Protective Effects of Interleukin‐1 Inhibition With Anakinra in Mouse Models of Ischemic Stroke With and Without Reperfusion
Nerea Chaparro‐Cabanillas, Alicia Aliena‐Valero, Jordi Pedragosa, Leire Pedrosa, Milagros Honores, Mercè Rossinyol‐Boladeres, Juan B. Salom, Ángel Chamorro, Juan I. Aróstegui, Xabier Urra, Carles Justicia, Anna M. Planas
Abstract
BACKGROUND: Severe brain ischemia is associated with life-threatening edema and inflammation. Interleukin-1 is a crucial mediator of inflammation, and its blockade showed benefits in experimental stroke. We studied anakinra, a modified recombinant human interleukin-1 receptor antagonist, in mouse models of moderate to severe ischemia/reperfusion and large hemispheric infarctions. Due to anakinra's short half-life, we used a novel subcutaneous infusion protocol and tested 2 drug doses. METHODS AND RESULTS: We performed transient or permanent intraluminal middle cerebral artery occlusion (MCAo) in male C57BL/6J and Balb/c mice, the latter of which have poorer collaterals. Mice received a subcutaneous anakinra bolus (24 mg/kg), followed by continuous infusion of either 24 or 120 mg/kg per day, starting at reperfusion or 15 minutes after permanent MCAo. We evaluated acute (24 hours/48 hours) infarct volume and edema by magnetic resonance imaging, neurological function, and inflammatory responses. The mortality rate tended to be higher in Balb/c compared with C57BL/6J mice. In both strains, prolonged ischemia expanded the infarct size, with intraluminal permanent MCAo resulting in larger hemispheric infarctions and edema than transient MCAo. The high dose of anakinra reduced infarct volume and inflammation in C57BL/6 mice and improved the functional deficits in Balb/c mice following transient MCAo. It also showed a trend toward reducing infarction and edema after permanent MCAo in C57BL/6 mice. CONCLUSIONS: The study demonstrates that a high dose of anakinra improves outcomes in mouse models of moderate infarction following ischemia/reperfusion, whereas its effect was less pronounced in a malignant hemispheric infarction model without reperfusion, where only a nonsignificant trend toward protection was observed.