Wang Xue, Yu Yang, Ma Rui, Shao Na, Meng Hongmei
Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Changchun, Jilin, People's Republic of China.
Neuroreport. 2018 Nov 7;29(16):1384-1390. doi: 10.1097/WNR.0000000000001123.
Mossy fiber sprouting (MFS) and neuronal loss are important pathological features of chronic epilepsy closely related to the development of spontaneous recurrent seizures. However, the pathological mechanism of MFS remains unclear. Collapsin response mediator protein 2 (CRMP2) is a cytoplasmic protein highly expressed in the nervous system and is involved in axon/dendrite specification and axonal growth. It is possibly associated with the development of MFS. Lacosamide (LCM), a novel antiepileptic drug, was recently found to inhibit the CRMP2-mediated neurite outgrowth. Therefore, we studied the relationships between LCM, CRMP2, and MFS, seeking potential therapeutic targets for epileptogenesis and a better understanding of the mechanism of action of LCM. We used kainic acid to induce status epilepticus in an animal model and examined the resultant changes in protein expression by Western blot and changes in histology by specific staining for cell death and MFS. Our results showed that the expression level of CRMP2 was elevated and the expression level of phosphorylated CRMP2 (p-CRMP2) was reduced following status epilepticus. Administration of LCM not only reversed this effect but also suppressed spontaneous recurrent seizures and reduced MFS and loss of hippocampal neurons. This study reveals that, in addition to its antiseizure efficacy, LCM has a neuroprotective effect and inhibits the development of epilepsy. CRMP2 is possibly involved in the mechanism by which LCM suppresses MFS and is expected to be a new therapeutic target for treating epileptogenesis.
苔藓纤维出芽（MFS）和神经元丢失是慢性癫痫的重要病理特征，与自发性反复癫痫发作的发展密切相关。然而，MFS的病理机制仍不清楚。坍塌反应调节蛋白2（CRMP2）是一种在神经系统中高度表达的胞质蛋白，参与轴突/树突的特化和轴突生长。它可能与MFS的发展有关。拉科酰胺（LCM）是一种新型抗癫痫药物，最近发现它能抑制CRMP2介导的神经突生长。因此，我们研究了LCM、CRMP2和MFS之间的关系，寻找癫痫发生的潜在治疗靶点，并更好地理解LCM的作用机制。我们在动物模型中用 kainic 酸诱导癫痫持续状态，并通过蛋白质印迹法检测由此产生的蛋白质表达变化，以及通过细胞死亡和MFS的特异性染色检测组织学变化。我们的结果表明，癫痫持续状态后CRMP2的表达水平升高，磷酸化CRMP2（p-CRMP2）的表达水平降低。给予LCM不仅逆转了这种效应，还抑制了自发性反复癫痫发作，减少了MFS和海马神经元的丢失。这项研究表明，除了其抗癫痫疗效外，LCM还具有神经保护作用，并抑制癫痫的发展。CRMP2可能参与了LCM抑制MFS的机制，有望成为治疗癫痫发生的新治疗靶点。
