Reduction of epileptiform activity by valproic acid in a mouse model of Alzheimer's disease is not long-lasting after treatment discontinuation

作者：Ziyatdinova Sofya; Viswanathan Jayashree; Hiltunen Mikko; Tanila Heikki; Pitkanen Asia^*

来源：Epilepsy Research, 2015, 112: 43-55.

DOI：10.1016/j.eplepsyres.2015.02.005

• Alzheimer's disease
• Amyloid-beta
• Epilepsy
• Epileptiform discharge
• Histone acetylation
• Valproic acid

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-beta (A beta), 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 A beta levels. Here we used an APdE9 mouse model of Alzheimer's disease with overproduction of A beta to assess whether treatment with valproic acid initiated immediately after epilepsy onset modifies the occurrence of epileptifornn 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 30 mg/kg valproic acid for 1 week. After a 3-week wash-out, the same animals received injections of a higher dose of valproic acid (300 mg/kg) daily for 1 week. Long-term video-electroencephalography monitoring was performed prior to, during, and after the treatments. A beta and total histone H3 and H4 acetylation levels were measured at 1 month after the final valproic acid treatment. While 30 mg/kg valproic acid reduced spontaneous seizures in APdE9 mice (p < 0.05, chi-square), epileptiform discharges were not reduced. Administration of 300 mg/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 A beta 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.

• 出版日期2015-5