Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice
Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice
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DOI：
10.1016/j.brainresbull.2007.10.004
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发表时间：
2008-03-28
影响因子：
3.8
通讯作者：
Bosetti, Francesca
中科院分区：
文献类型：
--
作者：
Toscano, Christopher D.;Ueda, Yumi;Bosetti, Francesca
兴奋性毒性涉及大脑兴奋性谷氨酸受体的过度激活，并与神经系统疾病、神经退行性疾病和神经精神病有关。花生四烯酸（AA）通过磷脂酶A（2）（PLA（2））/胰高血糖素-内过氧化物合酶（PTGS）途径的代谢在兴奋性毒性刺激后增加。然而，PTGS同种型在这一过程中的个体作用尚未完全确定。我们通过将PTGS-1（PTGS-1（-/-））或PTGS-2（PTGS-2（-/-））缺陷的小鼠暴露于原型兴奋性毒素红藻氨酸（KA）来评估PTGS亚型在兴奋性毒性过程中的作用。KA暴露的PTGS-2（-/-）小鼠癫痫发作强度和神经元损伤显著升高，但PTGS-1（-/-）小鼠则无此现象。增加的易感性与KA受体结合活性的改变或通过CBI内源性大麻素受体介导的改变无关。PTGS-2（-/-）小鼠海马CA 1区锥体神经元自发抑制性突触后电流（sIPSC）频率降低，提示GABA能功能改变。在野生型小鼠中，用PTGS-2选择性抑制剂塞来昔布治疗6周，重现了在PTGS-2（-/-）小鼠中观察到的对KA诱导的兴奋性毒性的易感性增加，进一步支持了PTGS-2在兴奋性毒性过程中的作用。对KA的易感性增加也与脑内PGE（2）水平降低有关，PGE（2）是PTGS-2活性的生物标志物。我们的研究结果表明，PTGS-2活性及其特定的产品可能通过影响GABA能神经传递调节神经元兴奋性。此外，抑制PTGS-2而不是PTGS-1可能增加癫痫发作的易感性。爱思唯尔公司出版
Excitotoxicity involves over activation of brain excitatory glutamate receptors and has been implicated in neurological, neurodegenerative and neuropsychiatrie diseases. Metabolism of arachidonic acid (AA) through the phospholipase A(2) (PLA(2))/prostaglandin-endoperoxide synthase (PTGS) pathway is increased after excitotoxic stimulation. However, the individual roles of the PTGS isoforms in this process are not well established. We assessed the role of the PTGS isoforms in the process of excitotoxicity by exposing mice deficientin either PTGS-1 (PTGS-1(-/-)) or PTGS-2 (PTGS-2(-/-)) to the prototypic excitotoxin, kainic acid (KA). Seizure intensity and neuronal damage were significantly elevated in KA-exposed PTGS-2(-/-), but not in PTGS-1(-/-), mice. The increased susceptibility was not associated with an alteration in KA receptor binding activity or mediated through the CBI endocannabinoid receptor. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was decreased in the CA1 pyramidal neurons of PTGS-2(-/-) mice, suggesting an alteration of GABAergic function. In wild-type mice, six weeks treatment with the PTGS-2 selective inhibitor celecoxib recapitulated the increased susceptibility to KA-induced excitotoxicity observed in PTGS-2(-/-) mice, further supporting the role of PTGS-2 in the excitotoxic process. The increased susceptibility to KA was also associated with decreased brain levels of PGE(2), a biomarker of PTGS-2 activity. Our results suggest that PTGS-2 activity and its specific products may modulate neuronal excitability by affecting GABAergic neurotransmission. Further, inhibition of PTGS-2, but not PTGS-1, may increase the susceptibility to seizures. Published by Elsevier Inc.