Cyclooxygenase‐2 Induction in Cerebral Cortex: An Intracellular Response to Synaptic Excitation
Cyclooxygenase‐2 Induction in Cerebral Cortex: An Intracellular Response to Synaptic Excitation
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大脑皮层环氧合酶-2 诱导：突触兴奋的细胞内反应
DOI：
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发表时间：
1996
影响因子：
4.7
通讯作者：
J. de Belleroche
中科院分区：
文献类型：
--
作者：
J. Adams;Y. Collaço;J. de Belleroche
摘要：我们研究了刺激毒素注射到基底核对大鼠大脑皮层中有丝分裂原诱导形式的环氧合酶COX-2的诱导作用。这一模型与强烈刺激大脑皮层的上行通路、癫痫发作、随后同侧皮质诱导各种即刻早期基因(IEGs)，包括c-fos、c-jun和Zif268，以及鸟氨酸脱羧酶活性和mRNA有关，所有这些过程都对N-甲基-d-天冬氨酸(NMDA)受体拮抗剂MK-801处理敏感。在本研究中，我们发现注射刺激性毒素也能显著诱导同侧大脑皮质COX-2mRNA的表达，1h可检测到COX-2mRNA的表达，4h达高峰，其中COX-2mRNA的表达水平是未手术动物的19倍。环氧合酶-2的表达在24 h仍显著升高，假手术组在1 h即可见COX-2的早期诱导，但在注射激毒素后4 h，环氧合酶-2的表达水平显著高于假手术组(4.4倍)。MK-801(1.5 mg/kg)、拉莫三嗪(10 mg/kg)和糖皮质激素地塞米松(3 mg/kg)可显著抑制突触前谷氨酸的释放，后者对磷脂酶A2和环氧合酶活性有间接抑制作用。这些结果表明，COX-2mRNA的诱导有两种不同的机制：对组织损伤的快速和瞬时反应和第二种延迟和更实质性的反应，这种反应由兴奋性毒素刺激启动，并由突触前谷氨酸释放、NMDA受体激活和随后的磷脂酶A2活性介导。我们提出了一个模型来证明COX-2和IEG mRNA诱导之间的相似性，并强调了磷脂酶A2途径诱导性质上可能的机制差异。
Abstract: We have characterised the induction of the mitogen‐inducible form of cyclooxygenase, COX‐2, in the rat cerebral cortex in response to excitotoxin injection into the nucleus basalis. This model is associated with intense stimulation of the ascending pathway to the cerebral cortex, seizure activity, and subsequent ipsilateral cortical induction of various immediate early genes (IEGs), including c‐fos, c‐jun, and zif268, and ornithine decarboxylase enzyme activity and mRNA, all of which processes are sensitive to treatment with the N‐methyl‐d‐aspartate (NMDA) receptor antagonist MK‐801. In this study we show that excitotoxin injection also causes a marked induction of COX‐2 mRNA in ipsilateral cortex detectable at 1 h and peaking at 4 h, where COX‐2 mRNA levels were 19 times those in unoperated animals. Levels of COX‐2 mRNA remained significantly elevated at 24 h. The early induction of COX‐2 at 1 h was also seen in sham‐operated animals, but at 4 h the COX‐2 mRNA level was significantly increased (4.4‐fold) in animals injected with excitotoxin compared with sham‐operated animals. The induction at this time point (4 h) was explored pharmacologically and found to be significantly attenuated by treatment with MK‐801 (1.5 mg/kg), lamotrigine (10 mg/kg), which prevents presynaptic glutamate release by blocking voltage‐sensitive Na+ channels, and the glucocorticoid dexamethasone (3 mg/kg), which has an indirect inhibitory effect on phospholipase A2 and COX activity. These results demonstrate that the induction of COX‐2 mRNA occurs by two distinct mechanisms: the rapid and transient response to tissue damage and a second delayed and more substantial response, which is initiated by excitotoxin stimulation and is mediated by presynaptic glutamate release, NMDA receptor activation, and subsequent phospholipase A2 activity. We propose a model to demonstrate the similarities between COX‐2 and IEG mRNA induction and highlight possible mechanistic differences in the nature of the induction by the phospholipase A2 pathway.
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DOI：
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发表时间：
1993-10
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
J. Sirois;J. Richards
通讯作者：
J. Sirois;J. Richards
“一种将 DNA 限制性内切酶片段放射性标记至高比活性的技术”。
影响因子：
2.9
作者：
Feinberg,AP;Vogelstein,B
通讯作者：
Vogelstein,B
DOI：
10.1073/pnas.88.7.2692
发表时间：
1991-04-01
影响因子：
11.1
作者：
XIE, WL;CHIPMAN, JG;SIMMONS, DL
通讯作者：
SIMMONS, DL
DOI：
10.1016/s0021-9258(19)50326-x
发表时间：
1993-06
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
J. Sirois;L. Daniel;Simmons;Joanne;Richards
通讯作者：
J. Sirois;L. Daniel;Simmons;Joanne;Richards
DOI：
10.1016/s0021-9258(18)98774-0
发表时间：
1991-07
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
D. Kujubu;B. Fletcher;B. Varnum;R. Lim;H. Herschman
通讯作者：
D. Kujubu;B. Fletcher;B. Varnum;R. Lim;H. Herschman