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Autonomic Neuroscience: Basic and Clinical 158 (2010) 8–12
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Autonomic Neuroscience: Basic and Clinical
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The role of the vagus nerve in stroke
Boris Mravec ⁎ Institute of Pathophysiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia
⁎ Institute of Pathophysiology, Faculty of Medicine, C 4, 811 08 Bratislava, Slovakia. Tel.: +421 2 59357389; f
E-mail address: [email protected]
1566-0702/$ – see front matter © 2010 Elsevier B.V. A doi:10.1016/j.autneu.2010.08.009
a b s t r a c t
Article history: Received 21 January 2010 Received in revised form 20 May 2010 Accepted 29 August 2010
Keywords: Cholinergic anti-inflammatory pathway Inflammation Monoaminergic neurotransmission Neuroplasticity Spleen Stem cells
The initiation and progression of ischemic and hemorrhagic stroke are the result of a complex cascade of processes that determine both the extent of the lesion and long-term outcome. Several of these processes, including peripheral inflammation, neuroinflammation, and neuroplasticity are influenced by the activity of the afferent as well as efferent pathways of the vagus nerve. It was shown that vagus nerve stimulation significantly reduces the extent of stroke-induced lesion of brain parenchyma. However, the mechanisms of beneficial effect of increased vagal activity on pathological processes related to stroke remains largely unclear. The aim of this article is to describe the role of afferent and efferent vagal pathways in the mechanisms that influence the initiation of stroke as well as its detrimental effects.
omenius University, Sasinkova ax: +421 2 59357601.
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© 2010 Elsevier B.V. All rights reserved.
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 2. The vagus nerve and stroke: assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.1. The vagus nerve and peripheral inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2.2. The vagus nerve and neuroinflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2.3. The vagus nerve and neuronal plasticity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
3. The vagus nerve and stroke: evidences. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.1. The role of efferent vagal pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.2. The role of afferent vagal pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Experimental and clinical findings indicate that the initiation and progression of stroke are subject to regulation by a variety of molecular processes triggered by brain ischemia or hemorrhage. These processes include loss of metabolic stores, excessive intracel- lular calcium accumulation, oxidative stress, formation of clot-derived substances, and potentiation of the inflammatory response (Brouns and De Deyn, 2009; Xi et al., 2006; Zheng et al., 2003). Several of these
factors (e.g. peripheral inflammation, neuroinflammation, neuroplas- ticity) are also influenced by the activity of the afferent as well as efferent pathways of the vagus nerve (Fig. 1). However even if it is proven that vagus nerve stimulation (VNS) significantly reduces the extent of stroke-induced lesion of brain parenchyma (Ay et al., 2009), the mechanism underlying the beneficial effect of the activated vagus nerve remains largely unclear.
2. The vagus nerve and stroke: assumptions
Inflammation during the prestroke period. Inflammation repre- sents a basic host defense reaction to infection and injury with beneficial consequences. However, inappropriate (in time, place or
Fig. 1. Activation of vagal afferent and efferent pathways may influence factors related to initiation and progression of stroke through several mechanisms. Afferent pathways of the vagus nerve influence neuroplasticity and neuroinflammation through modulation of monoaminergic neurons activity. Efferent pathways of the vagus nerve inhibit peripheral inflammation either directly or through modulation of the activity of immune cells within the spleen. ACTH – adrenocorticotropic hormone; BBB – blood- brain barrier; BDNF – brain-derived neurotrophic factor; CRH – corticotropin-releasing hormone; HPA axis – hypothalamic-pituitary-adrenal axis (solid line – neuronal pathways; dashed lines – humoral pathways; “+” activation; “−” inhibition).
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magnitude) inflammation is increasingly implicated in several disease states including diabetes mellitus, obesity, atherosclerosis, heart disease, cancer, and both neurological and psychiatric disease. Importantly, strong correlations exist between inflammatory status and stroke susceptibility. Moreover, recent experimental and clinical studies support the assumption that systemic inflammatory status prior to and at the time of stroke is a key determinant of acute outcome and long-term prognosis (Denes et al., 2010; McColl et al., 2009).
