Therapeutic potential of anti-inflammatory drugs in focal stroke

Abstract

The importance of cytokines, especially TNF-alpha and IL-1beta, are emphasised in the propagation and maintenance of the brain inflammatory response to injury. Much data supports the case that ischaemia and trauma elicit an inflammatory response in the injured brain. This inflammatory response consists of mediators (cytokines, chemokines and adhesion molecules) followed by cells (neutrophils early after the onset of brain injury and then a later monocyte infiltration). De novo upregulation of pro-inflammatory cytokines, chemokines and endothelial-leukocyte adhesion molecules occurs soon after focal ischaemia and trauma, as well as at the time when the tissue injury is evolving. The significance of this brain inflammatory response and its contribution to brain injury is now becoming more understood. In this review, we discuss the role of TNF-alpha and IL-1beta in traumatic and ischaemic brain injury and associated inflammation and the co-operative actions of chemokines and adhesion molecules in this process. We also address novel approaches to target cytokines and reduce the brain inflammatory response and thus brain injury, in stroke and neurotrauma. The mitogen-activated protein kinase (MAPK), p38, has been linked to inflammatory cytokine production and cell death following cellular stress. Stroke-induced p38 enzyme activation in the brain has been demonstrated and treatment with a second generation p38 MAPK inhibitor, SB-239063, provides a significant reduction in infarct size, neurological deficits and inflammatory cytokine expression produced by focal stroke. SB-239063 can also provide direct protection of cultured brain tissue to in vitro ischaemia. This robust SB-239063-induced neuroprotection emphasises a significant opportunity for targeting MAPK pathways in ischaemic stroke injury and also suggests that p38 inhibition should be evaluated for protective effects in other experimental models of nervous system injury and neurodegeneration.