Blocking receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4) prevents posttraumatic epileptogenesis in mice.
Blocking receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4) prevents posttraumatic epileptogenesis in mice.
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目前仍没有预防创伤后癫痫的有效治疗方法。在此，我们试图确定阻断晚期糖基化终末产物受体（RAGE）或Toll样受体4（TLR4）信号通路是否能预防创伤后癫痫的发生。
在创伤后癫痫的小鼠咬除模型中，连续1周每日注射生理盐水、RAGE单克隆抗体（mAb）或TAK242（一种TLR4抑制剂）。分别在伤后2周通过戊四氮（PTZ）试验评估它们对癫痫发作敏感性的影响，在伤后2 - 6周通过连续视频和无线脑电图（EEG）监测评估它们对自发性癫痫发作的影响。还通过PTZ试验评估了RAGE基因敲除小鼠咬除后的癫痫发作敏感性。用免疫组织学方法分析受损皮质。
接受RAGE mAb或TAK242治疗的咬除动物比接受生理盐水治疗的咬除小鼠癫痫发作阈值显著提高。一致地，在PTZ试验中，RAGE基因敲除小鼠的咬除损伤未导致癫痫发作阈值降低。脑电图和视频记录显示，RAGE mAb或TAK242治疗组的累积自发性癫痫发作事件显著减少（当RAGE mAb或TAK242组与生理盐水组比较时，p < 0.001）。与生理盐水治疗的咬除组相比，RAGE mAb或TAK242治疗的咬除组受损皮质组织的尼氏染色神经元密度更高，GAD67免疫反应性中间神经元密度也更高。对GFAP和Iba - 1的免疫染色显示，治疗组皮质中的星形胶质细胞和小胶质细胞密度较低，表明胶质细胞活化减少。
RAGE和TLR4信号通路在创伤后癫痫发生中起关键作用。在创伤性脑损伤后早期阻断这些通路是预防创伤后癫痫的一种有前景的策略。
Effective treatment for the prevention of posttraumatic epilepsy is still not available. Here, we sought to determine whether blocking receptor for advanced glycation end-products (RAGE) or toll like receptor 4 (TLR4) signaling pathways would prevent posttraumatic epileptogenesis. In a mouse undercut model of posttraumatic epilepsy, daily injections of saline, RAGE monoclonal antibody (mAb), or TAK242, a TLR4 inhibitor, were made for 1 week. Their effects on seizure susceptibility and spontaneous epileptic seizures were evaluated with a pentylenetetrazol (PTZ) test in 2 weeks and with continuous video and wireless electroencephalographic (EEG) monitoring between 2–6 weeks after injury, respectively. Seizure susceptibility after undercut in RAGE knockout mice was also evaluated with the PTZ test. The lesioned cortex was analyzed with immunohistology. Undercut animals treated with RAGE mAb or TAK242 showed significantly higher seizure threshold than saline-treated undercut mice. Consistently, undercut injury in RAGE knockout mice didn’t cause a reduction in seizure threshold in the PTZ test. EEG and video recordings revealed a significant decrease in the cumulative spontaneous seizure events in RAGE mAb or TAK242 treated group (p < 0.001, when the RAGE mAb or TAK242 group is compared with the saline group). The lesioned cortical tissues of RAGE mAb or TAK242 treated undercut group showed higher neuronal densities of Nissl staining and higher densities of GAD67-immunoreactive interneurons than the saline treated undercut group. Immunostaining to GFAP and Iba-1 revealed lower densities of astrocytes and microglia in cortex of the treatment groups, suggesting reduced glia activation. RAGE and TLR4 signaling are critically involved in posttraumatic epileptogenesis. Blocking these pathways early after traumatic brain injury is a promising strategy for preventing posttraumatic epilepsy.
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DOI：
10.1016/j.bbi.2014.06.199
发表时间：
2014-11
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Allette YM;Due MR;Wilson SM;Feldman P;Ripsch MS;Khanna R;White FA
通讯作者：
White FA
TAK-242 是 Toll 样受体 4 的拮抗剂，可预防小鼠急性脑缺血/再灌注损伤。
DOI：
10.1038/jcbfm.2014.240
发表时间：
2015-03-31
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.2
作者：
Laird MD;Shields JS;Sukumari-Ramesh S;Kimbler DE;Fessler RD;Shakir B;Youssef P;Yanasak N;Vender JR;Dhandapani KM
通讯作者：
Dhandapani KM
影响因子：
3.4
作者：
Gao, Tie-Lei;Yuan, Xiang-Tian;Fu, Zhi-Jun
通讯作者：
Fu, Zhi-Jun
影响因子：
82.9
作者：
Maroso, Mattia;Balosso, Silvia;Vezzani, Annamaria
通讯作者：
Vezzani, Annamaria