EFFECTS OF PROLONGED ADMINISTRATION OF PHENYTOIN ON GENE EXPRESSION IN THE RAT BRAIN ASSESSED BY MICROARRAYS

In recent years, a growing number of anticonvulsant drugs commonly utilized for epilepsy treatment, like as Valproate and Carbamazepine showed to be effective in the bipolar disorder treatment, and Valproate is now the most widely prescribed mood-stabilizing drug. Phenytoin, like Valproate and Carbamazepine, is an anticonvulsant drug, which has been used successfully for many years to treat epilepsy, but not as mood stabilizer. The potentiality of Phenytoin to treat bipolar disorder has been evaluated only recently by clinical studies with promising results. The Phenytoin mechanism of action, however, is still not fully understood. Phenytoin shares with other anticonvulsants the ability of blocking voltage-gated sodium channels but probably this is not the only mechanism of action of Phenytoin. Some reports suggest that the modulation of glutamate and GABA release might contribute to the anticonvulsant effect of Phenytoin but data concerning this hypothesis are still few and divergent. In order to elucidate the molecular mechanisms of action of Phenytoin and to verify the hypothesis that Phenytoin might act as a mood stabilizer, we examined by microarray analysis the gene expression profiles in the hippocampus and frontal cortex of three rats chronically treated with Phenytoin in comparison with three untreated rats. We found 508 differentially regulated genes in hippocampus and 62 differentially regulated genes in frontal cortex. To interpret the obtained gene expression data, we performed pathway analyses and an accurate investigation of scientific literature. We found that Phenytoin increases the GABAergic system, strongly implicated in mood disorder pathophysiology, by inducing the expression of Glutamate decarboxylase 1 (GAD1), Glutamate dehydrogenase1 (GLUD1) and Gamma- aminobutyric acid A receptor, alfa 5 (GABRA5) genes; it exerts a neuroprotective effect by inducing the expression of survival-promoting and antioxidant genes like as Extracellular signal-regulated kinase 1 (ERK1), v-akt murine thymoma viral oncogene homolog 1 (AKT1), protein kinase C epsilon (PKCe), NF-kappa-B-repressing factor (NFKB), Activator protein-1 (AP-1), glutatione reductase (GSR) e glutamate cysteine ligase, catalytic subunit (GCLC), and induces the expression of genes associated to known mechanisms of mood regulation, like as adenylate cyclase-associated protein 1 (CAP1), TAU, Dopamine ß-Hydroxylase (DBH), Glial Fibrillary Acidic Protein (GFAP) and Prodynorphin (PDYN). Data arising from this study support the clinical observations that Phenytoin may act as a mood stabilizer. Many of the genes regulated by Phenytoin, in fact, are molecular targets of classical mood stabilizers. Besides these genes, we identified other genes that might give new molecular incites about the mechanisms of action of these drugs. These novel target genes might also contribute in understanding molecular mechanisms underlying the lack of response to drug treatment that sometime is observed in patients.