Stroke-induced inflammation. It is well documented that brain ischemic injury triggers a robust in situ inflammatory reaction. Ischemia of brain tissue is a powerful stimulus for expression of transcriptional factors determining the production of wide variety of inflammatory mediators within the brain. This response leads to migration of peripheral circulating leukocytes into the area of injury necessary to remove cell debris and activate regenerative processes. However, this inflammatory reaction can exacerbate cerebral damage and is involved in secondary brain damage (Brea et al., 2009; Zheng et al., 2003). Even if experimental studies of cerebral ischemia have shown that key inflammatory mediators (e.g. cytokines and inflam- matory cells) contribute directly to ischemic brain injury, the
importance of systemic (peripheral) versus brain (central) inflam- mation in cerebral ischemia remains to be determined (Denes et al., 2010).
2.1. The vagus nerve and peripheral inflammation
The central nervous system modulates inflammation through humoral and neural pathways. Whereas the immunomodulatory effect of glucocorticoids, other humoral mediators, and sympathetic nervous system has been studied extensively in past decades, vagal control of inflammatory processes has been described only recently. It was found that efferent fibers of the vagus nerve constitute the so called cholinergic anti-inflammatory pathway that plays a prominent role in the neural control of inflammation (Tracey, 2007). Animal studies have shown that electrical, chemical, or mechanical stimula- tion of efferent fibers of the vagus nerve attenuates the production of pro-inflammatory cytokines in various animal models with inflam- matory components (Rosas-Ballina and Tracey, 2009). Recent findings have also indicated the crucial role of the spleen in vagal anti- inflammatory effects (Huston et al., 2006). These findings are also of interest because it has been shown that intravenous injection of neural stem cells induces an anti-inflammatory effect that promotes neuroprotection primarily by interrupting the peripheral, especially splenic, inflammatory response to intracerebral hemorrhage in rats (Kleinig and Vink, 2009; Lee et al., 2008).
2.2. The vagus nerve and neuroinflammation
The vagus nerve may influence neuroinflammation by several mechanisms:
Activation of noradrenergic neurons. The existence of intrinsic regulatory neuronal pathways providing protection in neuroinflam- matory conditions is supported by findings that certain neurotrans- mitters, including monoamines, elicit anti-inflammatory effects in the brain via receptors located on microglia and astrocytes, thereby playing a key role in controlling neuroinflammation (Heneka and O'Banion, 2007). This concept is the extension of the principle of “central neurogenic neuroprotection” based on the assumption of the existence of neuronal circuits that protect the brain against the damage initiated by excitotoxic injury (Galea et al., 2003). These circuits also include noradrenergic pathways (Feinstein et al., 2002). It is well established that the norepinephrine acts as an endogenous immunomodulator in the brain and exerts potent anti-inflammatory properties, thus playing an important role in maintaining the immunosuppressive environment within the brain (O'Sullivan et al., 2009). Several experimental studies have confirmed that afferent pathways of the vagus nerve influence central noradrenergic transmission. The nucleus of the solitary tract, the major viscerosen- sory station receiving information carried by afferent vagal pathways, provides input to the locus coeruleus, the major source of norepi- nephrine in the brain (Zec and Kinney, 2003). Electrophysiological and biochemical studies in the rat have showed that VNS increases the firing rate of noradrenergic neurons after 1 day of stimulation (Manta et al., 2009) and increases extracellular concentration of norepineph- rine in the hippocampus and cortex of rats (Roosevelt et al., 2006). Therefore, it can be suggested that activation of noradrenergic neurons by stimulation of the vagal afferent pathway may reduce inflammation in the brain.
Reduction of peripheral inflammation. It has been shown that peripheral inflammation may induce inflammation in the brain (Miller et al., 2009). Therefore, reduction of peripheral inflammation by activation of the cholinergic anti-inflammatory pathway of the vagus nerve may attenuate the development of systemic inflamma- tion-induced neuroinflammation.
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2.3. The vagus nerve and neuronal plasticity
Stroke results in damage to neuronal networks and consequent impairment of neuronal processes. Experimental studies indicate that there is a time-limited window of neuroplasticity following stroke, duringwhich the greatest gains in recovery occurs. These neuroplastic mechanisms include activity-depending rewiring, the strengthening of synapses, and production of new neurons (Murphy and Corbett, 2009).
