Long-Term Valproate Treatment Increases Brain Neuropeptide Y Expression and Decreases Seizure Expression in a Genetic Rat Model of Absence Epilepsy

Johanna Elms,Stefanie Dedeurwaerdere,Kim L Powell,Leena Van Raay,Margaret J Morris,Terence J O’Brien,Alice Y W Chang

doi:10.1371/journal.pone.0073505

Abstract

The mechanisms by which valproate, one of the most widely prescribed anti-epileptic drugs, suppresses seizures have not been fully elucidated but may involve up-regulation of neuropeptide Y (NPY). We investigated the effects of valproate treatment in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) on brain NPY mRNA expression and seizure control. GAERS were administered either valproate (42 mg.kg−1 hr−1) or saline continuously for 5 days. Electroencephalograms were recorded for 24 hrs on treatment days 1, 3 and 5 and the percentage of time spent in seizure activity was analysed. NPY mRNA expression was measured in different brain regions using qPCR. Valproate treatment suppressed seizures by 80% in GAERS (p<0.05) and increased NPY mRNA expression in the thalamus (p<0.05) compared to saline treatment. These results demonstrate that long-term valproate treatment results in an upregulation of thalamic expression of NPY implicating this as a potential contributor to the mechanism by which valproate suppresses absence seizures.

Highlights

Valproate is one of most commonly prescribed anti-epileptic drugs and is effective in a broad range of seizure types
This study is the first to investigate whether neuropeptide Y (NPY) mRNA expression is up-regulated after valproate treatment in an animal model of genetic generalised epilepsy
We demonstrated that longterm valproate treatment suppressed seizures in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and this was associated with a significant increase in NPY mRNA expression in the thalamus

Summary

Introduction

Valproate is one of most commonly prescribed anti-epileptic drugs and is effective in a broad range of seizure types. A variety of mechanisms have been implicated as being involved in mediating valproate’s pharmacological effects These include increased GABA synthesis and release resulting in increased GABAergic transmission [3,4,5], decreases excitatory synaptic activity through the modulation of postsynaptic non-NMDA receptors [6] and blockade of voltage-dependent sodium channels [7,8]. In vitro experiments show that valproate has an early effect to inhibit cellular excitability, which is exerted from the extracellular side of the neuronal membrane, and a more delayed effect resulting from intracellular actions [9,10]. These data indicate that there are both immediate and long-term actions of valproate on cellular excitability

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Conclusion