NMDA-induced seizure intensity is enhanced in COX-2 deficient mice.
NMDA-induced seizure intensity is enhanced in COX-2 deficient mice.
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DOI：
10.1016/j.neuro.2008.08.008
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发表时间：
2008-11
期刊：
影响因子：
3.4
通讯作者：
Bosetti F
中科院分区：
文献类型：
--
作者：
Toscano CD;Kingsley PJ;Marnett LJ;Bosetti F
药理学抑制或基因删除环氧合酶（考克斯）-2，而不是考克斯-1，已被证明增加易感性红藻氨酸（KA）诱导的兴奋性毒性。然而，目前尚不清楚对通过其他神经递质受体起作用的兴奋性毒素的易感性是否会因考克斯-2抑制而改变。为了进一步了解考克斯-2参与调节兴奋性毒性的易感性，我们研究了考克斯-2缺失对外周注射N-甲基-D-天冬氨酸（NMDA，一种NMDA受体的特异性激动剂）或林诺明（一种GABAA受体拮抗剂）诱导的兴奋性毒性的影响。与考克斯-2+/+小鼠相比，腹膜内注射NMDA（50-100 mg/kg）的考克斯-2−/−小鼠表现出显著增加的中位癫痫发作强度。此外，通过Fluoro Jade B（FJB）染色检测，暴露于NMDA的考克斯-2−/−小鼠在海马CA 3区显示神经元损伤。在暴露于林丹的考克斯-2+/+和考克斯-2-/-小鼠中，没有FJB染色，中位或最大癫痫发作强度也没有任何显着差异。考克斯-2−/−小鼠脑前列腺素谱的LC-MS/MS分析表明，给予兴奋毒性剂量的KA后1小时，PGF 2 α、TXB 2、PGE 2和PGD 2表达显著增加，但NMDA未增加。我们的研究结果表明，考克斯-2调节敏感性KA和NMDA兴奋毒性，这直接激活多巴胺能神经传递，但不linetamine，这间接改变多巴胺能神经传递。此外，癫痫发作后的阿糖胞苷水平升高与神经元损伤的一致表现相关。
Pharmacological inhibition or genetic deletion of cyclooxygenase (COX)-2, but not COX-1, has been shown to increase susceptibility to kainic acid (KA)-induced excitotoxicity. However, it is unclear if susceptibility to excitotoxins that act through other neurotransmitter receptors is altered by COX-2 inhibition. To further understand the involvement of COX-2 in regulating susceptibility to excitotoxicity, we investigated the effect of COX-2 deletion on excitotoxicity induced by peripheral injection of N-methyl-D-aspartate (NMDA, a specific agonist of the NMDA receptors) or lindane (a GABAA receptor antagonist). COX-2−/− mice injected intraperitoneally with NMDA (50-100 mg/kg) exhibited significantly increased median seizure intensity when compared to COX-2+/+ mice. Further, COX-2−/− mice exposed to NMDA showed neuronal damage, detected by Fluoro Jade B (FJB) staining, in the CA3 region of the hippocampus. There was no FJB staining nor any significant difference in median or maximal seizure intensity in COX-2+/+ and COX-2−/− mice exposed to lindane. LC-MS/MS analysis of brain prostaglandin profile in COX-2−/− mice demonstrated a significant increase in PGF2α, TXB2, PGE2 and PGD2 expression 1 hour after administration of an excitotoxic dose of KA, but not of NMDA. Our findings demonstrate that COX-2 regulates susceptibility to KA and NMDA excitotoxicity, which directly activate glutamatergic neurotransmission, but not to lindane, which indirectly alters glutamatergic neurotransmission. Furthermore, increased levels of prostaglandins after seizures are associated with consistent manifestation of neuronal damage.
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