TARGETING NEUROINFLAMMATION: A DOUBLE-EDGED SWORD FOR STROKE THERAPY

An early inflammatory signalling is activated in the brain within hours from the ischemic insult, consisting in release of cytokines (e.g., IL-1beta) and chemokines from distinct cells. These soluble mediators promote expression of adhesion molecules on endothelial cells facilitating the adhesion and transendothelial migration of circulating neutrophils and monocytes. Infiltrating leukocytes participate to the evolution of ischemic brain damage by releasing pro-inflammatory mediators. Matrix metalloproteinases (MMPs) exert an early detrimental effect by cleaving protein components of the extracellular matrix and by processing cell surface and soluble proteins including IL-1beta; whereas, during the late repair phases, MMPs promote release of growth factors that contribute to neurovascular regeneration. Neuroprotective cytokines (e.g. IL-6), growth factors and hormones (e.g., estradiol, leptin) signal through STAT-3, a transcription factor subjected to a time- and region-specific phosphorylation during stroke. Its early activation in penumbra astrocytes may promote neuronal survival, whereas its late activation in microglia/macrophages may contribute to a detrimental neuroinflammatory response by inducing expression of IL-1beta and TNF-alfa. Being involved in all stages of the ischemic cascade, from the early damaging events triggered by arterial occlusion to the late regenerative processes, the neuroinflammatory response should be targeted in a time- and mechanism-specific way for the development of novel effective therapeutics.