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Project
The role of the locus coeruleus and hippocampal noradrenergic neurotransmission in the anti-epileptic effect of of vagus nerve stimulation. (FWOAL569)
The mechanism of action of vagus nerve stimulation VNS is still unknown but activation of afferent fibers of the vagal nerve is thought to be responsible for the anti-epileptic effect of VNS. A projection area of the vagal nerve which is believed to play a major role in the seizure suppressive effect of VNS is the locus coeruleus (LC). This pontine nucleus contains a large amount of noradrenergic neurons and is the major source of noradrenaline in the brain. NVS induces an increase in neuronal activity in the LC which is most probably responsible for an increase of noradrenaline concentration in the projection areas of the LC such as the hippocampus and the cortex. The reversal of VNS-induced anti-epileptic effects due to selective lesion of noradrenergic neurons further supports a possible role of the LC in the anti-epileptic effect of VNS.
A collaborative study done by the Laboratory for Clinical and Experimental Neurophysiology (LCEN, UGent) and the Department of Pharmaceutical Chemistry and Drug Analysis (labo FASC, VUB) demonstrated antiepileptic effects of NVS in the focal (intrahippocampal) pilocarpine model. In this model for partial (limbic) epilepsy a proconvulsive compound, pilocarpine, is administrated in the hippocampus of rats through a microdialysis probe. VNS is administrated to the rats by using custom-made "cuff"-electrodes. Video-EEG registration in freely moving rats with pilocarpine-induced epileptic seizures showed a suppression of seizure activity in response to NVS. Reduction of seizure activity was associated with an increase of noradrenalin concentration in the hippocampus. Additionally this pilot study showed a positive correlation between the degree of seizure suppression and the increase of hippocampal noradrenalin concentration in response to VNS (manuscript in preparation).
Evidence from literature and results of our pilot study in the pilocarpine model suggest the crucial role of LC noradrenergic neurons in the anti-epileptic effect of VNS. Firstly, this project aims at further unraveling the role of the LC neurons and hippocampal noradrenergic neurotransmission in the mechanism of action of VNS. In order to investigate this selective lesions, specific agonists and antagonists and state-of-the art neurophysiological and analytical techniques will be used. Secondly, it will be investigated whether activation of the noradrenergic signaling pathway could be used as biomarker for the efficacy of VNS.
A collaborative study done by the Laboratory for Clinical and Experimental Neurophysiology (LCEN, UGent) and the Department of Pharmaceutical Chemistry and Drug Analysis (labo FASC, VUB) demonstrated antiepileptic effects of NVS in the focal (intrahippocampal) pilocarpine model. In this model for partial (limbic) epilepsy a proconvulsive compound, pilocarpine, is administrated in the hippocampus of rats through a microdialysis probe. VNS is administrated to the rats by using custom-made "cuff"-electrodes. Video-EEG registration in freely moving rats with pilocarpine-induced epileptic seizures showed a suppression of seizure activity in response to NVS. Reduction of seizure activity was associated with an increase of noradrenalin concentration in the hippocampus. Additionally this pilot study showed a positive correlation between the degree of seizure suppression and the increase of hippocampal noradrenalin concentration in response to VNS (manuscript in preparation).
Evidence from literature and results of our pilot study in the pilocarpine model suggest the crucial role of LC noradrenergic neurons in the anti-epileptic effect of VNS. Firstly, this project aims at further unraveling the role of the LC neurons and hippocampal noradrenergic neurotransmission in the mechanism of action of VNS. In order to investigate this selective lesions, specific agonists and antagonists and state-of-the art neurophysiological and analytical techniques will be used. Secondly, it will be investigated whether activation of the noradrenergic signaling pathway could be used as biomarker for the efficacy of VNS.
Date:1 Jan 2010 → 31 Dec 2013
Keywords:Aminoacids, Parkinsons Disease, Neuro-Transmitters, Neuropharmacology, clinical pharmacy, Stroke, Receptors, Rat Models, Neurochemistry, Pharmacokinetics, Microdialysis, neuroscience, Drug Research, Bioanalysis, Epilepsy, seamless care, Monoamines, Neurosciences, Liquid Chromatography, pharmaceutical care, Electrochemical Detection
Disciplines:(Bio)chemical engineering, Basic sciences, Health sciences, Pharmaceutical sciences