Interleukin-1 Receptor Antagonist in Animal Models of Stroke: A Fair Summing Up?

Parry‐Jones, Adrian; Boutin, Hervé; McColl, Barry W.; Hopkins, Stephen; Allan, Stuart M.; Tyrrell, Pippa J.

doi:10.1016/j.jstrokecerebrovasdis.2010.01.005

Cited by 4 publications

(5 citation statements)

References 9 publications

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“…This finding is partly in contradiction with a more recent study [33] which showed no effect of minocycline on [ 11 C]-(R)-PK11195 uptake nor infarct size, although it must be noted that this study used a model of permanent stroke by microembolism rather than a temporary MCAO model [26]. These two studies suggest that the overall inhibition of microglial proliferation might not be the best strategy when compared to other approaches targeting specific cytokines [34][35][36][37][38][39][40], at least in the context of stroke. However, the study by Martin et al [28], together with the clinical study by Dodel et al [41], still support the use of TSPO PET imaging as a valid biomarker of microglial proliferation and/or activation for therapeutic read-out.…”

Section: Transient Ischemiacontrasting

confidence: 82%

TSPO imaging in stroke: from animal models to human subjects

Boutin

Pinborg

2015

Clin Transl Imaging

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Stroke is a major health problem in developed countries and neuroinflammation has emerged over the last 2 decades as major contributor to the pathophysiological processes of brain damage following stroke. PET imaging of the translocator 18kDa protein (TSPO) provides a unique non-invasive point of access to neuroinflammatory processes and more specifically microglial and astrocytic reaction after stroke in both animal models and patients. Here we are reviewing both the experimental and clinical literature about in vivo TSPO PET and SPECT imaging in stroke. The studies in animal models of stroke reviewed here highlight a slightly faster time-course for TSPO expression in permanent vs. temporary stroke and a stronger activation in the infarct core in temporary stroke vs. a stronger activation in peri-infarct areas in permanent stroke. Altogether these findings suggest that areas where neuroinflammatory events occur post-stroke are at higher risk of secondary damage. The time-course of TSPO expression is slower in humans versus animal models of stroke. In human studies the TSPO expression in the peri-infarct areas peaks 3-4 weeks after stroke and increased TSPO expression is demonstrated for months after the stroke in remote areas both ipsilesional to pyramidal tracts damage and in the contralesional hemisphere. Further clinical studies are warranted to address the role of TSPO and neuroinflammation in functional recovery and reorganisation after stroke and the possible therapeutic implications. TSPO imaging appears to be a valid biomarker for demonstrating the dynamic process of neuroinflammation in stroke. But it is also clear that as the processes of microglial activation are increasingly complex, the need for new biomarkers and tracers targeting other aspect of glial reaction are needed to further investigate neuroinflammatory processes in patients.

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Section: Transient Ischemiacontrasting

confidence: 82%

TSPO imaging in stroke: from animal models to human subjects

Boutin

Pinborg

2015

Clin Transl Imaging

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“…IL-1Ra has the advantages of specificity, absence of safety concerns in patients and extensive pre-clinical studies [4,101,102]. In a small phase 2 clinical study of stroke, IL-1Ra was safe.…”

Section: Il-1ra: Meeting the Stair Criteriamentioning

confidence: 99%

“…Despite concerns about certain interpretations made in this article [4], as the quality of experiment was deemed to have increased, so did the efficacy of IL-1Ra. Therefore, IL-1 appears to be a very promising target for stroke.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-1 and Stroke: Biomarker, Harbinger of Damage, and Therapeutic Target

Pinteaux¹,

Rothwell²,

Allan³

2011

Cerebrovasc Dis

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104

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Inflammation is established as a contributor to cerebrovascular disease. Risk factors for stroke include many conditions associated with chronic or acute inflammation, and inflammatory changes in the brain after cerebrovascular events contribute to outcome in experimental studies, with growing evidence from clinical research. The brain is extremely susceptible to inflammatory challenge, but resident glia, endothelial cells and neurones can all mount a pronounced inflammatory response to infection or injury. Recent discoveries highlight the importance of peripherally-derived immune cells and inflammatory molecules in various central nervous system disorders, including stroke. The inflammatory cytokine, interleukin-1 (IL-1), plays a pivotal role in both local and systemic inflammation, and is a key driver of peripheral and central immune responses to infection or injury. Inhibition of IL-1 has beneficial effects in a variety of experimental paradigms of acute brain injury and is a promising clinical target in stroke. We propose that blockade of IL-1 could be therapeutically useful in several diseases which are risk factors for stroke, and there is already considerable pre-clinical and clinical evidence that inhibition of IL-1 by IL-1 receptor antagonist may be valuable in the management of acute stroke.

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“…That publication led to a letter [12] to the journal editor raising concerns about the utility of an aggregate quality “score” and about the importance attached in our review to the demonstration of efficacy in animals with co-morbidities. Subsequently, we have focussed in our systematic reviews on the prevalence of individual risk of bias items rather than calculating an overall score, but a lower efficacy in animals with co-morbidities has been demonstrated for a number of candidate neuroprotective drugs [5, 13].…”

Section: Introductionmentioning

confidence: 99%

Systematic Review and Meta-Analysis of the Efficacy of Interleukin-1 Receptor Antagonist in Animal Models of Stroke: an Update

McCann

Cramond

Macleod

et al. 2016

Transl. Stroke Res.

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Summary/AbstractInterleukin-1 receptor antagonist (IL-1 RA) is an anti-inflammatory protein used clinically to treat rheumatoid arthritis and is considered a promising candidate therapy for stroke. Here, we sought to update the existing systematic review and meta-analysis of IL-1 RA in models of ischaemic stroke, published in 2009, to assess efficacy, the range of circumstances in which efficacy has been tested and whether the data appear to be confounded due to reported study quality and publication bias. We included 25 sources of data, 11 of which were additional to the original review. Overall, IL-1 RA reduced infarct volume by 36.2 % (95 % confidence interval 31.6–40.7, n = 76 comparisons from 1283 animals). Assessments for publication bias suggest 30 theoretically missing studies which reduce efficacy to 21.9 % (17.3–26.4). Efficacy was higher where IL-1 RA was administered directly into the ventricles rather than peripherally, and studies not reporting allocation concealment during the induction of ischaemia reported larger treatment effects. The preclinical data supporting IL-1 RA as a candidate therapy for ischaemic stroke have improved. The reporting of measures to reduce the risk of bias has improved substantially in this update, and studies now include the use of animals with relevant co-morbidities.Electronic supplementary materialThe online version of this article (doi:10.1007/s12975-016-0489-z) contains supplementary material, which is available to authorized users.

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Interleukin-1 Receptor Antagonist in Animal Models of Stroke: A Fair Summing Up?

Cited by 4 publications

References 9 publications

TSPO imaging in stroke: from animal models to human subjects

TSPO imaging in stroke: from animal models to human subjects

Interleukin-1 and Stroke: Biomarker, Harbinger of Damage, and Therapeutic Target

Systematic Review and Meta-Analysis of the Efficacy of Interleukin-1 Receptor Antagonist in Animal Models of Stroke: an Update

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