reparixin and Brain-Ischemia

Ischemic stroke may result from transient or permanent reductions of regional cerebral blood flow. Polymorphonuclear neutrophils have been described as the earliest inflammatory cells to arrive in ischemic tissue. CXCR1/2 receptors are involved in the recruitment of these cells. However, the contribution of these chemokine receptors during transient brain ischemia in mice remains poorly understood. In this work, we investigated the effects of reparixin, an allosteric antagonist of CXCR1/2 receptors, in a model of middle cerebral artery occlusion and reperfusion in mice.. C57BL/6J male mice treated with reparixin or vehicle were subjected to a middle cerebral artery occlusion procedure 1 h after the treatment. Ninety minutes after ischemia induction, the monofilament that prevented blood flow was removed. Twenty-four hours after the reperfusion procedure, behavioral changes, including motor signs, were analyzed with the SmithKline/Harwell/lmperial College/Royal Hospital/Phenotype Assessment (SHIRPA) battery. The animals were sacrificed, and brain tissue was removed for histological and biochemical analyses. Histological sections were stained with hematoxylin and eosin, neutrophil infiltration was estimated by myeloperoxidase activity and the inflammatory cytokine IL-iβ was measured by ELISA.. Pre-treatment with reparixin reduced the motor deficits observed in this model of ischemia and reperfusion. Myeloperoxidase activity and IL-iβ were reduced in the reparixin-treated group. Histological analysis revealed that ischemic injury was also attenuated by reparixin pre-treatment.. Our results suggest that the blockade of the CXCR1/2 receptors by reparixin promotes neuroprotective effects by reducing the levels of polymorphonuclear infiltration in the brain and the tissue damage associated with middle cerebral artery occlusion and reperfusion.

Topics: Animals; Brain Injuries; Brain Ischemia; Enzyme-Linked Immunosorbent Assay; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Peroxidase; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Reproducibility of Results; Stroke; Sulfonamides; Time Factors; Treatment Outcome

Infiltration of polymorphonuclear neutrophils (PMNs) is thought to play a role in ischemic brain damage. The present study investigated the effect of repertaxin, a new noncompetitive allosteric inhibitor for the receptors of the inflammatory chemokine CXC ligand 8 (CXCL8)/interleukin-8 (IL-8), on PMN infiltration and tissue injury in rats. Cerebral ischemia was induced by permanent or transient occlusion of the middle cerebral artery and myeloperoxidase activity, a marker of PMN infiltration, and infarct volume were evaluated 24 h later. Repertaxin (15 mg/kg) was administered systemically at the time of ischemia and every 2 h for four times. In permanent ischemia repertaxin reduced PMN infiltration by 40% in the brain cortex but did not limit tissue damage. In transient ischemia (90-min ischemia followed by reperfusion), repertaxin inhibited PMN infiltration by 54% and gave 44% protection from tissue damage. Repertaxin had anti-inflammatory and neuroprotective effects also when given at reperfusion and even at 2 h of reperfusion. The protective effect of repertaxin did not interfere with brain levels of the chemokine. Since the PMN infiltration and its inhibition by repertaxin were comparable in the two models we conclude that reperfusion induces PMN activation, and inhibition of CXCL8 by repertaxin might be of pharmacological interest in transient ischemia.

Topics: Animals; Brain; Brain Ischemia; Chemokine CCL8; Inflammation; Ischemic Attack, Transient; Male; Monocyte Chemoattractant Proteins; Neuroprotective Agents; Rats; Reperfusion Injury; Sulfonamides; Time Factors