Department of Pathology, Jefferson Medical College, 1020 Locust St., Rm. 251, Philadelphia, PA 19107, USA.
FASEB J. 2011 Feb;25(2):737-53. doi: 10.1096/fj.10-161851. Epub 2010 Oct 12.
Chemokines may play a role in leukocyte migration across the blood-brain barrier (BBB) during neuroinflammation and other neuropathological processes, such as epilepsy. We investigated the role of the chemokine receptor CCR5 in seizures. We used a rat model based on intraperitoneal kainic acid (KA) administration. Four months before KA injection, adult rats were given femoral intramarrow inoculations of SV (RNAiR5-RevM10.AU1), which carries an interfering RNA (RNAi) against CCR5, plus a marker epitope (AU1), or its monofunctional RNAi-carrying homologue, SV(RNAiR5). This treatment lowered expression of CCR5 in circulating cells. In control rats, seizures induced elevated expression of CCR5 ligands MIP-1α and RANTES in the microvasculature, increased BBB leakage and CCR5(+) cells, as well as neuronal loss, inflammation, and gliosis in the hippocampi. Animals given either the bifunctional or the monofunctional vector were largely protected from KA-induced seizures, neuroinflammation, BBB damage, and neuron loss. Brain CCR5 mRNA was reduced. Rats receiving RNAiR5-bearing vectors showed far greater repair responses: increased neuronal proliferation, and decreased production of MIP-1α and RANTES. Controls received unrelated SV(BUGT) vectors. Decrease in CCR5 in circulating cells strongly protected from excitotoxin-induced seizures, BBB leakage, CNS injury, and inflammation, and facilitated neurogenic repair.
趋化因子可能在神经炎症和其他神经病理过程（如癫痫）期间白细胞穿过血脑屏障（BBB）的迁移中发挥作用。我们研究了趋化因子受体 CCR5 在癫痫发作中的作用。我们使用基于腹腔内给予海人酸（KA）的大鼠模型。在 KA 注射前 4 个月，成年大鼠接受了股骨骨髓内接种 SV（RNAiR5-RevM10.AU1），该载体携带针对 CCR5 的干扰 RNA（RNAi）和一个标记表位（AU1），或其单功能 RNAi 携带的同源物 SV（RNAiR5）。这种治疗方法降低了循环细胞中 CCR5 的表达。在对照大鼠中，癫痫发作诱导微脉管系统中 CCR5 配体 MIP-1α 和 RANTES 的表达升高，BBB 渗漏和 CCR5(+)细胞增加，以及海马神经元丢失、炎症和神经胶质增生。接受双功能或单功能载体的动物在很大程度上免受 KA 诱导的癫痫发作、神经炎症、BBB 损伤和神经元丢失的影响。脑 CCR5 mRNA 减少。接受携带 RNAiR5 载体的大鼠表现出更强的修复反应：神经元增殖增加，MIP-1α 和 RANTES 的产生减少。对照组接受了不相关的 SV(BUGT)载体。循环细胞中 CCR5 的减少强烈保护免受兴奋性毒素诱导的癫痫发作、BBB 渗漏、中枢神经系统损伤和炎症，并促进了神经发生修复。
