The Role of Chemokines in Brain Ischemia

Despite the fact that numerous chemokines or chemokine receptors have been implicated in the pathology of MS, a chemokinergic therapy is still not in sight. BX-471 is a selective CCRl antagonist and inhibits a number of CCRl-mediated effects including calcium mobilization and leukocyte migration [55]. BX-471 has been evaluated in various peripheral inflammatory disease conditions [56-58]. Although it has been found safe in Phase I clinical trials in MS, it failed to have an effect in Phase II studies [59]. 

Very early after ischemia neutrophils infiltrate the ischemic brain area. Neutrophil infiltration is later followed by blood macrophages, natural killer cells and Tcells [61]. 

Specific chemokines are induced during/after ischemia and their time-dependent induction seems in accordance with the temporal profile of infiltration of blood cells. It is likely that the expression of chemokines is induced by proinflammatory cytokines which are produced in the ischemic area. For example, TNF-a and IL-1(3 activate transcription factors such as nuclear factor xB [62] that regulate the transcription of chemokines indicating that these proinflammatory cytokines activate the production of chemokines. Indeed expression of CCL2 mRN A in monocytes and astrocytes is induced by cytokines like IL-1 3 and TNFa and TGFp [63-65]. Furthermore, expression of CXCLIO in the brain is induced by interferon-y [66] and presumably also by factors such as IL-1 3 and TNFa. Cytokines produced in the ischemic area may thus be involved in the regulation of chemokine expression during the ischemic process. 

The time course of chemokine expression seems clearly associated with the time-dependent infiltration of different immune cells in the ischemic brain area. Particularly, early expression of CXC chemokines like CXCLl, CXCL2, CXCL3 and CINC [67-69] has been observed and precedes infiltration of neutrophils [70, 71]. CXCL8 is a potent neutrophil chemotactic and activating factor and most likely plays an important role in neutrophil-mediated acute inflammation [72]. In addition to 

The early infiltration of the ischemic area by neutrophils is followed by subsequent infiltration by monocytes and, accordingly, the expression of CXC chemokines is followed by expression of CC chemokines. 

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