Delayed administration of the nucleic acid analog 2Cl-C.OXT-A attenuates brain damage and enhances functional recovery after ischemic stroke
Delayed administration of the nucleic acid analog 2Cl-C.OXT-A attenuates brain damage and enhances functional recovery after ischemic stroke
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DOI：
10.1016/j.brainres.2013.02.009
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发表时间：
2013-04
期刊：
影响因子：
2.9
通讯作者：
N. Okabe;Emi Nakamura;Naoyuki Himi;K. Narita;I. Tsukamoto;T. Maruyama;N. Sakakibara;Takehiro Nakamura;T. Itano;O. Miyamoto
中科院分区：
文献类型：
--
作者：
N. Okabe;Emi Nakamura;Naoyuki Himi;K. Narita;I. Tsukamoto;T. Maruyama;N. Sakakibara;Takehiro Nakamura;T. Itano;O. Miyamoto
2Cl-C.OXT-A（COA-Cl）是一种新的核酸类似物，其通过细胞外信号调节激酶1或2（ERK 1/2）激活来增强血管生成。ERK 1/2是一种众所周知的激酶，调节中枢神经系统中的细胞存活、增殖和分化。我们进行了体外和体内实验，以研究COA-Cl是否可以减轻脑缺血后神经元的损伤和促进恢复。在原代皮层神经元培养物中，COA-Cl在2小时的氧-葡萄糖剥夺后防止神经元损伤。COA-Cl以剂量依赖性方式增加磷酸化ERK水平，COA-Cl诱导的神经保护作用和ERK 1/2激活被苏拉明或PD 98059抑制。在体动物模型采用大脑中动脉夹闭60 min结合双侧颈总动脉夹闭的方法评价COA-Cl的作用。再灌注5 min侧脑室注射COA-Cl或生理盐水。在注射15或30μg/kg COA-Cl后，COA-Cl显著减少梗死体积并改善神经功能缺损。此外，COA-Cl减少缺血边界的TUNEL阳性细胞数，而COA-Cl给药对rCBF无显著影响。我们还通过在再灌注后1至8天连续给予COA-Cl来评估延迟给予COA-Cl对脑缺血恢复的影响。延迟的连续COA-Cl给药也减少了梗死体积。此外，COA-Cl增强梗死周围血管生成和突触发生，导致改善的运动功能恢复。我们的研究结果表明，COA-Cl在广泛的治疗时间窗内发挥神经保护和神经恢复作用，这表明COA-Cl可能是一种新的和有效的治疗缺血性中风的药物。
2Cl-C.OXT-A (COA-Cl) is a novel nucleic acid analog that enhances angiogenesis through extracellular signal-regulated kinase 1 or 2 (ERK1/2) activation. ERK1/2 is a well-known kinase that regulates cell survival, proliferation and differentiation in the central nervous system. We performed in vitro and in vivo experiments to investigate whether COA-Cl can attenuate neuronal damage and enhance recovery after brain ischemia. In primary cortical neuron cultures, COA-Cl prevented neuronal injury after 2h of oxygen-glucose deprivation. COA-Cl increased phospho-ERK levels in a dose-dependent manner and COA-Cl-induced neuroprotection and ERK1/2 activation was inhibited by suramin or PD98059. The effect of COA-Cl was evaluated in vivo with 60min of middle cerebral artery occlusion combined with bilateral common carotid artery occlusion. COA-Cl or saline was injected intracerebroventricularly 5min after reperfusion. COA-Cl significantly reduced infarct volume and improved neurological deficits upon injection of 15 or 30μg/kg COA-Cl. Moreover, COA-Cl reduced the number of TUNEL positive cells in ischemic boundary, while rCBF was not significantly changed by COA-Cl administration. We also evaluated the effect of delayed COA-Cl administration on recovery from brain ischemia by continuous administration of COA-Cl from 1 to 8 days after reperfusion. Delayed continuous COA-Cl administration also reduced infarct volume. Furthermore, COA-Cl enhanced peri-infarct angiogenesis and synaptogenesis, resulting in improved motor function recovery. Our findings demonstrate that COA-Cl exerts both neuroprotective and neurorestorative effects over a broad therapeutic time window, suggesting COA-Cl might be a novel and potent therapeutic agent for ischemic stroke.