5-Lipoxygenase Inhibitor Zileuton Inhibits Neuronal Apoptosis Following Focal Cerebral Ischemia
5-Lipoxygenase Inhibitor Zileuton Inhibits Neuronal Apoptosis Following Focal Cerebral Ischemia
复制标题
5-脂氧合酶抑制剂齐留通抑制局灶性脑缺血后神经元凋亡
DOI：
10.1007/s10753-013-9657-4
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发表时间：
2013-12-01
期刊：
影响因子：
5.1
通讯作者：
Chen, Yan
中科院分区：
文献类型：
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作者：
Shi, Song-sheng;Yang, Wei-zhong;Chen, Yan
本实验室先前的研究表明，选择性5-脂氧合酶（5-LOX）抑制剂zileuton可减轻局灶性脑缺血大鼠的缺血性脑损伤。大量证据表明，炎症反应和神经元凋亡是脑缺血损伤的两个重要病理生理事件。我们之前的研究表明zileuton通过抑制炎症反应来减轻缺血性脑损伤。本研究旨在探讨5-LOX抑制剂zileuton是否能减轻局灶性脑缺血后的神经元凋亡，并进一步探讨其神经保护作用的有效机制。成年雄性Sprague-Dawley大鼠进行永久性大脑中动脉闭塞（MCAO） 72h， MCAO发作后分别以zileuton或载药灌胃。在MCAO 72小时后测量神经功能缺损评分、脑梗死体积和神经元损伤。TUNEL染色检测神经元凋亡程度。逆转录聚合酶链反应检测caspase-1 mRNA的表达。Western blot检测大鼠脑组织中procaspase-3和cleaved - caspase-3的表达。服用zileuton后，神经功能缺损评分、梗死体积和神经元损伤明显减轻。MCAO引起大鼠神经细胞凋亡水平升高，而zileuton可明显抑制MCAO引起的细胞凋亡。MCAO引起caspase-1和cleaved - caspase-3过表达，这两种表达均被zileuton显著抑制。MCAO后procaspase-3的表达减少，而zileuton显著上调procaspase-3的表达。我们的研究表明，5-LOX抑制剂zileuton可以减轻mcao诱导的脑损伤和神经元凋亡，这可能与抑制caspase-1和调节caspase-3有关。
Previous studies from our laboratory demonstrated that zileuton, a selective 5-lipoxygenase (5-LOX) inhibitor, attenuates ischemic brain damage in rats of focal cerebral ischemia. Enormous evidences showed that inflammatory reaction and neuronal apoptosis are the two important pathophysiological events in ischemia-induced brain damage. Our previous studies demonstrate that zileuton attenuates ischemic brain damage via inhibiting inflammatory reaction. The present study was performed to explore whether 5-LOX inhibitor zileuton attenuates neuronal apoptosis following focal cerebral ischemia and further investigate the potent mechanisms underlying its neuroprotection. Adult male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (MCAO) for 72 h, then received intragastric gavage with zileuton or vehicle as a bolus after the onset of MCAO. Neurological deficit scores, cerebral infarct volume, and neuronal damage were measured 72 h after MCAO. TUNEL staining was performed to measure the extent of neuronal apoptosis. Reverse transcription-polymerase chain reaction was performed to determine the expression of caspase-1 mRNA. Western blot was performed to determine the expression of procaspase-3 and cleaved caspase-3 in rat brain. Neurological deficit scores, infarct volume, and neuronal damage were significantly attenuated by administration of zileuton. MCAO caused the elevation of neuronal apoptosis, which was significantly inhibited by the administration of zileuton. MCAO caused the over-expression of caspase-1 and cleaved caspase-3, both of which were significantly inhibited by the administration of zileuton. Expression of procaspase-3 was reduced after MCAO, which was significantly up-regulated by administration of zileuton. Our studies suggested that 5-LOX inhibitor zileuton reduces MCAO-induced brain damage and neuronal apoptosis, which might be associated with the inhibition of caspase-1 and the regulation of caspase-3.