The Role of Neurogenic Inflammation in Blood-Brain Barrier Disruption and Development of Cerebral Oedema Following Acute Central Nervous System (CNS) Injury (original) (raw)
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Inhibition of neurogenic inflammation as a novel treatment for ischemic stroke
Drug News & Perspectives, 2007
Each year, 15 million people suffer a stroke, of which 5 million die and 5 million are left permanently disabled. Cerebral swelling is of particular concern following stroke as it accounts for much of the death and disability. However, the mechanisms leading to cerebral swelling are not yet fully understood. Recent studies from our laboratory suggest that neuropeptides, and specifically substance P, may be involved in the injury processes that occur following acute insults to the brain such as stroke and trauma, and may be responsible, in part, for oedema formation. Levels of substance P are increased following CNS injury, indicative of neurogenic inflammation, and this is associated with injury to the blood brain barrier, the development of cerebral oedema, cell death and functional deficits. Subsequent studies inhibiting neuropeptide release have consistently shown decreased cerebral oedema and improved neurological outcome. While substance P antagonists administered after the insult are efficacious in reducing post-stroke cerebral oedema and neurological deficits. The current review summarises the evidence supporting the benefits of inhibiting neurogenic inflammation to treat ischaemic stroke.
Inflammation in acute CNS injury: a focus on the role of substance P
British journal of pharmacology, 2015
Recently, a number of reports have shown that neurogenic inflammation may play a role in the secondary injury response following acute injury to the central nervous system (CNS), including traumatic brain injury (TBI) and stroke. In particular substance P (SP) release appears to be critically involved. Specifically, expression of the neuropeptide SP is increased in acute CNS injury, with the magnitude of SP release being related to both the frequency and magnitude of the insult. SP release is associated with an increase in blood-brain barrier permeability and the development of vasogenic oedema as well as neuronal injury and worsened functional outcome. Moreover, inhibiting the actions of SP through use of a NK1 antagonist is highly beneficial in both focal and diffuse models of TBI, as well as in ischaemic stroke, with a therapeutic window of up to 12h. We propose that NK1 antagonists represent a novel therapeutic option for treatment of neurogenic inflammation following acute CNS ...
Journal of Cerebral Blood Flow & Metabolism, 2009
Brain edema and swelling is a critical factor in the high mortality and morbidity associated with traumatic brain injury (TBI). Despite this, the mechanisms associated with its development are poorly understood and interventions have not changed in over 30 years. Although neuropeptides and neurogenic inflammation have been implicated in peripheral edema formation, their role in the development of central nervous system edema after brain trauma has not been investigated. This study examines the role of the neuropeptide, substance P (SP), in the development of edema and functional deficits after brain trauma in rats. After severe diffuse TBI in adult male rats, neuronal and perivascular SP immunoreactivity were increased markedly. Perivascular SP colocalized with exogenously administered Evans blue, supporting a role for SP in vascular permeability. Inhibition of SP action by administration of the neurokinin-1 (NK 1 ) antagonist, N-acetyl-L-tryptophan, at 30 mins after trauma attenuated vascular permeability and edema formation. Administration of the NK 1 antagonist also improved both motor and cognitive neurologic outcomes. These findings suggest that SP release is integrally linked to the increased vascular permeability and edema formation after brain trauma, and that treatment with an NK 1 receptor antagonist reduces edema and improves neurologic outcome.
Inflammatory Mechanisms as Potential Therapeutic Targets in Stroke
Abstract. Stroke is an important public health issue due to high rates of disability, morbidity/mortality and is now the third leading cause of death after heart disease and cancer affecting 15 million people worldwide each year. In spite of extensive research in the field of stroke during past decade the current therapeutic strategies have been largely unsuccessful. One possible explanation is that research and pharmacological management have focused on very early events in brain ischemia. Two important pathophysiological mechanisms involved during ischemic stroke are oxidative stress and inflammation. Brain tissue is not well equipped with antioxidant defenses, so reactive oxygen species and other free radicals/oxidants, released by inflammatory cells, threaten tissue viability in the vicinity of the ischemic core. Recent studies have shown that brain ischemia and trauma elicit strong inflammatory reactions driven by both external and brain cells. Clinical observations suggest that patients with stroke have higher plasma levels of inflammatory cytokines or soluble adhesion molecules and anti-inflammatory therapy is effective at reducing stroke incidence in not only animal models, but in humans as well. This suggests that inflammation might directly affect the onset of stroke. The recognition of inflammation as a fundamental response to brain ischemia provides novel opportunities for new anti-inflammatory therapies. Currently, little is known about endogenous counter regulatory immune mechanisms. Statins have been shown to decrease the stroke incidence via anti-inflammatory effects that are both dependent and independent of their cholesterol-lowering effects. Here in this review we will discuss the molecular aspects of oxidative stress and inflammation in ischemic stroke. We will also present the latest findings about the cellular and humoral aspects of immune and inflammatory reactions in the brain. This will increase our understanding regarding neuro-injuries and role immune reactions play in the brain milieu. This all may have an impact on the potential therapeutic strategies that target neuro-inflammation and the innate immune system.
