Kim Jin Hee, Lee Dong Won, Choi Bo Young, Sohn Min, Lee Song Hee, Choi Hui Chul, Song Hong Ki, Suh Sang Won
Department of Physiology, Hallym University, College of Medicine, Chuncheon, Republic of Korea.
Department of Neurology, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
Brain Res. 2015 Jan 21;1595:156-65. doi: 10.1016/j.brainres.2014.11.011. Epub 2014 Nov 15.
Citicoline (CDP-choline; cytidine 5'-diphosphocholine) is an important intermediate in the biosynthesis of cell membrane phospholipids. Citicoline serves as a choline donor in the biosynthetic pathways of acetylcholine and neuronal membrane phospholipids, mainly phosphatidylcholine. The ability of citicoline to reverse neuronal injury has been tested in animal models of cerebral ischemia and clinical trials have been performed in stroke patients. However, no studies have examined the effect of citicoline on seizure-induced neuronal death. To clarify the potential therapeutic effects of citicoline on seizure-induced neuronal death, we used an animal model of pilocarpine-induced epilepsy. Temporal lobe epilepsy (TLE) was induced by intraperitoneal injection of pilocarpine (25mg/kg) in adult male rats. Citicoline (100 or 300 mg/kg) was injected into the intraperitoneal space two hours after seizure onset and a second injection was performed 24h after the seizure. Citicoline was injected once per day for one week after pilocarpine- or kainate-induced seizure. Neuronal injury and microglial activation were evaluated at 1 week post-seizure. Surprisingly, rather than offering protection, citicoline treatment actually enhanced seizure-induced neuronal death and microglial activation in the hippocampus compared to vehicle treated controls. Citicoline administration after seizure-induction increased immunoglobulin leakage via BBB disruption in the hippocampus compared with the vehicle-only group. To clarify if this adverse effect of citicoline is generalizable across alternative seizure models, we induced seizure by kainate injection (10mg/kg, i.p.) and then injected citicoline as in pilocarpine-induced seizure. We found that citicoline did not modulate kainate seizure-induced neuronal death, BBB disruption or microglial activation. These results suggest that citicoline may not have neuroprotective effects after seizure and that clinical application of citicoline after seizure needs careful consideration.
胞磷胆碱（CDP - 胆碱；胞苷5'-二磷酸胆碱）是细胞膜磷脂生物合成中的重要中间体。胞磷胆碱在乙酰胆碱和神经元膜磷脂（主要是磷脂酰胆碱）的生物合成途径中作为胆碱供体。胞磷胆碱逆转神经元损伤的能力已在脑缺血动物模型中进行了测试，并在中风患者中开展了临床试验。然而，尚无研究考察胞磷胆碱对癫痫诱导的神经元死亡的影响。为了阐明胞磷胆碱对癫痫诱导的神经元死亡的潜在治疗作用，我们使用了毛果芸香碱诱导的癫痫动物模型。通过向成年雄性大鼠腹腔注射毛果芸香碱（25mg/kg）诱导颞叶癫痫（TLE）。在癫痫发作开始两小时后，将胞磷胆碱（100或300mg/kg）注入腹腔，癫痫发作24小时后进行第二次注射。在毛果芸香碱或海藻酸诱导癫痫发作后，每天注射一次胞磷胆碱，持续一周。在癫痫发作后1周评估神经元损伤和小胶质细胞激活情况。令人惊讶的是，与给予赋形剂处理的对照组相比，胞磷胆碱治疗实际上增强了癫痫诱导的海马神经元死亡和小胶质细胞激活。与仅给予赋形剂的组相比，癫痫诱导后给予胞磷胆碱增加了海马区血脑屏障破坏导致的免疫球蛋白渗漏。为了阐明胞磷胆碱的这种不良反应是否在其他癫痫模型中普遍存在，我们通过注射海藻酸（10mg/kg，腹腔注射）诱导癫痫发作，然后如在毛果芸香碱诱导的癫痫发作中那样注射胞磷胆碱。我们发现胞磷胆碱并未调节海藻酸癫痫发作诱导的神经元死亡、血脑屏障破坏或小胶质细胞激活。这些结果表明，胞磷胆碱在癫痫发作后可能没有神经保护作用，癫痫发作后胞磷胆碱的临床应用需要谨慎考虑。
