Department of Experimental Pathology, Medical Biotechnology, Infectious Diseases and Epidemiology, University of Pisa, Italy.
Exp Biol Med (Maywood). 2010 Mar;235(3):300-10. doi: 10.1258/ebm.2009.009225.
Preliminary clinical trials have recently shown that phenytoin, an antiepileptic drug, may also be beneficial for treatment of bipolar disorder. To examine molecular mechanisms of action of phenytoin as a potential mood stabilizer, DNA microarrays were used to study the effect of phenytoin on gene expression in the hippocampus and frontal cortex of Sprague-Dawley rats. While our particular interest is in bipolar disorder, this is the first DNA microarray study on the effect of phenytoin in brain tissue, in general. As compared with control rats, treated rats had 508 differentially expressed genes in the hippocampus and 62 in the frontal cortex. Phenytoin modulated the expression of genes which may affect neurotransmission, e.g. glutamate decarboxylase 1 (Gad1) and gamma-aminobutyric acid A receptor, alpha 5 (Gabra5). Phenytoin also exerted an effect on neuroprotection-related genes, namely the survival-promoting and antioxidant genes v-akt murine thymoma viral oncogene homolog 1 (Akt1), FK506 binding protein 12-rapamycin associated protein 1 (Frap1), glutathione reductase (Gsr) and glutamate cysteine ligase catalytic subunit (Gclc). The expression of genes potentially associated with mechanisms of mood regulation such as adenylate cyclase-associated protein 1 (Cap1), Glial Fibrillary Acidic Protein (Gfap) and prodynorphin (Pdyn) was also altered. Some of the above genes are regarded as targets of classical mood stabilizers and their modulation supports the clinical observation that phenytoin may have mood-stabilizing effects. The results may provide new insights regarding the mechanism of action of phenytoin and genes found differentially expressed following phenytoin administration may play a role in the pathophysiology of either bipolar disorder or epilepsy.
初步的临床试验最近表明，抗癫痫药物苯妥英可能对双相情感障碍的治疗也有益。为了研究苯妥英作为潜在心境稳定剂的作用机制，我们使用 DNA 微阵列研究了苯妥英对 Sprague-Dawley 大鼠海马和前额叶皮质基因表达的影响。虽然我们特别关注双相情感障碍，但这是关于苯妥英在脑组织中作用的第一项 DNA 微阵列研究，通常情况下。与对照组大鼠相比，治疗组大鼠的海马中有 508 个差异表达基因，前额叶中有 62 个基因。苯妥英调节了可能影响神经递质传递的基因的表达，例如谷氨酸脱羧酶 1（Gad1）和γ-氨基丁酸 A 受体，α 5（Gabra5）。苯妥英还对神经保护相关基因产生了影响，即促进生存和抗氧化的基因 v-akt 鼠胸腺瘤病毒癌基因同源物 1（Akt1）、FK506 结合蛋白 12-雷帕霉素相关蛋白 1（Frap1）、谷胱甘肽还原酶（Gsr）和谷氨酸半胱氨酸连接酶催化亚基（Gclc）。与情绪调节机制相关的基因表达也发生了改变，如腺苷酸环化酶相关蛋白 1（Cap1）、胶质纤维酸性蛋白（Gfap）和前原啡肽（Pdyn）。其中一些基因被认为是经典心境稳定剂的靶点，它们的调节支持了苯妥英可能具有稳定情绪作用的临床观察。这些结果可能为苯妥英的作用机制提供新的见解，并且发现苯妥英给药后差异表达的基因可能在双相情感障碍或癫痫的病理生理学中发挥作用。
