Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, Jiangsu Province, China.
Neuroscience. 2011 Sep 8;190:339-45. doi: 10.1016/j.neuroscience.2011.06.004. Epub 2011 Jun 13.
High-mobility group box 1 (HMGB1), an active receptor for advanced glycation endproducts (RAGE), functions as a potent proinflammatory cytokine-like factor that contributes to the pathogenesis of vasculature. Diabetes mellitus (DM) is associated with accelerated development of both microvascular and macrovascular disease and increases the risk of ischemic stroke. Using a model of streptozotocin-induced type-1 diabetes (T1DM) in rats, we investigated the changes in HMGB and RAGE and tested the effects of Niaspan, a slow release form of niacin, on the expression of pro-inflammatory proteins in rats after stroke.
T1DM rats were subjected to transient middle cerebral artery occlusion (MCAo) and treated without or with Niaspan (40 mg/kg) daily for 14 days after MCAo. Non-streptozotocin rats (WT) were also subjected to MCAo. Immunostaining for inflammatory mediators including HMGB1, RAGE, matrix metalloproteinase-9 (MMP-9) and toll-like receptor 4 (TLR4) immunostaining (n=8/group) and Western blotting (n=4/group) were performed.
Compared to WT-MCAo rats, T1DM-MCAo rats showed an increased expression of HMGB1 (0.82±0.07 vs. 1.81±0.98, P<0.05), RAGE (1.31±0.22 vs. 3.77±0.72, P<0.05), MMP-9 (0.74±0.08 vs. 1.61±0.09, P<0.05) and TLR4 (2.85±0.22 vs. 6.72±0.44, P<0.05) after stroke. Niaspan treatment significantly attenuated the expression of HMGB1 (1.80±0.98 vs. 1.31±0.01, P<0.05), RAGE (3.77±0.71 vs. 1.78±0.45, P<0.05), MMP-9 (1.61±0.09 vs. 0.97±0.07, P<0.05) and TLR4 (6.72±0.44 vs. 2.28±0.43, P<0.05) in the ischemic brain in T1DM-MCAo rats.
T1DM increases HMGB1/RAGE, TLR4 and MMP-9 expression after stroke. Niaspan treatment of stroke in T1DM rats inhibits HMGB1/RAGE, TLR4 and MMP-9 expression which may contribute to the reduced inflammatory response after stroke in T1DM rats.
高迁移率族蛋白 B1（HMGB1）是晚期糖基化终产物（RAGE）的活性受体，作为一种潜在的促炎细胞因子样因子，在血管发病机制中起作用。糖尿病（DM）与微血管和大血管疾病的加速发展有关，并增加缺血性中风的风险。我们使用链脲佐菌素诱导的 1 型糖尿病（T1DM）大鼠模型，研究了 HMGB 和 RAGE 的变化，并测试了尼可司他（Niaspan），一种烟酸的缓释形式，对中风后大鼠炎症蛋白表达的影响。
T1DM 大鼠接受短暂性大脑中动脉闭塞（MCAo），并在 MCAo 后每天接受或不接受 Niaspan（40mg/kg）治疗 14 天。非链脲佐菌素大鼠（WT）也接受 MCAo。进行免疫染色，包括 HMGB1、RAGE、基质金属蛋白酶-9（MMP-9）和 Toll 样受体 4（TLR4）免疫染色（n=8/组）和 Western blot（n=4/组）。
与 WT-MCAo 大鼠相比，T1DM-MCAo 大鼠中风后 HMGB1（0.82±0.07 与 1.81±0.98，P<0.05）、RAGE（1.31±0.22 与 3.77±0.72，P<0.05）、MMP-9（0.74±0.08 与 1.61±0.09，P<0.05）和 TLR4（2.85±0.22 与 6.72±0.44，P<0.05）的表达增加。尼可司他治疗显著减弱了缺血大脑中 HMGB1（1.80±0.98 与 1.31±0.01，P<0.05）、RAGE（3.77±0.71 与 1.78±0.45，P<0.05）、MMP-9（1.61±0.09 与 0.97±0.07，P<0.05）和 TLR4（6.72±0.44 与 2.28±0.43，P<0.05）的表达。
T1DM 增加了中风后 HMGB1/RAGE、TLR4 和 MMP-9 的表达。尼可司他治疗 T1DM 大鼠中风抑制了 HMGB1/RAGE、TLR4 和 MMP-9 的表达，这可能有助于降低 T1DM 大鼠中风后的炎症反应。
