Liu Xi, Ou Shu, Yin Maojia, Xu Tao, Wang Teng, Liu Ying, Ding Xueying, Yu Xinyuan, Yuan Jinxian, Huang Hao, Zhang Xiuhang, Tan Xinjie, Chen Lifen, Chen Yangmei
Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Neurology, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou, China.
Discov Med. 2017 Apr;23(127):221-234.
The mechanism of epilepsy-induced axonal impairment is poorly understood. N-methyl-D-aspartate receptors (NMDARs) play important roles in epilepsy and mediate structural and functional axonal impairment. GSK-3β and Cdk5 affect axons and are regulated by NMDARs, while their roles in epilepsy-induced axonal impairment are unclear. We demonstrated that axonal impairment is characterized by neurofilament heavy (NFH) reduction, amyloid precursor protein (APP) accumulation, and increased tau phosphorylation accompanied by a decrease of total tau in temporal lobe epilepsy (TLE) patients and pentylenetetrazol (PTZ)-kindled rats. Inhibiting NMDARs using memantine and ifenprodil alleviated NFH reduction and APP accumulation, decreased Cdk5 expression, and inhibited the activity of GSK-3β in the white matter of PTZ-kindled rats. Inhibiting GSK-3β and Cdk5 using lithium chloride and roscovitine also alleviated axonal impairment induced by PTZ. Therefore, axonal impairment in TLE may be mediated by NMDAR via GSK-3β and Cdk5. In addition, inhibiting either NMDARs or GSK-3β lowered the relative tau phosphorylation level by reversing the decrease of total tau without affecting phosphorylated tau S396 and T231. Meanwhile inhibiting Cdk5 lowered the tau phosphorylation level by reducing phosphorylated tau without affecting total tau, indicating a possible role of GSK-3β in NMDAR-mediated tau phosphorylation in epilepsy.
癫痫诱发轴突损伤的机制尚不清楚。N-甲基-D-天冬氨酸受体（NMDARs）在癫痫中起重要作用，并介导轴突的结构和功能损伤。糖原合成酶激酶-3β（GSK-3β）和细胞周期蛋白依赖性激酶5（Cdk5）影响轴突，并受NMDARs调节，但其在癫痫诱发轴突损伤中的作用尚不清楚。我们发现，在颞叶癫痫（TLE）患者和戊四氮（PTZ）点燃的大鼠中，轴突损伤的特征是神经丝重链（NFH）减少、淀粉样前体蛋白（APP）积累、tau蛋白磷酸化增加，同时总tau蛋白减少。使用美金刚和艾芬地尔抑制NMDARs可减轻NFH减少和APP积累，降低Cdk5表达，并抑制PTZ点燃大鼠白质中GSK-3β的活性。使用氯化锂和roscovitine抑制GSK-3β和Cdk5也可减轻PTZ诱导的轴突损伤。因此，TLE中的轴突损伤可能由NMDAR通过GSK-3β和Cdk5介导。此外，抑制NMDARs或GSK-3β可通过逆转总tau蛋白的减少而降低相对tau蛋白磷酸化水平，而不影响磷酸化tau蛋白S396和T231。同时抑制Cdk5可通过减少磷酸化tau蛋白而降低tau蛋白磷酸化水平，而不影响总tau蛋白，这表明GSK-3β在癫痫中NMDAR介导的tau蛋白磷酸化中可能起作用。
