A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke

Maysami, Samaneh; Wong, Raymond; Pradillo, Jesús M.; Dénes, Ádám; Dhungana, Hiramani; Malm, Tarja; Koistinaho, Jari; Orset, Cyrille; Rahman, Mahbubur; Rubio, Marina; Schwaninger, Markus; Vivien, Denis; Bath, Philip M; Rothwell, Nancy J.; Allan, Stuart M.

doi:10.1177/0271678x15606714

Cited by 66 publications

(73 citation statements)

References 20 publications

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“…In a multicenter international project examining the short-and longterm efects of IL-1Ra therapy in preclinical models of AIS, consistent decreases in lesion size on days 1 and 7 were noted via histology and MRI after treatment with subcutaneous IL-1Ra [121]. Improvements in neurologic deicits/function ("sensorimotor asymmetry") for up to 28 days post-treatment were also noted in this study across AIS models [121].…”

Section: Inlammatory Il-1β In Aissupporting

confidence: 71%

“…A meta-analysis analyzing IL-1R antagonists in rodent models of stroke, reported an overall decrease in infarct volumes and an improvement in functional outcomes [241]. A recent cross-laboratory study of subcutaneous IL-1R antagonist treatment in AIS also found consistent decreases in neurologic deicits and lesion volume across preclinical models of AIS in multiple laboratories [121]. Pradillo et al demonstrated that post-AIS subcutaneous administration of IL-1Ra in old rats with comorbidities and in young rats increased neurogenesis and functional outcomes in both populations [242].…”

Section: Biological Response Modiiers In Tbi and Aismentioning

confidence: 95%

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Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

Dugue¹,

Nath²,

Dugue³

et al. 2017

Mechanisms of Neuroinflammation

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This chapter will introduce the reader to the pathophysiology of two devastating neurologic events, traumatic brain injury (TBI) and acute ischemic stroke (AIS). Here we focus on the role of key pro-inlammatory and anti-inlammatory cytokines. Several experimental interventions have been found to modulate cytokine production and brain injury after AIS or TBI. Here minocycline, biological response modiiers, hormonal therapies, omega-3 faty acids, N-acetylcysteine, and cannabinoids will be discussed. In addition, the role of cytokine-induced inlammasomes in both TBI and AIS will be addressed and followed by discussion of pro-inlammatory cytokines (e.g., TNF-α, IL-1β, IL-18, and IFN-γ). Finally, the main anti-inlammatory cytokines, IL-33, IL-10, IL-6, and IL-4, will be discussed in the context of both TBI and AIS. It should be noted that the role of these cytokines is diverse and the dichotomization of classically pro-versus anti-inlammatory cytokines is being re-examined, as many of these cytokines have been found to play dual roles in TBI and AIS brain injury.Keywords: traumatic brain injury, ischemic stroke, cytokines, interleukins, inlammasome Pathophysiology of traumatic brain injuryTraumatic brain injury (TBI) is a major cause of death and disability worldwide [1,2]. It is one of the most commonly diagnosed neurological disorders in the United States, impacting people of a variety of ages and segments of society [3]. In Europe, the economic cost of © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.TBI is over 33 billion euros per year [4]. Continued surveillance and research is being done to reduce primary and secondary TBI [as well as acute ischemic stroke(AIS)]-induced brain injury [1].The pathophysiology of TBI begins with the initial brain trauma (i.e., the primary injury). This primary injury results from mechanical damage that disrupts the blood-brain barrier (BBB), alters the vasculature and damages brain tissue. The resulting injured glia and neurons release their intracellular contents (i.e., damage-associated molecular paterns; (DAMPs)) into the extracellular space and activate neighboring glia and neurons. Activated glia and neurons then produce molecular signals that can both exacerbate and mend the acute injury and contribute to long-term recovery [5][6][7][8][9]. These downstream molecular and cellular processes (i.e., the secondary injury in TBI) are the focus of many pre-clinical and clinical therapeutic studies. Secondary injury in TBI involves a host of molecular and cellular responses to the The pathophysiology of AIS and TBI share common mechanisms. The initial insult in AIS, an occlusion of blood low resulting in a core infarct zone surrounded by a poorly perfused penumbra, versus the initial primary physical impact in TBI both result in pe...

