Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures.
Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures.
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DOI：
10.1016/j.nbd.2012.02.006
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发表时间：
2012-05
影响因子：
6.1
通讯作者：
Koh, Sookyong
中科院分区：
文献类型：
--
作者：
Abraham, Jayne;Fox, Patrick D.;Condello, Carlo;Bartolini, Alyssa;Koh, Sookyong
小胶质细胞介导的先天免疫在癫痫诱导的炎症反应的启动和传播中起着至关重要的作用。为了探讨激活的小胶质细胞在儿童癫痫发病机制中的作用，我们首先研究了小胶质细胞被荧光标记的Cx3cr1GFP/+转基因小鼠在红藻氨酸诱导的癫痫持续状态(KA-SE)后激活的时间进程。然后，我们确定这种癫痫诱导的小胶质细胞激活是否启动了中枢免疫反应，使其反应过度，并增加了以后生活中第二次癫痫发作的易感性。我们使用小胶质细胞激活的抑制剂米诺环素来阻断癫痫诱导的炎症，以确定先天免疫是否在介导早期癫痫的长期致痫效应中起因果作用。首次癫痫持续状态发生在出生后第25天，第二次持续状态发生在出生后第39天。P25的KA-SE在24小时内使小胶质细胞的激活增加了近两倍。癫痫引起的显著激活持续7天，并在14天时恢复到基线水平。预先接触KA-SE的P39动物不仅对KA的“二次打击”有更大的小胶质细胞激活反应，而且表现为癫痫发作的潜伏期更短。治疗后7天用米诺环素抑制癫痫引起的炎症，既消除了被夸大的小胶质细胞激活，又增加了在以后生活中第二次癫痫发作的易感性。早期癫痫发作的启动效应伴随着修饰和快速激活的小胶质细胞。我们的结果表明，SE后的抗炎治疗可能有助于阻断癫痫的形成过程，减轻早期癫痫发作的长期损害效应。
Innate immunity mediated by microglia appears to play a crucial role in initiating and propagating seizure-induced inflammatory responses. To address the role of activated microglia in the pathogenesis of childhood epilepsy, we first examined the time course of microglia activation following kainic acid induced status epilepticus (KA-SE) in Cx3cr1GFP/+ transgenic mice whose microglia are fluorescently labeled. We then determined whether this seizure-induced microglia activation primes the central immune response to overreact and to increase the susceptibility to a second seizure later in life. We used an inhibitor of microglia activation, minocycline, to block the seizure-induced inflammation to determine whether innate immunity plays a causal role in mediating the long-term epileptogenic effects of early-life seizure. First status epilepticus was induced at postnatal day (P) 25 and a second status at P39. KA-SE at P25 caused nearly a twofold increase in microglia activation within 24 hours. Significant seizure-induced activation persisted for 7 days and returned to baseline by 14 days. P39 animals with prior exposure to KA-SE not only responded with greater microglial activation in response to “second hit” of KA, but shorter latency to express seizures. Inhibition of seizure-induced inflammation by 7 day minocycline post-treatment abrogated both the exaggerated microglia activation and the increased susceptibility to the second seizure later in life. The priming effect of early-life seizures is accompanied by modified and rapidly reactivated microglia. Our results suggest that anti-inflammatory therapy after SE may be useful to block the epileptogenic process and mitigate the long-term damaging effects of early-life seizures.
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影响因子：
3.7
作者：
Hu W;Metselaar J;Ben LH;Cravens PD;Singh MP;Frohman EM;Eagar TN;Racke MK;Kieseier BC;Stüve O
通讯作者：
Stüve O
脊髓细胞细胞募集会导致急性病毒性脑膜炎期间致命的中枢神经系统损伤。
影响因子：
64.8
作者：
Kim, Jiyun V.;Kang, Silvia S.;Dustin, Michael L.;McGavern, Dorian B.
通讯作者：
McGavern, Dorian B.
影响因子：
4.2
作者：
Buttini, M;Limonta, S;Boddeke, HWGM
通讯作者：
Boddeke, HWGM
影响因子：
11.2
作者：
Holmes, GL;Gairsa, JL;Ben-Ari, Y
通讯作者：
Ben-Ari, Y
影响因子：
2.9
作者：
Hu, RQ;Koh, S;Cole, AJ
通讯作者：
Cole, AJ