Abstract
Leukocyte infiltration is viewed as a pharmacological target in cerebral ischemia. We previously reported that reparixin, a CXCL8 receptor blocker that inhibits neutrophil infiltration, and related molecules can reduce infarct size in a rat model of transient middle cerebral artery occlusion (MCAO). The study aims were to compare the effects of reparixin in transient and permanent MCAO using varied treatment schedules and therapeutic windows to evaluate effects on long-term neurological deficits and late inflammatory response. Reparixin, administered for 1 to 3 days, 3.5 to 6 h after MCAO, ameliorates neurological function recovery and inhibits long-term inflammation. The infarct size reduction at 24 h, evaluated by TTC staining, is more pronounced in transient MCAO. MRI analysis identified a decrease in the progression of infarct size by reparixin that was more evident at 48 h in permanent MCAO, and was associated with a significantly improved recovery from long-term neurological deficits.
Highlights
Blockade of inflammation is considered a possible approach to the therapy of cerebral ischemia
We first confirmed the efficacy of reparixin in the model of transient cerebral ischemia used in our earlier work [8] and, investigated the regional selectivity of its protective action
The protective action of reparixin demonstrates the pathogenic role of inflammation induced by chemokines, polymorphonuclear neutrophils (PMN) chemoattractants acting on CXCR1/2, in cerebral ischemia [27,28]
Summary
Blockade of inflammation is considered a possible approach to the therapy of cerebral ischemia. Leukocytic infiltration, of polymorphonuclear neutrophils (PMN) is a key aspect of the deleterious aspects of inflammation in stroke [1,2,3], and CXCL8 or related chemokines are induced in stroke in animal models [4] as well as in patients [5,6]. We described reparixin (formerly termed repertaxin), a small molecular weight inhibitor of CXCR1 and CXCR2, the receptors for the CXCL8 family of chemokines implicated in the recruitment of PMN active in vivo [7], and the drug is undergoing clinical trials for other indications. Infarct size only partially correlates with functional outcome in patients, and it is suggested it should only be used as a surrogate marker in clinical trials [9]
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