Receptor for Advanced Glycation End-Product Antagonist Reduces Blood–Brain Barrier Damage After Intracerebral Hemorrhage

Abstract

Background and Purpose-To determine whether the receptor for advanced glycation end-products (RAGE) plays a role in early brain injury from intracerebral hemorrhage (ICH), RAGE expression and activation after injury were examined in a rat model of ICH with or without administration of a RAGE-specific antagonist (FPS-ZM1). Methods-Autologous arterial blood was injected into the basal ganglia of rats to induce ICH. The motor function of the rats was examined, and water content was detected after euthanization. Blood-brain barrier permeability was determined by Evans blue staining and colloidal gold nanoparticle tracers. Nerve fiber injury in white matter was determined by diffusion tensor imaging analysis, and the expression of target genes was analyzed by Western blotting and quantitative reverse transcription polymerase chain reaction. FPS-ZM1 was administered by intraperitoneal injection. Results-Expression of RAGE and its ligand high-mobility group protein B1 were increased at 12 hours after ICH, along with blood-brain barrier permeability and perihematomal nerve fiber injury. RAGE and nuclear factor-κB p65 upregulation were also observed when FeCl 2 was infused into the basal ganglia at 24 hours. FPS-ZM1 administration resulted in significant improvements of blood-brain barrier damage, brain edema, motor dysfunction, and nerve fiber injury, and the expression of RAGE, nuclear factor-κB p65, proinflammatory mediators interleukin 1β, interleukin-6, interleukin-8R, cyclooxygenase-2, inducible nitric oxide synthase, and matrix metallopeptidase-9 was attenuated. Moreover, decreases in claudin-5 and occludin expression were partially recovered. FPS-ZM1 also reversed FeCl 2 -induced RAGE and nuclear factor-κB p65 upregulation. Conclusions-RAGE signaling is involved in blood-brain barrier and white matter fiber damage after ICH, the initiation of which is associated with iron. RAGE antagonists represent a novel therapeutic intervention to prevent early brain injury after ICH. .).The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl

Cattle encephalon glycoside and ignotin reduced white matter injury and prevented post-hemorrhagic hydrocephalus in a rat model of intracerebral hemorrhage

“…The results of the present study demonstrated that the subcortical white matter surrounding the hematoma was impaired at an early stage of IVH/ICH, and difficulty recovering in the presence of a hematoma was detected over the long-term (Figs 3 and 4 and data not shown), which is consistent with previous observations16. ICH causes primary white matter injury by direct mechanical compression and hematoma expansion, and then it induces secondary injury through the coagulation cascade (especially thrombin)17.…”

Multimodality MRI assessment of grey and white matter injury and blood-brain barrier disruption after intracerebral haemorrhage in mice

“…The first study showed decreased FA value at day 3 together with histologically determined neuronal degeneration, which continued to 120 days after collagenase-induced ICH in rats18. The second study, which used the blood-injection ICH model in rats, also showed a decrease in FA in the tissue near the haemorrhagic region on days 1 and 3 but did not present longer-term data38. We were the first group to show decreases in FA values of the ipsilateral CC on day 28 in a mouse collagenase-induced ICH model19.…”

“…DTI/MRI has been investigated as a promising technique to evaluate functional outcome and compare treatment effects in patients with ICH37. Only a few preclinical ICH studies have used FA to estimate white matter injury and repair181938. The first study showed decreased FA value at day 3 together with histologically determined neuronal degeneration, which continued to 120 days after collagenase-induced ICH in rats18.…”

Anti-high mobility group box-1 (HMGB1) antibody inhibits hemorrhage-induced brain injury and improved neurological deficits in rats

“…Although ICH was shown to significantly up-regulate the expression of all three receptors of HMGB1, only treatment with the RAGE antagonist (FPS-ZM1) significantly reduced ICH-induced infiltration of inflammatory cells and the expressions of IL-1β and MMP-9 in the peri-hematomal region2529. In contrast, TLR2/4 antagonists had no influence on the ICH-induced infiltration of inflammatory cells, even though they did slightly reduce the expressions of IL-1 and MMP-925.…”