Neuroplastic processes are influenced by afferent pathways of the vagus nerve. It has been found that acute VNS increases the expression of brain-derived neurotrophic factor and fibroblast growth factor in the hippocampus and cerebral cortex of rats. Moreover, it was found that 2 days of VNS induces an increase in the number of available progenitor cells in the adult rat dentate gyrus. These studies demonstrate that in the rat brain, VNS triggers molecular and cellular neurotrophic processes (Follesa et al., 2007; Revesz et al., 2008).
3. The vagus nerve and stroke: evidences
The role of transmission of signals through efferent and afferent pathways of the vagus nerve in stroke has been shown by experiments investigating the effect of chemical activation of the cholinergic anti-inflammatory pathway or electrical stimulation of the vagus nerve in animal models.
3.1. The role of efferent vagal pathways
It is suggested that heart rate variability indirectly reflects the activity of cholinergic anti-inflammatory pathway of the vagus nerve (Tracey, 2007). Reduced heart rate variability in patients with ischemic stroke has been found to be associated with unfavorable functional outcomes (Bassi et al., 2007). Therefore, it can be inferred that reduced activity of the cholinergic anti-inflammatory pathway may negatively influence the extent of brain lesion in ischemic stroke patients.
Activity of cholinergic anti-inflammatory pathway is regulated at the central level also bymelanocortins-synthesizing neurons (Giuliani et al., 2009). Animal and human studies have shown that melano- cortins have protective effects against brain damage following ischemic stroke. In support of this, administration of melanocortin improved functional recovery in animal stroke model. Melanocortin also increased production of the anti-inflammatory cytokine IL-10. Moreover, low plasma levels of IL-10 are associated with early worsening of neurological symptoms in patients with acute ischemic stroke. Furthermore, acute traumatic brain injury patients with very low plasma levels of α-melanocyte stimulating hormone have an unfavorable outcome compared to patients with higher plasma levels of α-melanocyte stimulating hormone. The role of vagal pathways in melanocortin's protective effects has also been demonstrated via an experiment in which bilateral vagotomy or administration of nicotine receptor antagonists blunted the protective effect of melanocortins on stroke induced by microinjection of intrastriatal endothelin-1 in rats. These findings indicate that during ischemic stroke, endogenous melanocortins could be involved in both neuroprotection and protection against the systemic effects of stroke, most likely through the activation of cholinergic anti-inflammatory pathway of the vagus nerve (Ottani et al., 2009).
VNS initiated 30 min after the induction of focal cerebral ischemia in rats reduces ischemic lesion volume (Ay et al., 2009). Intracer- ebroventricular administration of muscarine (an activator of efferent vagal pathways) following induction of intracerebrovascular hemor- rhage by collagenase injection in rats improved neurological out- comes, reduced brain water content, and decreased levels of inflammatory mediators in the brain as well as in the spleen. These findings clearly suggest that VNS and pharmacological activation of
the cholinergic anti-inflammatory pathway of the vagus nerve offer protection against acute ischemic brain injury and counteracts the inflammatory response following hemorrhagic stroke. However, central administration of muscarine was ineffective at reducing cerebral edema in splenectomised rats, suggesting that the spleen plays a crucial role in these processes (Ay et al., 2009; Lee et al., 2010). Moreover, several experiments have demonstrated that the spleen is a significant promoter of cerebral inflammation. For example, cerebral ischemia results in significant increases of pro-inflammatory mediators in the spleen (Offner et al., 2006) and splenectomy results in decreased number of activated microglia, macrophages, and neutrophils in brain tissue (Ajmo et al., 2008). Therefore the spleen may represent an important target for anti-inflammatory intervention in stroke (Lee et al., 2010).
