MRI detection of early endothelial activation in brain inflammation

MRI is an increasingly important clinical tool, but it is clear that conventional imaging fails to identify the full extent of lesion load in certain conditions, such as multiple sclerosis. The aim of this study was to determine whether a novel contrast agent (Gd-DTPA-B(sLeX)A, which contains an sLeX mimetic moiety that enables it to bind to the adhesion molecule E-selectin) can be used to identify endothelial activation in the brain. Microinjection of the proinflammatory cytokines IL-1beta or TNF-alpha into the striatum of Wistar rats rapidly induces focal adhesion molecule expression on the endothelium in the absence of MRI-visible changes. This phenomenon was used to investigate the potential of Gd-DTPA-B(sLeX)A to reveal MRI-invisible brain pathology. T1-weighted serial images were acquired in anesthetized animals before and after administration of Gd-DTPA-B(sLeX)A, 3-4 hr after cytokine was injected intracerebrally. Both TNF-alpha and IL-1beta up-regulated E-selectin on the brain endothelium, which correlated with increased signal intensity observed after administration of the novel contrast agent. No enhancement was visible with the nonselective contrast agent Gd-DTPA-BMA, indicating that there was no leakage of the agent across the blood-brain barrier (BBB) or nonselective binding to the endothelium. These data demonstrate the potential of such contrast agents for the early detection of brain injury and inflammation.