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      The Effects of Vagus Nerve Stimulation on Pro- and Anti-Inflammatory Cytokines in Humans: A Preliminary Report

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          Objective: Vagus nerve stimulation (VNS) is a novel therapy in resistant epilepsy, and is undergoing clinical trials in resistant depression. The mechanism of action of VNS is assumed to be due to modulation of deep brain structures via its afferent connections. As the vagus nerve has potentially important immunological actions that may have relevance to its therapeutic effects, we hypothesised that an additional mechanism may occur via vagally mediated actions on cytokine synthesis. Methods: Patients (n = 10) with resistant depression were studied in the weeks prior to, and 3 months following, implantation of a vagus nerve stimulator. No medication changes were made during the course of the study. High-sensitivity ELISA kits were used to measure plasma IL-1β, IL-6, TNF-α, IL-10 and TGF-β concentrations. C-reactive protein (CRP) was measured using a high sensitivity immunonephelometry assay. Results: There were highly significant increases in the plasma levels of IL-6, TNF-α and TGF-β. Increases seen with IL-10 and IL-1β were not significant. Plasma CRP levels were unchanged. Conclusion: VNS is associated with marked peripheral increases in pro- and anti-inflammatory circulating cytokines. Such changes are unlikely to be non-specific inflammatory reactions, reflected by CRP levels. In view of gathering evidence supporting a role for the immune system in modulating affect, as well as seizure activity, these effects of VNS may be therapeutically relevant.

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          Most cited references 9

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          Depression, stress and immunological activation: The role of cytokines in depressive disorders

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            The role of cytokines and growth factors in seizures and their sequelae.

            Although the neuropathological changes caused by severe or repeated seizures have been well characterized, many questions about the molecular mechanisms involved remain unanswered. Neuronal cell death, reactive gliosis, enhanced neurogenesis, and axonal sprouting are four of the best-studied sequelae of seizures. In vitro, each of these pathological processes can be substantially influenced by soluble protein factors, including neurotrophins, cytokines, and growth factors. Furthermore, many of these proteins and their receptors are expressed in the adult brain and are up-regulated in response to neuronal activity and injury. We review the evidence that these intercellular signaling proteins regulate seizure activity as well as subsequent pathology in vivo. As nerve growth factor and brain derived neurotrophic factor are the best-studied proteins of this class, we begin by discussing the evidence linking these neurotrophins to epilepsy and seizure. More than a dozen additional cytokines, growth factors, and neurotrophins that have been examined in the context of epilepsy models are then considered. We discuss the effect of seizure on expression of cytokines and growth factors, and explore the regulation of seizure development and aftermath by exogenous application or antagonist perturbation of these proteins. The experimental evidence supports a role for these factors in each aspect of seizure and pathology, and suggests potential targets for future therapeutics.
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              Regional induction of fos immunoreactivity in the brain by anticonvulsant stimulation of the vagus nerve.

              Electrical stimulation of the vagus nerve exerts an antiepileptic effect on human partial-onset epilepsy, but little is known about the brain structures that mediate this phenomenon. Fos is a nuclear protein that is expressed under conditions of high neuronal activity. We utilized fos immunolabeling techniques on Sprague-Dawley rat brains to identify regions that are activated by antiepileptic stimulation of the left vagus nerve. Vagus nerve stimulation (VNS) induced specific nuclear fos immunolabeling in several forebrain structures, including the posterior cortical amygdaloid nucleus, cingulate and retrosplenial cortex, ventromedial and arcuate hypothalamic nuclei. In the brainstem, there was specific immunolabeling in vagus nerve nuclei, in the A5 and locus ceruleus noradrenergic nuclei, and in the cochlear nucleus. No labeling of these structures occurred in sham-operated, unstimulated control animals. Intense labeling also occurred in habenular nucleus of thalamus after vagus nerve stimulation, whereas only mild staining occurred in unstimulated animals. Several of the brain structures activated by VNS are important for genesis or regulation of seizures in the forebrain. These structures may mediate the antiepileptic effect of VNS.

                Author and article information

                S. Karger AG
                September 2005
                21 September 2005
                : 12
                : 5
                : 307-309
                aDepartment of Psychiatry, Beaumont Hospital, and Royal College of Surgeons in Ireland, and bDepartment of Physiology and Trinity College Institute of Neuroscience, University of Dublin, Trinity College, Dublin, Ireland
                87109 Neuroimmunomodulation 2005;12:307–309
                © 2005 S. Karger AG, Basel

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                Tables: 1, References: 15, Pages: 3
                Original Paper


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