Activation of the High-Mobility Group Box 1 Protein-Receptor for Advanced Glycation End-Products Signaling Pathway in Rats During Neurogenesis After Intracerebral Hemorrhage

Background and Purpose-Following intracerebral hemorrhage (ICH), high-mobility group box 1 protein (HMGB1) may promote neurogenesis that supports functional recovery. How HMGB1 regulates or participates in this process is unclear, as are the pattern recognition receptors and signaling pathways involved. Methods-ICH was induced by injection of collagenase in Sprague-Dawley rats, which were treated 3 days later with saline, with the HMGB1 inhibitor ethyl pyruvate or with FPS-ZM1, an antagonist of the receptor for advanced glycation end-products. A Sham group was treated with saline solution instead of collagenase and then treated 3 days later with saline again or with ethyl pyruvate or N-benzyl-4-chloro-N-cyclohexylbenzamide (FPS-ZM1). Expression of the following proteins was measured by Western blot, immunohistochemistry, or immunofluorescence: HMGB1, receptor for advanced glycation end-products, toll-like receptor (TLR)-2, TLR4, brain-derived neurotrophic factor, and matrix metalloproteinase-9. The number of cells positive for 5-bromo-2-deoxyuridine or doublecortin was determined by immunohistochemistry and immunofluorescence. Results-Levels of HMGB1, receptor for advanced glycation end-products, TLR4, TLR2, brain-derived neurotrophic factor, and matrix metalloproteinase-9 were significantly higher 14 days after ICH than at baseline, as were the numbers of 5-bromo-2-deoxyuridine-or doublecortin-positive cells. At the same time, HMGB1 moved from the nucleus into the cytoplasm. Administering ethyl pyruvate significantly reduced all these ICH-induced increases, except the increase in TLR4 and TLR2. Administering FPS-ZM1 reduced the ICH-induced increases in the expression of brain-derived neurotrophic factor and matrix metalloproteinase-9 and in the numbers of 5-bromo-2-deoxyuridine-or doublecortin-positive cells. Conclusions-These findings suggest that HMGB1 acts via the receptor for advanced glycation end-products signaling pathway to promote neurogenesis in later phases of ICH.