Department of Physiology and Biophysics, College of Medicine, Inha University, Incheon, South Korea.
Glia. 2010 Nov 15;58(15):1881-92. doi: 10.1002/glia.21058.
We investigated the neuroprotective effect of glucosamine (GlcN) in a rat middle cerebral artery occlusion model. At the highest dose used, intraperitoneal GlcN reduced infarct volume to 14.3% ± 7.4% that of untreated controls and afforded a reduction in motor impairment and neurological deficits. Neuroprotective effects were not reproduced by other amine sugars or acetylated-GlcN, and GlcN suppressed postischemic microglial activation. Moreover, GlcN suppressed lipopolysaccharide (LPS)-induced upregulation of proinflammatory mediators both in vivo and in culture systems using microglial or macrophage cells. The anti-inflammatory effects of GlcN were mainly attributable to its ability to inhibit nuclear factor kappaB (NF-κB) activation. GlcN inhibited LPS-induced nuclear translocation and DNA binding of p65 to both NF-κB consensus sequence and NF-κB binding sequence of inducible nitric oxide synthase promoter. In addition, we found that GlcN strongly repressed p65 transactivation in BV2 cells using Gal4-p65 chimeras system. P65 displayed increased O-GlcNAcylation in response to LPS; this effect was also reversed by GlcN. The LPS-induced increase in p65 O-GlcNAcylation was paralleled by an increase in interaction with O-GlcNAc transferase, which was reversed by GlcN. Finally, our results suggest that GlcN or its derivatives may serve as novel neuroprotective or anti-inflammatory agents.
我们研究了氨基葡萄糖（GlcN）在大鼠大脑中动脉闭塞模型中的神经保护作用。在使用的最高剂量下，腹腔内给予 GlcN 可将未治疗对照的梗死体积减少到 14.3%±7.4%，并减轻运动障碍和神经功能缺损。其他胺糖或乙酰化-GlcN 并未重现神经保护作用，GlcN 抑制了缺血后小胶质细胞的激活。此外，GlcN 抑制了脂多糖（LPS）诱导的促炎介质在体内和体外培养系统中的上调，使用小胶质细胞或巨噬细胞细胞。GlcN 的抗炎作用主要归因于其抑制核因子 kappaB（NF-κB）激活的能力。GlcN 抑制 LPS 诱导的 p65 核易位和 DNA 结合到 NF-κB 共有序列和诱导型一氧化氮合酶启动子的 NF-κB 结合序列。此外，我们发现 GlcN 在使用 Gal4-p65 嵌合体系统的 BV2 细胞中强烈抑制了 p65 的反式激活。LPS 诱导的 p65 O-GlcNAcylation 增加；这一效应也被 GlcN 逆转。LPS 诱导的 p65 O-GlcNAcylation 增加与 O-GlcNAc 转移酶的相互作用增加平行，GlcN 可逆转这种相互作用。最后，我们的结果表明 GlcN 或其衍生物可能作为新型神经保护或抗炎剂。
