Abstract
BackgroundTumor necrosis factor, which exists both as a soluble (solTNF) and a transmembrane (tmTNF) protein, plays an important role in post-stroke inflammation. The objective of the present study was to test the effect of topical versus intracerebroventricular administration of XPro1595 (a solTNF inhibitor) and etanercept (a solTNF and tmTNF inhibitor) compared to saline on output measures such as infarct volume and post-stroke inflammation in mice.MethodsAdult male C57BL/6 mice were treated topically (2.5 mg/ml/1μl/h for 3 consecutive days) or intracerebroventricularly (1.25 mg/kg/0.5 ml, once) with saline, XPro1595, or etanercept immediately after permanent middle cerebral artery occlusion (pMCAO). Mice were allowed to survive 1 or 3 days. Infarct volume, microglial and leukocyte profiles, and inflammatory markers were evaluated.ResultsWe found that topical, and not intracerebroventricular, administration of XPro1595 reduced infarct volume at both 1 and 3 days after pMCAO. Etanercept showed no effect. We observed no changes in microglial or leukocyte populations. XPro1595 increased gene expression of P2ry12 at 1 day and Trem2 at 1 and 3 days, while decreasing Cx3cr1 expression at 1 and 3 days after pMCAO, suggesting a change in microglial activation toward a phagocytic phenotype.ConclusionOur data demonstrate that topical administration of XPro1595 for 3 consecutive days decreases infarct volumes after ischemic stroke, while modifying microglial activation and the inflammatory response post-stroke. This suggests that inhibitors of solTNF hold great promise for future neuroprotective treatment in ischemic stroke.
Highlights
Inflammatory events after ischemic stroke contribute to secondary injury mechanisms that can expand tissue injury and are targets of new treatment options (Lambertsen et al, 2018)
We have previously shown that using etanercept and XPro1595 for systemic inhibition of Tumor necrosis factor (TNF) improved functional outcome and affected the inflammatory response after permanent middle cerebral artery occlusion (pMCAO) in mice, but with no effect on infarct volume (Clausen et al, 2014)
Infarct volumes were estimated in Toluidine blue-stained brain sections from mice treated topically or i.c.v. with saline, XPro1595, or etanercept and allowed to survive 1 or 3 days after pMCAO (Figure 1 and Supplementary Figure 1A)
Summary
Inflammatory events after ischemic stroke contribute to secondary injury mechanisms that can expand tissue injury and are targets of new treatment options (Lambertsen et al, 2018). Tumor necrosis factor (TNF) is a multifunctional, proinflammatory cytokine that participates in all phases of ischemic stroke, from development to repair and long-term inflammatory effects (reviewed in Hallenbeck, 2002). It exists both as a transmembrane (tmTNF) and a soluble (solTNF) protein, the latter released via proteolytic cleavage by TNFα converting enzyme (TACE, called ADAM17) (Black et al, 1997). TNF plays an important role in infarct development (Lambertsen et al, 2018). Tumor necrosis factor, which exists both as a soluble (solTNF) and a transmembrane (tmTNF) protein, plays an important role in post-stroke inflammation. The objective of the present study was to test the effect of topical versus intracerebroventricular administration of XPro1595 (a solTNF inhibitor) and etanercept (a solTNF and tmTNF inhibitor) compared to saline on output measures such as infarct volume and post-stroke inflammation in mice
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