Protective effects of inhibiting both blood and vascular selectins after stroke and reperfusion

Abstract

Early intervention after acute ischemic stroke is essential to minimize brain cell injury. Although reperfusion of the ischemic brain is the treatment of choice for acute stroke, reperfusion itself may cause additional injury. The inflammatory cascade, characterized in part by early leukocyte interaction with endothelium, may contribute to this additional injury to blood vessels and surrounding brain tissue, extending the area of infarction. The selectin family of adhesion molecules mediates the initial, rolling and tethering of leukocytes to endothelium. P-selectin is rapidly expressed on ischemic endothelium in the brain vasculature, and L-selectin is expressed on leukocytes. Blocking the selectin-mediated tethering step may limit the inflammatory component of reperfusion injury in the brain. Fucoidin (FCN), a competitive inhibitor of P- and L-selectin, has been reported to decrease leukocyte accumulation during reperfusion of other organs. The effect of both leukocyte and endothelial selectin inhibition after cerebral ischemia and reperfusion has not been previously examined. The purpose of this study was to determine the effects of selectin adhesion molecule blockade on cerebral infarction size and neurological function after middle cerebral artery occlusion and reperfusion (MCAO-R) in the rat. MCAO was induced using the filament method. All animals were subjected to 4 h of MCAO and 24 h of reperfusion. After 24 h, brains were analyzed for size of infarction. Neurological function was assessed during stroke and 24 h after reperfusion. Two groups were studied, an untreated control group (n = 9) and a group treated with the selectin inhibitor, fucoidin (25 mg kg(-1)) (n = 9). We found that selectin blockade significantly reduced cerebral infarction size by 50% (p < 0.05) and improved neurological function (p < 0.05). In addition, a trend toward decreased cerebral edema was demonstrated with selectin inhibition. These results indicate that treatment of the blood and the endothelium with a selectin anti-inflammatory agent is protective after focal stroke and reperfusion in the rat.

The inflammatory response in stroke

“…Treating rabbits exposed to transient focal brain ischemia with an L-selectin antibody did not affect stroke outcome (Yenari et al, 2001). However, fucoidin, an inhibitor of both P-and L-selectin, significantly reduced infarct size and improved neurological function in experimental stroke in rats, but these observations could have been due to inhibition of P-selectin rather than Lselectin (Ruehl et al, 2002).…”

Role of Inflammation and Its Mediators in Acute Ischemic Stroke

“…Pre-clinical studies have demonstrated that inhibition of brain leukocyte infiltration using agents directly blocking adhesion molecules (e.g., CD11b/CD18, ICAM-1, P-selectin) and neutrophil inhibitory factor inhibition [Table 2] reduces infarct size, edema, and neurological deficits in transient MCAO models, even administrated up to 12–24h after ischemia, but the benefits do not extend to permanent stroke models [188,189,190] . Additionally, development of an anti-inflammatory milieu, and generation of pro-survival factors fostering tissue reconstruction and repair may be another useful therapeutic strategy.…”

Molecular Mechanisms of Apoptosis in Cerebral Ischemia: Multiple Neuroprotective Opportunities

“…Recent reports suggest that prostaglandin E2EP1 receptors may be the downstream effectors responsible for neurotoxicity of COX-2 in ischemic stroke, and inhibitor of EP1 receptor has shown significant protection when administered 6 h after MCAO [335]. Fucoidin, an inhibitor of both P-and Lselectin, significantly reduced infarct size and improved neurological function in experimental stroke and reperfusion in rats [336]. Overexpression or treatment with IL-1 receptor antagonist (IL-1ra), an endogenous inhibitor of IL-1 reduces the infarct size [337,338], whereas mice deficient of IL-1ra exhibited a significant increase in ischemic damage [339].…”