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Section: Inlammatory Il-1β In Aissupporting

confidence: 71%

Section: Biological Response Modiiers In Tbi and Aismentioning

confidence: 95%

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

Dugue¹,

Nath²,

Dugue³

et al. 2017

Mechanisms of Neuroinflammation

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“…1 The efficacy of IL-1Ra in experimental middle cerebral artery occlusion (MCAO) has been reproduced in a cross-laboratory study using a range of outcome measures, including longer-term functional recovery. 4 A recently updated meta-analysis of pre-clinical stroke studies showed that IL-1Ra treatment reduced infarct volume by 36% in pooled data from 1283 animals. 5 We have reported previously that IV IL-1Ra administered over 72 h in a placebo-controlled phase 2 study of patients with acute stroke was safe and significantly reduced plasma inflammatory markers.…”

Section: Introductionmentioning

confidence: 99%

SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke)

Smith

Hulme

Vail

et al. 2018

Stroke

141

103

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F o r S t r o k Background and PurposeThe pro-inflammatory cytokine interleukin-1 (IL-1) has a deleterious role in cerebral ischemia, which is attenuated by IL-1 receptor antagonist (IL-1Ra). IL-1 induces peripheral inflammatory mediators, such as interleukin-6 (IL-6), which are associated with worse prognosis after ischemic stroke. We investigated whether subcutaneous (SC) IL-1Ra reduces the peripheral inflammatory response in acute ischemic stroke. MethodsSCIL-STROKE was a single-center, double-blind, randomized, placebo-controlled phase 2 trial of SC IL-1Ra (100mg administered twice daily for three days) in patients presenting within 5h of ischemic stroke onset. Randomization was stratified for baseline NIHSS score and thrombolysis. Measurement of plasma IL-6 and other peripheral inflammatory markers was undertaken at five time points. The primary outcome was difference in concentration of log(IL-6) as area under the curve to Day 3. Secondary outcomes included exploratory effect of IL-1Ra on three month outcome with the modified Rankin Scale (mRS). ResultsWe recruited 80 patients (mean age 72, median NIHSS 12) of whom 73% received intravenous thrombolysis with alteplase. IL-1Ra significantly reduced plasma and plasma C-reactive protein (p<0.001). IL-1Ra was well-tolerated with no safety concerns.Allocation to IL-1Ra was not associated with a favorable outcome on mRS: OR (95% CI) = 0.67 (0.29 to 1.52); p=0.34. Exploratory mediation analysis suggested that IL-1Ra improved clinical outcome by reducing inflammation, but there was a statistically significant, alternative mechanism countering this benefit. ConclusionsIL-1Ra reduced plasma inflammatory markers which are known to be associated with worse clinical outcome in ischemic stroke. SC IL-1Ra is safe and well-tolerated. Further 3

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“…First multicenter preclinical stroke studies have recently been published. [38][39][40] Translational stroke research is not broken, but in need of an overhaul. Its engine must be made more efficient; its results must be made more predictive.…”

Section: Overcoming the Roadblockmentioning

confidence: 99%

Thomas Willis Lecture

Dirnagl

2016

Stroke

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Abstract-Based on research, mainly in rodents, tremendous progress has been made in our basic understanding of the pathophysiology of stroke. After many failures, however, few scientists today deny that bench-to-bedside translation in stroke has a disappointing track record. I here summarize many measures to improve the predictiveness of preclinical stroke research, some of which are currently in various stages of implementation: We must reduce preventable (detrimental) attrition. Key measures for this revolve around improving preclinical study design. Internal validity must be improved by reducing bias; external validity will improve by including aged, comorbid rodents of both sexes in our modeling. False-positives and inflated effect sizes can be reduced by increasing statistical power, which necessitates increasing group sizes. Compliance to reporting guidelines and checklists needs to be enforced by journals and funders. Customizing study designs to exploratory and confirmatory studies will leverage the complementary strengths of both modes of investigation. All studies should publish their full data sets. On the other hand, we should embrace inevitable NULL results. This entails planning experiments in such a way that they produce high-quality evidence when NULL results are obtained and making these available to the community. A collaborative effort is needed to implement some of these recommendations. Just as in clinical medicine, multicenter approaches help to obtain sufficient group sizes and robust results. Translational stroke research is not broken, but its engine needs an overhauling to render more predictive results.

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A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke

Cited by 66 publications

References 20 publications

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke)

Thomas Willis Lecture

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