Abstract
BackgroundStroke remains a leading cause of death and disability worldwide despite recent treatment breakthroughs. A primary event in stroke pathogenesis is the development of a potent and deleterious local and peripheral inflammatory response regulated by the pro-inflammatory cytokine interleukin-1 (IL-1). While the role of IL-1β (main released isoform) has been well studied in stroke, the role of the IL-1α isoform remains largely unknown. With increasing utilization of intravenous tissue plasminogen activator (t-PA) or thrombectomy to pharmacologically or mechanically remove ischemic stroke causing blood clots, respectively, there is interest in pairing successful cerebrovascular recanalization with neurotherapeutic pharmacological interventions (Fraser et al., J Cereb Blood Flow Metab 37:3531–3543, 2017; Hill et al., Lancet Neurol 11:942–950, 2012; Amaro et al., Stroke 47:2874–2876, 2016).MethodsTransient stroke was induced in mice via one of two methods. One group of mice were subjected to tandem ipsilateral common carotid artery and middle cerebral artery occlusion, while another group underwent the filament-based middle cerebral artery occlusion. We have recently developed an animal model of intra-arterial (IA) drug administration after recanalization (Maniskas et al., J Neurosci Met 240:22–27, 2015). Sub groups of the mice were treated with either saline or Il-1α, wherein the drug was administered either acutely (immediately after surgery) or subacutely (on the third day after stroke). This was followed by behavioral and histological analyses.ResultsWe now show in the above-mentioned mouse stroke models (transient tandem ipsilateral common carotid artery (CCA) and middle cerebral artery occlusion (MCA) occlusion, MCA suture occlusion) that IL-1α is neuroprotective when acutely given either intravenously (IV) or IA at low sub-pathologic doses. Furthermore, while IV administration induces transient hemodynamic side effects without affecting systemic markers of inflammation, IA delivery further improves overall outcomes while eliminating these side effects. Additionally, we show that delayed/subacute IV IL-1α administration ameliorates functional deficit and promotes neurorepair.ConclusionsTaken together, our present study suggests for the first time that IL-1α could, unexpectedly, be an effective ischemic stroke therapy with a broad therapeutic window.
Highlights
Stroke remains a leading cause of death and disability worldwide despite recent treatment breakthroughs
Interleukin-1 alpha isoform (IL-1α) is directly protective of primary cortical neurons after oxygenglucose deprivation (OGD) and NMDA toxicity in vitro As a proof of concept, we first investigated whether IL1α could impart protection to neurons undergoing the in vitro stroke analogue oxygen glucose deprivation
After clearly demonstrating that OGD decreased cell viability in the absence of IL-1α, we found that IL-1α significantly increased the cell viability after OGD (OGD vehicle: 57.20 ± 2.05% viability vs. 1 ng/mL IL-1α: 83.45 ± 0.98%, p < 0.0001) (Fig. 1a)
Summary
Stroke remains a leading cause of death and disability worldwide despite recent treatment breakthroughs. Post-stroke inflammation is characterized by the expression of inflammatory mediators via activated immune cells within the core of the infarct (in the brain parenchyma), such as microglia and astrocytes [36, 40, 48]. This leads to an activation of surrounding cerebrovasculature, and a subsequent opening of the bloodbrain barrier (BBB) resulting in edema and widespread secondary damage by peripheral immune cells [40]. While many preclinical and clinical trials have examined the use of anti-inflammatory therapeutics [46], attempts at targeting post-stroke inflammation have failed to significantly improve patient prognosis [12, 15]
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