Neuroprotective and antiepileptogenic effects of combination of anti-inflammatory drugs in the immature brain
Neuroprotective and antiepileptogenic effects of combination of anti-inflammatory drugs in the immature brain
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DOI：
10.1186/1742-2094-10-30
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发表时间：
2013-02-26
影响因子：
9.3
通讯作者：
Sankar, Raman
中科院分区：
文献类型：
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作者：
Kwon, Young Se;Pineda, Eduardo;Sankar, Raman
背景资料：由长时间癫痫发作引起的炎症信号传导可促成神经元损伤以及不良可塑性，导致自发性复发性癫痫发作（癫痫）和相关合并症的发展。在这项研究中，发育中的大鼠幼崽在2和3周龄时经历锂-匹罗卡品癫痫持续状态（SE），以研究抗炎药（AID）对SE诱导的海马损伤和自发性癫痫发作的发展的影响。我们选择了针对白细胞介素-1受体（IL-1 ra）的AIDS，IL-1 ra是一种环氧合酶-2（考克斯-2）抑制剂（CAY 10404），和半胱天冬酶-1的小胶质细胞活化的拮抗剂（米诺环素）。在SE后24 h的2周龄大鼠中研究SE后的急性损伤。研究了3周龄大鼠在初始损伤后4个月接受SE后复发性自发性癫痫发作的发展，当单独给药时，这些AID均不能有效减轻2周龄幼鼠的CA 1损伤或限制3周龄幼鼠自发性癫痫发作的发展。当尝试这些药物的经验性二元组合时，IL-1 r和考克斯-2的组合靶向导致这些动物中SE后24小时测定的急性CA 1损伤的减弱。相同的组合给药10天后，SE在3周龄的大鼠，减少自发性复发性癫痫发作的发展和限制苔藓纤维sprouting.Conclusions的程度：部署经验设计的“鸡尾酒药物”针对多种炎症信号通路的有限的时间后，最初的侮辱，如SE可能提供一个实用的方法，神经保护和抗癫痫治疗。
Background: Inflammatory signaling elicited by prolonged seizures can be contributory to neuronal injury as well as adverse plasticity leading to the development of spontaneous recurrent seizures (epilepsy) and associated co-morbidities. In this study, developing rat pups were subjected to lithium-pilocarpine status epilepticus (SE) at 2 and 3 weeks of age to study the effect of anti-inflammatory drugs (AID) on SE-induced hippocampal injury and the development of spontaneous seizures.Findings: We selected AIDs directed against interleukin-1 receptors (IL-1ra), a cyclooxygenase-2 (COX-2) inhibitor (CAY 10404), and an antagonist of microglia activation of caspase-1 (minocycline). Acute injury after SE was studied in the 2-week-old rats 24 h after SE. Development of recurrent spontaneous seizures was studied in 3-week-old rats subjected to SE 4 months after the initial insult.None of those AIDs were effective in attenuating CA1 injury in the 2-week-old pups or in limiting the development of spontaneous seizures in 3-week-old pups when administered individually. When empiric binary combinations of these drugs were tried, the combined targeting of IL-1r and COX-2 resulted in attenuation of acute CA1 injury, as determined 24 h after SE, in those animals. The same combination administered for 10 days following SE in 3-week -old rats, reduced the development of spontaneous recurrent seizures and limited the extent of mossy fiber sprouting.Conclusions: Deployment of an empirically designed 'drug cocktail' targeting multiple inflammatory signaling pathways for a limited duration after an initial insult like SE may provide a practical approach to neuroprotection and anti-epileptogenic therapy.