Peripheral Administration of Interleukin-1 Receptor Antagonist Inhibits Brain Damage after Focal Cerebral Ischemia in the Rat

Relton, Jane K.; Martin, David; Thompson, R.C.; Russell, D A

doi:10.1006/exnr.1996.0059

Cited by 195 publications

(105 citation statements)

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“…However, most of these have administered IL-1RA intracerebroventicularly, where it can readily penetrate brain tissue. Some studies have shown efficacy of IL-1RA administered subcutaneously (Martin et al, 1994; Relton et al, 1996), but we believe this is the first report to describe the effects of intravenous administration of IL-1RA on neuronal injury in experimental animals. The reduction in ischaemic brain injury reported here (32%) is slightly less than that seen after intracerebroventicular injection, suggesting that brain penetration may be a limiting factor, or that a higher rate of infusion or bolus may be more effective.…”

Section: Discussionmentioning

confidence: 71%

“…These data suggest that IL-1RA may be beneficial in brain disorders associated with ischaemic or excitotoxic processes and brain trauma. Although brain penetration of IL-1RA might be expected to be limited, because of its size (17 kDa), several studies have reported that very high doses of IL-1RA, given subcutaneously, are neuroprotective in rodents (Martin et al, 1994;Relton et al, 1996), and an active transport mechanism into brain has been reported in rats (Gutierrez et al, 1994). The hypothesis underlying this study was that peripherally administered IL-1RA would enter the cerebrospinal fluid (CSF) to decrease the extent of ischaemic damage in rats subjected to stroke and would penetrate the CSF in patients with subarachnoid haemorrhage (SAH) at similar concentrations.…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-1 Receptor Antagonist Penetrates Human Brain at Experimentally Therapeutic Concentrations

Clark

McMahon

Gueorguieva

et al. 2007

J Cereb Blood Flow Metab

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The proinflammatory cytokine interleukin (IL)-1 mediates several forms of experimentally induced acute brain injury and has been implicated in chronic neurodegenerative disorders. The IL-1 receptor antagonist, IL-1RA, protects rodents against ischaemic brain injury, but its molecular mass (17 kDa) potentially limits the brain penetration of peripherally administered IL-1RA. We therefore sought to identify whether therapeutically effective concentrations of IL-1RA in the rat were also achieved in brain of patients with subarachnoid haemorrhage (SAH), using a peripheral administration regime that had proved to be safe and reduce peripheral inflammation in patients after stroke. An intravenous bolus of IL-1RA, followed by infusion, was administered to rats after induction of focal cerebral ischaemia. The effects of IL-1RA on brain ischaemia and the concentrations achieved in cerebrospinal fluid (CSF), were determined. Interleukin-1 receptor antagonist was similarly administered to patients with SAH, and CSF was sampled via external ventricular drains. In rats, IL-1RA significantly reduced brain injury induced by focal cerebral ischaemia. The plasma IL-1RA concentrations reached 1262 lg/mL by 30 mins, and CSF concentrations were maintained between 91 and 232 ng/mL between 1 and 24 h of infusion. In patients with SAH, IL-1RA reached a steady-state plasma concentration of 2264 lg/mL by 15 mins, and CSF concentrations were maintained at 78 to 558 ng/mL between 1 and 24 h. Intravenous delivery of IL-1RA leads to CSF concentrations in patients comparable to those that are neuroprotective in rats, and might therefore be of therapeutic benefit.

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Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Interleukin-1 Receptor Antagonist Penetrates Human Brain at Experimentally Therapeutic Concentrations

Clark

McMahon

Gueorguieva

et al. 2007

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…(Relton and Rothwell, 1992;Martin et al, 1994;Betz et al, 1995;Garcia et al, 1995;Toulmond and Rothwell, 1995;Yamasaki et al, 1995;Loddick and Rothwell, 1996;Relton et al, 1996;Friedlander et al, 1997;Boutin et al, 2001). However, the mechanism(s) by which this occurs are poorly understood.…”

Section: Discussionmentioning

confidence: 99%

System x_c⁻Activity and Astrocytes Are Necessary for Interleukin-1β-Mediated Hypoxic Neuronal Injury

Fogal¹,

Li²,

Lobner³

et al. 2007

J. Neurosci.

101

118

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“…Barone et al [9] demonstrated that blocking endogenous TNF signiWcantly reduced infarct size in rats with the permanent or transient middle cerebral artery occlusion. A role for IL-1 in the pathogenesis of ischemic brain damage is supported by increased infarction resulting from intracerebroventricular injection of this cytokine in rat brain and conversely, neuroprotective eVects of interleukin-1 receptor antagonist [88,114,141]. In addition, short-term treatments with the antimicrobial/antiinXammatory agent minocycline alone or in combination conferred neuroprotection in experimental stroke [3,137,142,143].…”

Section: Inxammatory Response After Stroke: a Dual Role?mentioning

confidence: 99%

Inflammation, plasticity and real-time imaging after cerebral ischemia

2009

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With an incidence of approximately 350 in 100,000, stroke is the third leading cause of death and a major cause of disability in industrialized countries. At present, although progress has been made in understanding the molecular pathways that lead to ischemic cell death, the current clinical treatments remain poorly eVective. There is mounting evidence that inXammation plays an important role in cerebral ischemia. Experimentally and clinically, brain response to ischemic injury is associated with an acute and prolonged inXammatory process characterized by the activation of resident glial cells, production of inXammatory cytokines as well as leukocyte and monocyte inWltration in the brain, events that may contribute to ischemic brain injury and aVect brain recovery and plasticity. However, whether the post-ischemic inXammatory response is deleterious or beneWcial to brain recovery is presently a matter of debate and controversies. Here, we summarize the current knowledge on the molecular mechanisms underlying post-ischemic neuronal plasticity and the potential role of inXammation in regenerative processes and functional recovery after stroke. Furthermore, because of the dynamic nature of the brain inXammatory response, we highlight the importance of the development of novel experimental approaches such as real-time imaging. Finally, we discuss the novel transgenic reporter mice models that have allowed us to visualize and to analyze the processes such as neuroinXammation and neuronal repair from the ischemic brains of live animals.

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Peripheral Administration of Interleukin-1 Receptor Antagonist Inhibits Brain Damage after Focal Cerebral Ischemia in the Rat

Cited by 195 publications

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Interleukin-1 Receptor Antagonist Penetrates Human Brain at Experimentally Therapeutic Concentrations

Interleukin-1 Receptor Antagonist Penetrates Human Brain at Experimentally Therapeutic Concentrations

System x_c⁻Activity and Astrocytes Are Necessary for Interleukin-1β-Mediated Hypoxic Neuronal Injury

Inflammation, plasticity and real-time imaging after cerebral ischemia

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Peripheral Administration of Interleukin-1 Receptor Antagonist Inhibits Brain Damage after Focal Cerebral Ischemia in the Rat

Cited by 195 publications

References 0 publications

Interleukin-1 Receptor Antagonist Penetrates Human Brain at Experimentally Therapeutic Concentrations

Interleukin-1 Receptor Antagonist Penetrates Human Brain at Experimentally Therapeutic Concentrations

System xc−Activity and Astrocytes Are Necessary for Interleukin-1β-Mediated Hypoxic Neuronal Injury

Inflammation, plasticity and real-time imaging after cerebral ischemia

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System x_c⁻Activity and Astrocytes Are Necessary for Interleukin-1β-Mediated Hypoxic Neuronal Injury