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  • Valproic acid VPA is a first line treatment


    Valproic Cystamine dihydrochloride (VPA) is a first-line treatment for epilepsy and bipolar disorder, although its therapeutic mechanism of action is not fully understood. Considerable evidence suggests that VPA can act through the GABAergic system, NMDA receptors, and/or sodium channels (for review, see Löscher, 1999, Löscher, 2002, Rogawski and Löscher, 2004). However, VPA can also exert neurochemical effects on the NE system. For example, Baf et al. (1994) observed an increase in NE tissue levels in the hippocampus and brainstem following chronic VPA treatment. The expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in NE biosynthesis, is also increased in the LC of rats by acute and chronic VPA treatment (Sands et al., 2000). Furthermore, tricyclic antidepressants, which block the reuptake of NE and increase extracellular NE levels, have been shown to enhance the anticonvulsant effects of VPA (Kleinrok et al., 1991). Given the numerous clinical effects of VPA, its suggested influence on the NE system, and the purported anticonvulsant effects of NE, it is of interest to determine if disruption of NE signaling might alter the anticonvulsant properties of VPA. VPA acts on multiple targets involved in neurotransmission and NE may act in concert with these targets to modulate the anticonvulsant efficacy of VPA. The model used in the current study is a mouse with a genetic knockout of the dopamine β-hydroxylase (Dbh) gene (Dbh −/− mice). DBH is the enzyme that converts DA to NE; thus, Dbh −/− mice completely lack NE (Thomas et al., 1995). This model is especially relevant in light of previous findings showing that serum DBH activity is lower in patients with some types of epilepsy (Miras-Portugal et al., 1975). Dbh −/− mice show increased susceptibility to numerous seizure-inducing stimuli including flurothyl (Szot et al., 1999), the stimulus used for seizure induction in the present study. Interestingly, various subtype specific NE receptor agonists are capable of attenuating seizure hypersensitivity in these mice (Weinshenker et al., 2001, Weinshenker and Szot, 2002, Szot et al., 2004). In the current study, we evaluate the effectiveness of VPA in NE-deficient Dbh −/− mice. To date, few studies have examined the interaction of VPA and NE in the modulation of seizure sensitivity. Given the observations outlined above, we hypothesized that the anticonvulsant effects of VPA would be reduced in Dbh −/− mice. Because chronic VPA enhances TH and NE in the brain, we also examined the role of NE in the “carryover effect” observed after chronic administration of VPA (Lockhard and Levy, 1976, Löscher and Nau, 1982). The carryover effect is defined as the persistence of anticonvulsant activity after the disappearance of VPA from the bloodstream following cessation of chronic VPA treatment. Lastly, we evaluated whether enhancement of NE transmission by the NE reuptake inhibitor reboxetine could enhance the effectiveness of low dose, acute VPA treatment.
    Experimental procedures
    Discussion In the current experiments, we utilized a mouse that lacks NE to investigate the role of NE in the anticonvulsant effects of VPA. We observed flurothyl-induced seizure behavior following both acute and chronic VPA treatments. Given the purported anticonvulsant activity of NE itself and data suggesting that VPA can act on the NE system, we hypothesized that the Dbh −/− mice would be less responsive to the anticonvulsant effects of VPA.
    Conclusion In summary, these findings indicate that a functional NE system may be necessary for the full anticonvulsant effect of VPA on seizure susceptibility and seizure severity in mice. Other anticonvulsant therapies also depend on NE activity, including vagal nerve stimulation (Krahl et al., 1998), the ketogenic diet (Szot et al., 2001), and drug treatment with phenytoin, carbamazepine, or phenobarbital (Quattrone and Samanin, 1977, Quattrone et al., 1978, Crunelli et al., 1981, Waller and Buterbaugh, 1985). It appears as though several systems are involved in the anticonvulsant effects of VPA (for review, see Löscher, 1999), and we suggest here that NE contributes to the complex mechanism of action of this widely used drug. It is important to consider such results in the clinical treatment of epilepsy, as genetic variation in DBH activity exists in the human population (reviewed by Cubells and Zabetian, 2004). Analysis of DBH function through genetic screening could indicate portions of the population that may have decreased responsiveness to certain anticonvulsant treatments. Therefore, knowledge of genotype for the DBH enzyme could be used as a tool for directing clinical treatment of epilepsy.