title: Increased hippocampal noradrenaline is a biomarker for efficacy of vagus nerve stimulation in a limbic seizure model.
abstract: Vagus nerve stimulation (VNS) is an effective adjunctive treatment for medically refractory epilepsy. In this study, we measured VNS-induced changes in hippocampal neurotransmitter levels and determined their potential involvement in the anticonvulsive action of VNS, to elucidate the mechanism of action responsible for the seizure suppressing effect of VNS in an animal model for limbic seizures. We used in vivo intracerebral microdialysis to measure VNS-induced changes in hippocampal extracellular concentrations of noradrenaline, dopamine, serotonin and GABA in freely moving, male Wistar rats. During the same experiment, the effect of VNS on pilocarpine-induced limbic seizures was assessed using video-EEG monitoring. The involvement of VNS-induced increases in hippocampal noradrenaline in the mechanims of action of VNS was evaluated by blocking hippocampal α(2)-receptors. VNS produced a significant increase in hippocampal noradrenaline concentration (69 ± 16% above baseline levels). VNS also increased the latency between pilocarpine infusion and the onset of epileptiform discharges, and reduced the duration and severity of pilocarpine-induced limbic seizures. A strong positive correlation was found between the noradrenergic and anticonvulsive effects of VNS. Blockade of hippocampal α(2 -receptors reversed the seizure-suppressing effect of VNS. VNS induces increases in extracellular hippocampal noradrenaline, which are at least partly responsible for its seizure-suppressing effect in a model for limbic seizures, and constitute a potential biomarker for the efficacy of VNS in temporal lobe epilepsy.
authors.affiliation: Department of Neurology, Ghent University Hospital, Ghent, Belgium. robrecht.raedt@ugent.be
authors.forename: Robrecht
authors.initials: R
authors.lastname: Raedt
authors.forename: Ralph
authors.initials: R
authors.lastname: Clinckers
authors.forename: Lies
authors.initials: L
authors.lastname: Mollet
authors.forename: Kristl
authors.initials: K
authors.lastname: Vonck
authors.forename: Riëm
authors.initials: R
authors.lastname: El Tahry
authors.forename: Tine
authors.initials: T
authors.lastname: Wyckhuys
authors.forename: Veerle
authors.initials: V
authors.lastname: De Herdt
authors.forename: Evelien
authors.initials: E
authors.lastname: Carrette
authors.forename: Wytse
authors.initials: W
authors.lastname: Wadman
authors.forename: Yvette
authors.initials: Y
authors.lastname: Michotte
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
authors.forename: Paul
authors.initials: P
authors.lastname: Boon
authors.forename: Alfred
authors.initials: A
authors.lastname: Meurs
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004569:Electroencephalography; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017551:Microdialysis / Q000379:methods; D018721:Muscarinic Agonists / Q000009:adverse effects; D009638:Norepinephrine / Q000378:metabolism*; D010862:Pilocarpine / Q000009:adverse effects; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000473:pathology* / Q000628:therapy*; D013223:Statistics as Topic; D055536:Vagus Nerve Stimulation / Q000379:methods*; D014741:Video Recording / Q000379:methods
chemical_list: D000317:Adrenergic alpha-Antagonists; D001552:Benzazepines; D018721:Muscarinic Agonists; D010862:Pilocarpine; D009638:Norepinephrine; C039139:benalfocin