Neuroprotection in ischemia-reperfusion injury: An antiinflammatory approach using a novel broad-spectrum chemokine inhibitor

Cerebral ischemia-reperfusion injury is associated with a developing inflam matory response with pathologic contributions from vascular leukocytes and endogenous microglia. Signaling chemokines orchestrate the communication be tween the different inflammatory cell types and the damaged tissue leading to cellular chemotaxis and lesion occupation. Several therapies aimed at pr eventing this inflammatory response have demonstrated neuroprotective effic acy in experimental models of stroke, but to date, few investigators have u sed the chemokines as potential therapeutic targets. In the current study, the authors investigate the neuroprotective action of NR58-3.14.3, a novel broad-spectrum inhibitor of chemokine function (both CXC and CC types), in a rat model of cerebral ischemia-reperfusion injury. Rats were: subjected t o 90 minutes of focal ischemia by the filament method followed by 72 hours of reperfusion. Both the lesion volume, measured by serial magnetic resonan ce imaging, and the neurologic function were assessed daily. Intravenous NR 58-3.14.3 was administered, 2 mg/kg bolus followed by 0.5 mg/kg . hour cons tant infusion for the entire 72-hour period. At 72 hours, the cerebral leuk ocytic infiltrate, tumor necrosis factor-alpha (TNF-alpha), and interleukin -8 (IL-8)-like cytokines were analyzed by quantitative immuno-fluorescence. NR58-3.14.3 significantly reduced the lesion volume by up to 50% at 24, 48 , and 72 hours post-middle cerebral artery occlusion, which was associated with a marked functional improvement to 48 hours. In NR58-3.14.3-treated ra ts, the number of infiltrating granulocytes and macrophages within perilesi onal regions were reduced, but there were no detectable differences in infl ammatory cell numbers within core ischemic areas. The authors reported incr eased expression of the cytokines, TNF-alpha and IL-8-like cytokines within the ischemic lesion, but no differences between the NR58-3.14.3-treated ra ts and controls were reported. Although chemokines can have pro- or antiinf lammatory action, these data suggest the overall effect of chemokine up-reg ulation and expression in ischemia-reperfusion injury is detrimental to out come.