Ziyatdinova Sofya, Viswanathan Jayashree, Hiltunen Mikko, Tanila Heikki, Pitkänen Asla
A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland.
Epilepsy Res. 2015 May;112:43-55. doi: 10.1016/j.eplepsyres.2015.02.005. Epub 2015 Feb 14.
Patients with Alzheimer's disease are at increased risk for unprovoked seizures and epilepsy compared with age-matched controls. Experimental evidence suggests that neuronal hyperexcitability and epilepsy can be triggered by amyloid-β (Aβ), the main component of amyloid plaques. Previous studies demonstrated that the administration of an anticonvulsant and histone deacetylase inhibitor, valproic acid, leads to a long-lasting reduction in Aβ levels. Here we used an APdE9 mouse model of Alzheimer's disease with overproduction of Aβ to assess whether treatment with valproic acid initiated immediately after epilepsy onset modifies the occurrence of epileptiform activity. We also analyzed whether the effect is long-lasting and associated with antiamyloidogenesis and histone-modifications. Male APdE9 mice (15 week old) received daily intraperitoneal injections of 30mg/kg valproic acid for 1 week. After a 3-week wash-out, the same animals received injections of a higher dose of valproic acid (300mg/kg) daily for 1 week. Long-term video-electroencephalography monitoring was performed prior to, during, and after the treatments. Aβ and total histone H3 and H4 acetylation levels were measured at 1 month after the final valproic acid treatment. While 30mg/kg valproic acid reduced spontaneous seizures in APdE9 mice (p<0.05, chi-square), epileptiform discharges were not reduced. Administration of 300mg/kg valproic acid, however, reduced epileptiform discharges in APdE9 mice for at least 1 week after treatment discontinuation (p<0.05, Wilcoxon test), but there was no consistent long-term effects on epileptiform activity after treatment withdrawal. Further, we found no long-lasting effect on Aβ levels (p>0.05, Mann-Whitney test), only a meager increase in global acetylation of histone H3 (p<0.05), and no effects on H4 acetylation (p>0.05). In conclusion, valproic acid treatment of APdE9 mice at the stage when amyloid plaques are beginning to develop and epileptiform activity is detected reduced the amount of epileptiform activity, but the effect disappeared after treatment discontinuation.
与年龄匹配的对照组相比，阿尔茨海默病患者无诱因癫痫发作和癫痫的风险增加。实验证据表明，淀粉样斑块的主要成分β-淀粉样蛋白（Aβ）可引发神经元过度兴奋和癫痫。先前的研究表明，给予抗惊厥药和组蛋白脱乙酰酶抑制剂丙戊酸可使Aβ水平长期降低。在此，我们使用Aβ过量产生的阿尔茨海默病APdE9小鼠模型，评估癫痫发作后立即开始用丙戊酸治疗是否会改变癫痫样活动的发生。我们还分析了这种作用是否持久，以及是否与抗淀粉样蛋白生成和组蛋白修饰有关。15周龄的雄性APdE9小鼠每天腹腔注射30mg/kg丙戊酸，持续1周。经过3周的洗脱期后，相同的动物每天注射更高剂量的丙戊酸（300mg/kg），持续1周。在治疗前、治疗期间和治疗后进行长期视频脑电图监测。在最后一次丙戊酸治疗后1个月测量Aβ以及总组蛋白H3和H4的乙酰化水平。虽然30mg/kg丙戊酸可减少APdE9小鼠的自发癫痫发作（p<0.05，卡方检验），但癫痫样放电并未减少。然而，给予300mg/kg丙戊酸可在停药后至少1周内减少APdE9小鼠的癫痫样放电（p<0.05，威尔科克森检验），但停药后对癫痫样活动没有持续的长期影响。此外，我们发现对Aβ水平没有长期影响（p>0.05，曼-惠特尼检验），仅组蛋白H3的整体乙酰化略有增加（p<0.05），对H4乙酰化没有影响（p>0.05）。总之，在淀粉样斑块开始形成且检测到癫痫样活动的阶段，用丙戊酸治疗APdE9小鼠可减少癫痫样活动的量，但停药后这种作用消失。