3.2. The role of afferent vagal pathways
Besides its peripheral anti-inflammatory effects, the vagus nerve may also influence stroke progression via modulation of brain noradrenergic neuronal activity. It is suggested that norepinephrine exerts tonic anti-inflammatory action in brain tissue and therefore plays an endogenous neuroprotective role in brain diseases where inflammatory events contribute to pathological changes. This as- sumption is supported by the suppressive effect of norepinephrine reuptake inhibitors on chemokine and cell adhesion molecule expression in rat brain following a systemic challenge with lipopoly- saccharide (O'Sullivan et al., 2010). Moreover, it has been shown that norepinephrine-synthesizing neurons play a role in recovery from a variety of experimental models of brain injury. For example, administration of amphetamine or norepinephrine reuptake inhibi- tors has been demonstrated to improve function in animal models of stroke and in stroke patients (Barbay and Nudo, 2009; Liepert, 2008).
The involvement of vagal efferent and afferent pathways in the regulation of peripheral and central inflammation and in the modulation of processes related to neuroplasticity may elucidate the role of the vagus nerve in the initiation and progression of stroke, and lead to the introduction of new therapeutic approaches for treatment.
The role of the vagus nerve in stroke may be seen from two points of view: 1) Decreased anti-inflammatory effect mediated by the vagus nerve may by accompanied by an increase in the pro-inflammatory status of an organism. Therefore, decreased activity of the efferent pathways of the vagus nerve may represent a risk factor contributing to the initiation of stroke. 2) The stroke itself may alter vagal immunoregulatory functions that may consequently lead to augmen- tation of inflammatory reactions in the periphery as well as the brain. This assumption is supported by findings that stroke is often accompanied by signs of a systemic inflammatory response syndrome that worsens patient outcome (Catania et al., 2009; Chamorro et al., 2007).
Initiation and progression of stroke is modulated by a variety of molecular processes activated by brain ischemia or hemorrhage. There is growing evidence that central and peripheral inflammation, whether prestroke or stroke-induced, significantly influences stroke outcomes. Therefore, new therapeutic strategies targeting inflamma- tory processes will need to be developed (Gutierrez et al., 2009; Kleinig and Vink, 2009; Zheng et al., 2003). Activation of the vagal anti-inflammatory pathway and the consequent reduction of periph- eral as well as central inflammation may represent a new therapeutic tool for the treatment of stroke. The cholinergic anti-inflammatory pathway can be activated by invasive (e.g. electrical vagal nerve stimulation) and non-invasive methods (e.g. chemical and mechan- ical stimulation). Acute vagal stimulation in patients with stroke can by performed by either chemical or mechanical methods. Activity of
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efferent vagal pathways can be increased by administration of ACTH, ghrelin, leptin, and by ingestion of polyunsaturated fatty acids (Guarini et al., 2004; Luyer et al., 2005). It is also known that heart rate variability may reflect activity of the cholinergic anti- inflammatory pathway. Therefore, it can be suggested that the anti- inflammatory effect of the vagus nerve can also be induced by the administration of certain drugs known to increase heart rate variability. These drugs may include centrally acting α2-adrenergic receptors agonists, sartans, as well as statins (Chern et al., 2006; Ozdemir et al., 2007; Pehlivanidis et al., 2001; Szramka et al., 2007; Ulloa and Deitch, 2009; Vrtovec et al., 2005). Statins are an especially interesting group of drugs known for their pleiotropic effects, including a reduction of the risk for stroke (Rodriguez-Yanez et al., 2008). It is suggested that statin therapy might restore or preserve parasympathetic tone and thereby reduce immune response to inflammation via the cholinergic anti-inflammatory pathway (Wer- dan et al., 2009). The cholinergic anti-inflammatory pathway might also be activated by mechanical transcutaneous massage (Bauhofer and Torossian, 2007), which may represent a simple method for acute stimulation of the vagus nerve.
Restorative cell-based therapeutic strategies used in experimental stroke models substantially improve functional outcome (Burns et al., 2009; Zhang and Chopp, 2009). Stimulation of the vagus nerve may through inhibition of peripheral and central inflammation, induction of trophic processes, and modulation of locus coeruleus activity (Follesa et al., 2007; Naqui et al., 1999; Tracey, 2007) influence the migration and vitality of administered therapeutic cells and therefore can potentiate cell-based, therapeutic outcomes.
This work was supported by the European Regional Development Fund Research and Development Grant ITMS No. 26240120015, Slovak Research and Development Agency under the contract No. APVV-0045-06, and VEGA grants (1/0258/10 and 2/0010/09).
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