[Glu]e水平在再灌注后期的继发升高。tMCAO后24 h脑内输注谷氨酸转运体抑制剂l -反式吡啶-2,4-二羧酸可诱导[Glu]e水平升高，假手术组和ono -2506处理组均有明显升高，而盐水处理组则不明显。上述结果提示，ONO-2506等药理药物对活化星形胶质细胞的功能调节可能抑制再灌注后期[Glu]e水平的继发性升高，从而改善延迟性梗死扩展和神经功能缺损。(C) 2004 Elsevier Ltd.版权所有。
A novel agent, ONO-2506 [(R)-(-)-2-propyloctanoic acid, ONO Pharmaceutical Co. Ltd.] was previously shown to mitigate delayed infarct expansion through inhibition of the enhanced production of S-100beta, while inducing a prompt symptomatic improvement that attained a significant level as early as 24 h after drug administration. To elucidate the mechanism underlying the prompt symptomatic improvement, the present study aimed to examine whether ONO-2506 modulates the level of extracellular glutamate ([Glu]e) in the rat subjected to transient middle cerebral artery occlusion (tMCAO). In this model, it had been shown that ONO-2506 reduces the infarct volume, improves the neurological deficits, and enhances the mRNA expression of glial glutamate transporters (GLT-1 and GLAST). The [Glu]e levels in the ischemic cortices were continuously measured using intracerebral microdialysis. The alterations in the [Glu]e levels in the sham-operated and tMCAO-operated groups with or without drug administration were compared. In the tMCAO groups, the [Glu]e level increased during tMCAO to a similar extent, returned to normal on reperfusion, and increased again around 5 h. In the saline-treated group, however, the [Glu]e level further increased from 15 h on to reach about 280% of the normal level at 24 h. This secondary increase in the [Glu]e level in the late phase of reperfusion was prevented by ONO-2506. The intracerebral infusion of glutamate transporter inhibitor, L-trans-pyrrolidine-2,4-dicarboxylic acid, at 24 h after tMCAO induced an increase in the [Glu]e level, which was marked in both the sham-operated and ONO-2506-treated groups, but much less pronounced in the saline-treated group. The above results suggest that functional modulation of activated astrocytes by pharmacological agents like ONO-2506 may inhibit the secondary rise of [Glu]e level in the late phase of reperfusion, leading to amelioration of delayed infarct expansion and neurological deficits. (C) 2004 Elsevier Ltd. All rights reserved.