Enhanced microglial activation and proinflammatory cytokine upregulation are linked to increased susceptibility to seizures and neurologic injury in a 'two-hit' seizure model.
Enhanced microglial activation and proinflammatory cytokine upregulation are linked to increased susceptibility to seizures and neurologic injury in a 'two-hit' seizure model.
复制标题
DOI：
10.1016/j.brainres.2009.05.073
复制
发表时间：
2009-07-28
期刊：
影响因子：
2.9
通讯作者：
Wainwright MS
中科院分区：
文献类型：
--
作者：
Somera-Molina KC;Nair S;Van Eldik LJ;Watterson DM;Wainwright MS
早期癫痫发作会增加癫痫发作的易感性，并在成年后发生第二次侮辱，造成更大的神经损伤。早期癫痫发作与第二次发作后神经损伤易感性增加之间的联系机制尚不清楚。我们使用红藻氨酸(KA)诱导的大鼠二次打击癫痫模型，研究了小胶质细胞激活和促炎细胞因子产生增加对随后神经损伤易感性的影响。出生后第1天(P)15只大鼠被给予KA(早期癫痫)或生理盐水，然后在P45给予KA第二次打击，第一次暴露于KA(成人癫痫)，或生理盐水。在P45第二次打击12小时和10天后，我们检测了致炎细胞因子(IL-1β、肿瘤坏死因子-α和S100B)、趋化因子CCL_2、小胶质细胞激活、癫痫敏感性和神经元转归。与成年癫痫组相比，在P15和P45上暴露于KA的两次打击组有更高的细胞因子水平，更大的小胶质细胞激活，以及对癫痫和神经损伤的易感性增加。米诺扎克是一种小分子实验性治疗药物，目标是上调促炎细胞因子的产生，在早期癫痫发作后使用米诺扎克治疗，可以减弱增强的小胶质细胞和细胞因子反应，增加对癫痫的易感性，并减轻‘两次打击’组更大的神经元损伤。这些结果表明，小胶质细胞的激活是早期癫痫导致成年后对神经损伤易感性增加的一种机制，并表明早期干预的潜在长期好处是以促炎症细胞因子上调为目标的治疗。
Early-life seizures result in increased susceptibility to seizures and greater neurologic injury with a second insult in adulthood. The mechanisms which link seizures in early-life to increased susceptibility to neurologic injury following a ‘second hit’ are not known. We examined the contribution of microglial activation and increased proinflammatory cytokine production to the subsequent increase in susceptibility to neurologic injury using a kainic acid (KA)-induced, established ‘two-hit’ seizure model in rats. Postnatal day (P)15 rats were administered intraperitoneal KA (early-life seizures) or saline, followed on P45 with either a ‘second hit’ of KA, a first exposure to KA (adult seizures), or saline. We measured the levels of proinflammatory cytokines (IL-1β, TNF-α, and S100B), the chemokine CCL2, microglial activation, seizure susceptibility and neuronal outcomes in adult rats 12 hours and 10 days after the second hit on P45. The ‘two-hit’ group exposed to KA on both P15 and P45 had higher levels of cytokines, greater microglial activation, and increased susceptibility to seizures and neurologic injury compared to the adult seizures group. Treatment after early-life seizures with Minozac, a small molecule experimental therapeutic that targets up-regulated proinflammatory cytokine production, attenuated the enhanced microglial and cytokine responses, the increased susceptibility to seizures, and the greater neuronal injury in the ‘two-hit’ group. These results implicate microglial activation as one mechanism by which early-life seizures contribute to increased vulnerability to neurologic insults in adulthood, and indicate the potential longer term benefits of early-life intervention with therapies that target up-regulation of proinflammatory cytokines.
登录
查看更多内容
DOI：
10.1016/s0165-3806(99)00135-2
发表时间：
1999-12-10
期刊：
DEVELOPMENTAL BRAIN RESEARCH
影响因子：
--
作者：
Huang, LT;Cilio, MR;Holmes, GL
通讯作者：
Holmes, GL
影响因子：
3.4
作者：
Lynch, M;Sayin, Ü;Sutula, T
通讯作者：
Sutula, T
影响因子：
11.2
作者：
Cornejo, Brandon J.;Mesches, Michael H.;Benke, Timothy A.
通讯作者：
Benke, Timothy A.
影响因子：
5.3
作者：
Brewster, A;Bender, RA;Baram, TZ
通讯作者：
Baram, TZ
影响因子：
6.2
作者：
Knoch, Megan E.;Hartnett, Karen A.;Aizenman, Elias
通讯作者：
Aizenman, Elias