Neuroprotection in Ischemia-Reperfusion Injury: An Antiinflammatory Approach Using a Novel Broad-Spectrum Chemokine Inhibitor

• Published in: Journal of cerebral blood flow and metabolism Vol. 21; no. 6; pp. 683 - 689
• Main Authors: Beech, John S., Reckless, Jill, Mosedale, David E., Grainger, David J., Williams, Steve C. R., Menon, David K.
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01-06-2001; Lippincott Williams & Wilkins; Sage Publications Ltd
• Subjects: Animals; Biological and medical sciences; Brain - pathology; Cerebral Arteries; Chemokines - antagonists & inhibitors; Constriction; Fluorescent Antibody Technique; Granulocytes - pathology; Interleukin-8 - analysis; Ischemic Attack, Transient; Leukocytes - pathology; Lipopolysaccharide Receptors - analysis; Macrophages - immunology; Macrophages - pathology; Magnetic Resonance Imaging; Male; Medical sciences; Neuropharmacology; Neuroprotective agent; Neuroprotective Agents - therapeutic use; Peptides, Cyclic - therapeutic use; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Reperfusion Injury - pathology; Reperfusion Injury - prevention & control; Tumor Necrosis Factor-alpha - analysis; Ischemia-reperfusion; Neuroprotection; Inflammation; Chemokines; Prognosis; Rat; Cardiovascular disease; Vascular disease; Reperfusion; Ischemia; Mechanism of action; Cerebrovascular disease; Tumor necrosis factor α; Interleukin 8; Cerebral infarction; Nervous system diseases; Cytokine; Rodentia; Antiinflammatory agent; Neuroprotective agent; Cerebral disorder; Chemokine; Vertebrata; Chemotherapy; Mammalia; Treatment; Animal; Central nervous system disease; Inhibitor; Morphometry; Brain (vertebrata)
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1097/00004647-200106000-00006

Cerebral ischemia–reperfusion injury is associated with a developing inflammatory response with pathologic contributions from vascular leukocytes and endogenous microglia. Signaling chemokines orchestrate the communication between the different inflammatory cell types and the damaged tissue leading to cellular chemotaxis and lesion occupation. Several therapies aimed at preventing this inflammatory response have demonstrated neuroprotective efficacy in experimental models of stroke, but to date, few investigators have used 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 to 90 minutes of focal ischemia by the filament method followed by 72 hours of reperfusion. Both the lesion volume, measured by serial magnetic resonance imaging, and the neurologic function were assessed daily. Intravenous NR58–3.14.3 was administered, 2 mg/kg bolus followed by 0.5 mg/kg · hour constant infusion for the entire 72-hour period. At 72 hours, the cerebral leukocytic infiltrate, tumor necrosis factor-α (TNF-α), and interleukin-8 (IL-8)-like cytokines were analyzed by quantitative immunofluorescence. 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 rats, the number of infiltrating granulocytes and macrophages within perilesional regions were reduced, but there were no detectable differences in inflammatory cell numbers within core ischemic areas. The authors reported increased expression of the cytokines, TNF-α, and IL-8–like cytokines within the ischemic lesion, but no differences between the NR58–3.14.3-treated rats and controls were reported. Although chemokines can have pro-or antiinflammatory action, these data suggest the overall effect of chemokine up-regulation and expression in ischemia–reperfusion injury is detrimental to outcome.