Antiepileptic drugs in migraine: from clinical aspects to cellular mechanisms. TIPS

Clinica Neurologica, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, Perugia 06156, Italy.
Trends in Pharmacological Sciences (Impact Factor: 11.54). 05/2007; 28(4):188-95. DOI: 10.1016/
Source: PubMed


Migraine and epilepsy share several clinical features, and epilepsy is a comorbid condition of migraine. Clinical studies have shown that some antiepileptic drugs are effective at preventing migraine attacks. A rationale for their use in migraine prophylaxis is the hypothesis that migraine and epilepsy share several common pathogenetic mechanisms. An imbalance between excitatory glutamate-mediated transmission and GABA-mediated inhibition in specific brain areas has been postulated in these two pathological conditions. Moreover, abnormal activation of voltage-operated ionic channels has been implicated in both migraine and epilepsy. Cortical spreading depression has been found to be involved in the pathophysiology of epilepsy, in addition to the generation of migraine aura.

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    • "In addition, VPA is used in the treatment of various other conditions including migraine (Calabresi et al., 2007; Rodriguez-Sainz et al., 2013) and neuropathic pain (Cutrer and Moskowitz, 1996; Vorobeychik et al., 2011). Recent research is exploring possible therapeutic roles for VPA in cancer therapy, latent HIV infection and Alzheimer's disease (Terbach and Williams, 2009). "
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    ABSTRACT: Valproic acid (VPA) is a widely used antiepileptic drug and first-line treatment in bipolar disorder, although the mechanisms underlying its therapeutic effects are largely unknown. Recently, the recognition of VPA as an epigenetic drug offers new opportunities for understanding its therapeutic actions. In a rat serotonergic cell line (RN46A) we observed that VPA exposure has a strong upregulatory effect on the gene for sepiapterin reductase (SPR), a key enzyme involved in the tetrahydrobiopterin (BH4) synthetic pathway. BH4 is an essential cofactor in the biosynthesis of neurotransmitters like serotonin, dopamine and noradrenalin, and the BH4 pathway may thus be important in mood biology. Using real-time quantitative PCR we show that VPA, at therapeutically relevant doses, increases the expression of the Spr gene by about 8-fold in RN46A cells. In addition, Spr protein levels in VPA-exposed cells were elevated, as were the intracellular BH4 levels. HDAC inhibitors (HDACI) trichostatin A and sodium butyrate also upregulated Spr, but this was not observed using the VPA-analogue valpromide, which lacks HDAC inhibitory activity. Further examination of this effect revealed that exposure to VPA increased the acetylated histone mark H3K9/K14ac at the Spr promoter. The DNMT inhibitor 5'aza-dC also upregulated Spr by over 8-fold. However, DNA methylation status across the Spr promoter did not change in response to VPA. The BH4 pathway is fundamental to the regulation of neurotransmitters relevant to mood disorders, and this epigenetic effect of VPA at the Spr promoter may represent a novel mechanism through which VPA achieves its therapeutic action. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Jul 2015 · Neuropharmacology
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    • "In this study we analyzed miRNA expression profiles (miRNome) after neural differentiation of mESCs under the exposure to a well known developmental neurotoxicant: sodium valproate (salt of valproic acid, VPA) [27] to establish miRNA profiling as a molecular tool for DNT testing. VPA is a broadly used anti-epileptic drug, and is also applied for the treatment of bipolar disorder, cancer, and migraine [28]–[30]. The therapeutic effect of VPA is a combination of several effects on cellular signalling, including induction of GABAergic neurotransmission, promotion of neuronal remodelling, and neurogenesis [31]–[33]. "
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    ABSTRACT: Studying chemical disturbances during neural differentiation of murine embryonic stem cells (mESCs) has been established as an alternative in vitro testing approach for the identification of developmental neurotoxicants. miRNAs represent a class of small non-coding RNA molecules involved in the regulation of neural development and ESC differentiation and specification. Thus, neural differentiation of mESCs in vitro allows investigating the role of miRNAs in chemical-mediated developmental toxicity. We analyzed changes in miRNome and transcriptome during neural differentiation of mESCs exposed to the developmental neurotoxicant sodium valproate (VPA). A total of 110 miRNAs and 377 mRNAs were identified differently expressed in neurally differentiating mESCs upon VPA treatment. Based on miRNA profiling we observed that VPA shifts the lineage specification from neural to myogenic differentiation (upregulation of muscle-abundant miRNAs, mir-206, mir-133a and mir-10a, and downregulation of neural-specific mir-124a, mir-128 and mir-137). These findings were confirmed on the mRNA level and via immunochemistry. Particularly, the expression of myogenic regulatory factors (MRFs) as well as muscle-specific genes (Actc1, calponin, myosin light chain, asporin, decorin) were found elevated, while genes involved in neurogenesis (e.g. Otx1, 2, and Zic3, 4, 5) were repressed. These results were specific for valproate treatment and-based on the following two observations-most likely due to the inhibition of histone deacetylase (HDAC) activity: (i) we did not observe any induction of muscle-specific miRNAs in neurally differentiating mESCs exposed to the unrelated developmental neurotoxicant sodium arsenite; and (ii) the expression of muscle-abundant mir-206 and mir-10a was similarly increased in cells exposed to the structurally different HDAC inhibitor trichostatin A (TSA). Based on our results we conclude that miRNA expression profiling is a suitable molecular endpoint for developmental neurotoxicity. The observed lineage shift into myogenesis, where miRNAs may play an important role, could be one of the developmental neurotoxic mechanisms of VPA.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "VPA is a short-chain branched fatty acid that was discovered serendipitously as an anticonvulsant while being used as a solvent. Today VPA is used to treat a variety of psychiatric diseases such as seizure disorders, bipolar disorder and migraine [1], [2], that is supposed by targeting GABA transaminase, succinate semialdehyde dehydrogenase, and alpha-ketoglutarate dehydrogenase and Na+ channels [3], [4]. In 2001, histone deacetylases (HDACs) were identified as direct targets of VPA [5], [6]. "
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    ABSTRACT: We have been studying the action mechanisms of valproic acid (VPA) in fission yeast Schizosaccharomyces pombe by developing a genetic screen for mutants that show hypersensitivity to VPA. In the present study, we performed a genome-wide screen of 3004 haploid deletion strains and confirmed 148 deletion strains to be VPA sensitive. Of the 148 strains, 93 strains also showed sensitivity to another aliphatic acids HDAC inhibitor, sodium butyrate (SB), and 55 strains showed sensitivity to VPA but not to SB. Interestingly, we found that both VPA and SB treatment induced a marked increase in the transcription activity of Atf1 in wild-type cells. However, in clr6-1, a mutant allele the clr6+ gene encoding class I HDAC, neither VPA- nor SB induced the activation of Atf1 transcription activity. We also found that VPA, but not SB, caused an increase in cytoplasmic Ca2+ level. We further found that the cytoplasmic Ca2+ increase was caused by Ca2+ influx from extracellular medium via Cch1-Yam8 channel complex. Altogether, our present study indicates that VPA and SB play similar but distinct roles in multiple physiological processes in fission yeast.
    No preview · Article · Jul 2013 · PLoS ONE
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