Subarachnoid hemorrhage (SAH)‐linked brain inflammation contributes to arteriolar dilating dysfunction and neuropathology in rats

Abstract

Brain injury and death arising from SAH remains a substantial clinical problem. In the present study, rats were subjected to SAH, via suture perforation of the anterior cerebral artery. In pilot experiments, we detected marked elevations in CSF expression of the astrocytic protein, S100B, at 48h post‐SAH. Since S100B is a ligand for the pro‐inflammatory receptor, RAGE (the receptor for advanced glycation end products), we tested the hypothesis that brain inflammation leads to impairment of arteriolar dilating function and contributes to brain damage. In rats prepared with closed cranial windows at 1–3 days post‐SAH, pial arteriolar dilation assessments were performed using intravital microscopy/videometry. To evaluate the role of S100B and RAGE, rats were given the following treatments at 30 min post SAH: (1) ONO 2506 (10 mg/kg, ip), a novel S100B inhibitor; or (2) sRAGE (icv via osmotic pump), a soluble RAGE decoy. After SAH, we observed diminished pial arteriolar responses to hypercapnia, and topically‐applied adenosine, acetylcholine, and S‐nitroso‐N‐acetyl penicillamine, with maximum attenuation seen at 48 h post SAH. The applications of both ONO 2506 and sRAGE significantly prevented the impaired pial arteriolar dilating responses. Neuropathology at 48h post‐SAH was evaluated using FluoroJade B (FJB) staining, which detects damaged neurons. The high level FJB reactivity seen in the ipsilateral cortex, hippocampus, and striatum in vehicle controls was markedly diminished in ONO 2506‐ and sRAGE‐treated rats. Collectively, these results indicate that, the activation of the S100B/RAGE – related proinflammatory pathway plays an important role in SAH‐associated cerebral vascular dysfunction. Blockade of the enhanced S100B and RAGE interaction may provide a promising treatment against SAH‐associated brain damage.Support: NS63279; HL88259