慢性使用左乙拉西坦或苯妥英后大鼠脑内基因表达的区域特异性变化。
Region-specific changes in gene expression in rat brain after chronic treatment with levetiracetam or phenytoin.
机构信息
Department of Neurology, Division of Clinical Neuroscience, Rikshospitalet, Oslo, Norway.
出版信息
Epilepsia. 2010 Sep;51(9):1714-20. doi: 10.1111/j.1528-1167.2010.02545.x.
PURPOSE
It is commonly assumed that antiepileptic drugs (AEDs) act similarly in the various parts of the brain as long as their molecular targets are present. A few experimental studies on metabolic effects of vigabatrin, levetiracetam, valproate, and lamotrigine have shown that these drugs may act differently in different brain regions. We examined effects of chronic treatment with levetiracetam or phenytoin on mRNA levels to detect regional drug effects in a broad, nonbiased manner.
METHODS
mRNA levels were monitored in three brain regions with oligonucleotide-based microarrays.
RESULTS
Levetiracetam (150 mg/kg for 90 days) changed the expression of 65 genes in pons/medulla oblongata, two in hippocampus, and one in frontal cortex. Phenytoin (75 mg/kg), in contrast, changed the expression of only three genes in pons/medulla oblongata, but 64 genes in hippocampus, and 327 genes in frontal cortex. Very little overlap between regions or drug treatments was observed with respect to effects on gene expression.
DISCUSSION
We conclude that chronic treatment with levetiracetam or phenytoin causes region-specific and highly differential effects on gene expression in the brain. Regional effects on gene expression could reflect regional differences in molecular targets of AEDs, and they could influence the clinical profiles of AEDs.
目的
人们通常认为，只要抗癫痫药物（AEDs）的分子靶点存在，它们在大脑的各个部位的作用就相似。一些关于氨己烯酸、左乙拉西坦、丙戊酸钠和拉莫三嗪代谢作用的实验研究表明，这些药物在不同的脑区可能有不同的作用。我们通过慢性给予左乙拉西坦或苯妥英治疗，检测了广泛的、无偏倚的方法来检测药物对不同脑区的作用，以检测其对 mRNA 水平的影响。
方法
使用基于寡核苷酸的微阵列监测三个脑区的 mRNA 水平。
结果
左乙拉西坦（150mg/kg，90 天）改变了脑桥/延髓、海马体和额叶皮质中 65 个基因的表达，改变了 2 个基因在海马体中的表达，改变了 1 个基因在额叶皮质中的表达。相比之下，苯妥英（75mg/kg）仅改变了脑桥/延髓中的 3 个基因的表达，改变了海马体中的 64 个基因的表达，改变了额叶皮质中的 327 个基因的表达。基因表达的影响在区域或药物治疗之间几乎没有重叠。
讨论
我们的结论是，慢性给予左乙拉西坦或苯妥英治疗会导致大脑中基因表达的区域特异性和高度差异。基因表达的区域效应可能反映了 AEDs 的分子靶点在区域上的差异，也可能影响 AEDs 的临床特征。
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