Characterizing the role of the neuropeptide substance P in experimental subarachnoid hemorrhage
Brain Research, 2011
Background: Raised intracranial pressure (ICP) following SAH predicts poor outcome and is due to hemorrhage volume and possibly, brain edema, hydrocephalus and increased volume of circulating intracranial blood. Interventions that reduce edema may therefore reduce ICP and improve outcome. The neuropeptide substance P (SP) mediates vasogenic edema formation in animal models of ischemic stroke, intracerebral hemorrhage and brain trauma, and may contribute to development of increased ICP. SP (NK1 tachykinin receptor) blockade using n-acetyl-l-tryptophan (NAT) reduces edema and improves outcome in these models. This study therefore assessed whether SP mediates edema formation in experimental SAH. Methods: SAH was induced in rats by either injection of autologous blood into the prechiasmatic cistern (injection SAH) or by arterial puncture of the Circle of Willis (filament SAH). NAT was injected (i.v.) 30 min after SAH induction. Subgroups were assessed for brain water content, SP and albumin immunoreactivity, and functional outcome at 5, 24 and 48 h or ICP over 5 h. Results: A secondary ICP increase occurred within 2 h of SAH. Brain edema followed filament SAH (p < 0.001) and correlated with functional deficits (r = 0.8, p < 0.01). Increased albumin immunoreactivity (p < 0.001) indicated vasogenic edema. However, NAT treatment did not improve ICP, edema or outcome. Conclusions:
Post-ischemic brain damage: pathophysiology and role of inflammatory mediators
FEBS Journal, 2008
Stroke is a major cause of death and long-term disability worldwide and is associated with significant clinical and socioeconomical implications, emphasizing the need for effective therapies. In fact, current therapeutic approaches, including antiplatelet and thrombolytic drugs, only partially ameliorate the clinical outcome of stroke patients because such drugs are aimed at preserving or restoring cerebral blood flow rather than at preventing the actual mechanisms associated with neuronal cell death [1,2].
Substance P Antagonists as a Novel Intervention for Brain Edema and Raised Intracranial Pressure
Abstract Increased intracranial pressure (ICP) following acute brain injury requires the accumulation of additional water in the intracranial vault. One source of such water is the vasculature, although the mechanisms associated with control of blood–brain barrier permeability are unclear. We have recently shown that acute brain injury, such as neurotrauma and stroke, results in perivascular accumulation of the neuropeptide, substance P. This accumulation is associated with increased blood–brain barrier permeability and formation of vasogenic edema. Administration of a substance P antagonist targeting the tachykinin NK1 receptor profoundly reduced the increased blood–brain barrier permeability and edema formation, and in small animal models of acute brain injury, improved functional outcome. In a large, ovine model of experimental traumatic brain injury, trauma resulted in a significant increase in ICP. Administration of an NK1 antagonist caused a profound reduction in post-traumat...
Neuropeptides, 2004
The present study has used capsaicin-induced neuropeptide depletion to examine the role of neurogenic inflammation in the development of edema and functional deficits following traumatic brain injury (TBI). Adult, male rats were treated with capsaicin (neuropeptide-depleted) or equal volume vehicle (controls) 14 days prior to induction of moderate/severe diffuse TBI. Injury in vehicle treated control animals resulted in acute (4-5 h) edema formation, which was confirmed as being vasogenic in origin by diffusion weighted magnetic resonance imaging and the presence of increased permeability of the blood-brain barrier (BBB) to Evans blue dye. There was also a significant decline in brain magnesium concentration, as assessed by phosphorus magnetic resonance spectroscopy, and the development of profound motor and cognitive deficits. In contrast, capsaicin pre-treatment resulted in a significant reduction in post-traumatic edema formation (p < 0:001), BBB permeability (p < 0:001), free magnesium decline (p < 0:01) and both motor and cognitive deficits (p < 0:001). We conclude that neurogenic inflammation may play an integral role in the development of edema and functional deficits following TBI, and that neuropeptides may be a novel target for development of interventional pharmacological strategies.
Journal of Neuroinflammation, 2011
Background: Systemic inflammation impairs outcome in stroke patients and experimental animals via mechanisms which are poorly understood. Circulating inflammatory mediators can activate cerebrovascular endothelium or glial cells in the brain and impact on ischaemic brain injury. One of the most serious early clinical complications of cerebral ischaemia is brain oedema, which compromises survival in the first 24-48 h. It is not understood whether systemic inflammatory challenges impair outcome after stroke by increasing brain injury only or whether they have direct effects on brain oedema, cerebrovascular inflammation and blood-brain barrier damage. Methods: We used two different systemic inflammatory stimuli, acute endotoxin treatment and anaphylaxis to study mechanisms of brain injury after middle cerebral artery occlusion (MCAo). Ischaemic brain injury, blood-brain barrier damage and oedema were analysed by histological techniques. Systemic cytokine responses and inflammatory changes in the brain were analysed by cytometric bead array, immunofluorescence, in situ hibridization and quantitative real-time PCR. Results: Systemic inflammatory challenges profoundly impaired survival in the first 24 h after experimental stroke in mice, independently of an increase in infarct size. Systemic lipopolysaccharide (LPS) dose-dependently increased mortality (50-100%) minutes to hours after cerebral ischaemia. Acute anaphylactic challenge in ovalbuminsensitised mice affected stroke more seriously when induced via intraperitoneal administration compared to intravenous. Both LPS and anaphylaxis induced inflammatory changes in the blood and in the brain prior to experimental stroke. Plasma cytokine levels were significantly higher after LPS, while increased IL-10 levels were seen after anaphylaxis. After MCAo, both LPS and anaphylaxis increased microglial interleukin-1α (IL-1α) expression and blood-brain barrier breakdown. LPS caused marked granulocyte recruitment throughout the ipsilateral hemisphere. To investigate whether reduction of ischaemic damage can improve outcome in systemic inflammation, controlled hypothermia was performed. Hypothermia reduced infarct size in all treatment groups and moderately improved survival, but failed to reduce excess oedema formation after anaphylaxis and LPSinduced neuroinflammation. Conclusions: Our results suggest that systemic inflammatory conditions induce cerebrovascular inflammation via diverse mechanisms. Increased brain inflammation, blood-brain barrier injury and brain oedema formation can be major contributors to impaired outcome in mice after experimental stroke with systemic inflammatory stimuli, independently of infarct size.