Shanghai Institute for Pediatric Research, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
Brain Res. 2010 Jun 21;1339:60-9. doi: 10.1016/j.brainres.2010.04.014. Epub 2010 Apr 24.
Infection and inflammation leading to injury or death of pre-oligodendrocytes (preOLs) is one of the principal initiating mechanisms in the pathogenesis of preterm periventricular leukomalacia (PVL). The present study explores the possible protective effect of curcumin against the toxicity of lipopolysaccharide (LPS)-activated microglia on preOLs in vitro and in vivo. In vitro, preOLs in coculture with microglia exhibited increased apoptosis after exposure to LPS. LPS also induced significantly increased expression of inducible nitric oxide synthase (iNOS) and NADPH oxidase (NOX) subunits, p67-phox and gp91-phox in microglia. Our results suggest that iNOS and NOX contribute to the apoptosis of preOLs by activated microglia. The potential anti-inflammatory effects of curcumin were tested to determine if they could help to minimize microglia-mediated damage. Curcumin (10 microg/ml) was found to significantly inhibit the apoptosis of preOL and expression of either iNOS or NOX in the LPS-activated microglia. In vivo, curcumin was administered (50 mg/kg/day, i.p.) to two-day-old neonatal Sprague-Dawley rats subjected to intracerebral injection of LPS. Treatment with curcumin either 1h before or immediately after LPS injection significantly ameliorated white matter injury and loss of preOLs, decreased activated microglia, and inhibited microglial expression of iNOS and translocation of p67phox and gp91phox to the microglial cell membranes in neonatal rat brains following LPS injection. These results suggest that curcumin has a protective effect on infection-driven white matter injury, which is associated with suppression of iNOS and NOX activation. Consequently, curcumin may have potential as a protective agent against immature white matter injury.
在早产儿脑室周围白质软化症（PVL）的发病机制中，前少突胶质细胞（preOLs）的感染和炎症导致损伤或死亡是主要的起始机制之一。本研究探讨了姜黄素对体外和体内脂多糖（LPS）激活的小胶质细胞对 preOLs 毒性的可能保护作用。在体外，与小胶质细胞共培养的 preOLs 在暴露于 LPS 后表现出凋亡增加。LPS 还诱导小胶质细胞中诱导型一氧化氮合酶（iNOS）和 NADPH 氧化酶（NOX）亚基 p67-phox 和 gp91-phox 的表达显著增加。我们的结果表明，iNOS 和 NOX 通过激活的小胶质细胞促进 preOLs 的凋亡。测试了姜黄素的潜在抗炎作用，以确定它们是否有助于最小化小胶质细胞介导的损伤。发现姜黄素（10 μg/ml）可显著抑制 LPS 激活的小胶质细胞中 preOL 的凋亡和 iNOS 或 NOX 的表达。在体内，将姜黄素（50mg/kg/天，腹腔内注射）施用于接受脑内注射 LPS 的 2 日龄新生 Sprague-Dawley 大鼠。在 LPS 注射前 1 小时或立即给予姜黄素治疗可显著改善白质损伤和 preOLs 丢失，减少活化的小胶质细胞，并抑制 LPS 注射后新生大鼠脑中小胶质细胞中 iNOS 的表达和 p67phox 和 gp91phox 的易位到小胶质细胞膜上。这些结果表明，姜黄素对感染驱动的白质损伤具有保护作用，这与抑制 iNOS 和 NOX 激活有关。因此，姜黄素可能具有作为对抗未成熟白质损伤的保护剂的潜力。
