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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >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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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.

机译：通过新型药物ONO-2506减轻局灶性脑缺血后梗塞周围区域细胞外谷氨酸水平的延迟增加。

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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 24h 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 5h. 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 24h. 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 24h 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.
机译：先前已显示出一种新型药物ONO-2506 [（R）-（-）-2-丙基辛酸，ONO Pharmaceutical Co. Ltd.]可通过抑制S-100beta产量的增加来缓解梗塞扩展延迟，同时诱导提示症状改善，最早在给药后24小时达到显着水平。为了阐明迅速改善症状的根本机制，本研究旨在检查ONO-2506是否调节遭受短暂脑中动脉闭塞（tMCAO）的大鼠中细胞外谷氨酸（Glu）的水平。在该模型中，已显示ONO-2506减少了梗塞体积，改善了神经功能缺损，并增强了神经胶质谷氨酸转运蛋白（GLT-1和GLAST）的mRNA表达。使用脑内微透析连续测量缺血皮层中的葡萄糖水平。比较了在有或没有药物给药的假手术组和tMCAO手术组中Ge水平的变化。在tMCAO组中，在tMCAO期间，谷氨酸水平以相似的程度升高，在再灌注时恢复正常，并在5小时左右再次升高。然而，在盐水治疗组中，谷氨酸水平从15小时开始进一步增加，在24小时达到正常水平的约280％。 ONO-2506防止了再灌注后期血糖水平的二次增加。在tMCAO后24小时向脑内注入谷氨酸转运蛋白抑制剂l-反式-吡咯烷-2,4-二羧酸诱导了谷胱甘肽水平的升高，这在假手术和ONO-2506-治疗组，但在盐水治疗组中不明显。上述结果表明，由药理剂如ONO-2506对活化的星形胶质细胞的功能性调节可抑制再灌注后期的Gee水平的继发性升高，从而导致梗塞延迟扩展和神经功能缺损的改善。

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