Abstract
BackgroundNeuroinflammation evolves as a multi-facetted response to focal cerebral ischemia. It involves activation of resident glia cell populations, recruitment of blood-derived leucocytes as well as humoral responses. Among these processes, phagocyte accumulation has been suggested to be a surrogate marker of neuroinflammation. We previously assessed phagocyte accumulation in human stroke by MRI. We hypothesize that phagocyte accumulation in the macrosphere model may resemble the temporal and spatial patterns observed in human stroke.MethodsIn a rat model of permanent focal ischemia by embolisation of TiO2-spheres we assessed key features of post-ischemic neuroinflammation by the means of histology, immunocytochemistry of glial activation and influx of hematogeneous cells, and quantitative PCR of TNF-α, IL-1, IL-18, and iNOS mRNA.ResultsIn the boundary zone of the infarct, a transition of ramified microglia into ameboid phagocytic microglia was accompanied by an up-regulation of MHC class II on the cells after 3 days. By day 7, a hypercellular infiltrate consisting of activated microglia and phagocytic cells formed a thick rim around the ischemic infarct core. Interestingly, in the ischemic core microglia could only be observed at day 7. TNF-α was induced rapidly within hours, IL-1β and iNOS peaked within days, and IL-18 later at around 1 week after ischemia.ConclusionsThe macrosphere model closely resembles the characteristical dynamics of postischemic inflammation previously observed in human stroke. We therefore suggest that the macrosphere model is highly appropriate for studying the pathophysiology of stroke in a translational approach from rodent to human.
Highlights
Neuroinflammation evolves as a multi-facetted response to focal cerebral ischemia
Starting with the first in vivo visualization of peripheral benzodiazepine receptor-expressing inflammatory cells using Positron Emission Tomography (PET) and the radiotracer [11C]PK11195 [8], postischemic inflammation has been repeatedly characterized by PET [8,9,10,11], magnetic resonance imaging (MRI) [12], and cell specific contrast agents detected by MRI [13,14,15]
Characterization of the macrosphere model Four TiO2 spheres were injected into the internal carotid artery (ICA) after ligation of the pterygopalatine artery, leading to a permanent occlusion within the ICA/middle cerebral artery (MCA) vessel arborisation
Summary
Neuroinflammation evolves as a multi-facetted response to focal cerebral ischemia It involves activation of resident glia cell populations, recruitment of blood-derived leucocytes as well as humoral responses. Among these processes, phagocyte accumulation has been suggested to be a surrogate marker of neuroinflammation. Animal research has characterized postischemic inflammation as a multi-facetted response involving activation of resident glia cells and recruitment of bloodderived leucocytes as well as cascades of humoral. In the classical tMCAO model, tissue damage and glia activation evolve in complex spatial and temporal dynamics that make it difficult to interpret the results and to translate them into the human situation [16,17]. We searched for an experimental stroke model with particular regard to the dynamics of postischemic inflammation that resembles the human situation
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