Imai Kenji, Kotani Tomomi, Tsuda Hiroyuki, Mano Yukio, Nakano Tomoko, Ushida Takafumi, Li Hua, Miki Rika, Sumigama Seiji, Iwase Akira, Hirakawa Akihiro, Ohno Kinji, Toyokuni Shinya, Takeuchi Hideyuki, Mizuno Tetsuya, Suzumura Akio, Kikkawa Fumitaka
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Free Radic Biol Med. 2016 Feb;91:154-63. doi: 10.1016/j.freeradbiomed.2015.12.015. Epub 2015 Dec 22.
Exposure to inflammation in utero is related to perinatal brain injury, which is itself associated with high rates of long-term morbidity and mortality in children. Novel therapeutic interventions during the perinatal period are required to prevent inflammation, but its pathogenesis is incompletely understood. Activated microglia are known to play a central role in brain injury by producing a variety of pro-inflammatory cytokines and releasing oxidative products. The study is aimed to investigate the preventative potential of molecular hydrogen (H2), which is an antioxidant and anti-inflammatory agent without mutagenicity. Pregnant ICR mice were injected with lipopolysaccharide (LPS) intraperitoneally on embryonic day 17 to create a model of perinatal brain injury caused by prenatal inflammation. In this model, the effect of maternal administration of hydrogen water (HW) on pups was also evaluated. The levels of pro-inflammatory cytokines, oxidative damage and activation of microglia were determined in the fetal brains. H2 reduced the LPS-induced expression of pro-inflammatory cytokines, oxidative damage and microglial activation in the fetal brains. Next, we investigated how H2 contributes to neuroprotection, focusing on microglia, using primary cultured microglia and neurons. H2 prevented LPS- or cytokine-induced generation of reactive oxidative species by microglia and reduced LPS-induced microglial neurotoxicity. Finally, we identified several molecules influenced by H2, involved in the process of activating microglia. These results suggested that H2 holds promise for the prevention of inflammation related to perinatal brain injury.
子宫内暴露于炎症与围产期脑损伤有关，而围产期脑损伤本身又与儿童的高长期发病率和死亡率相关。需要在围产期采取新的治疗干预措施来预防炎症，但其发病机制尚未完全了解。已知活化的小胶质细胞通过产生多种促炎细胞因子和释放氧化产物在脑损伤中起核心作用。本研究旨在探讨分子氢（H2）的预防潜力，H2是一种无致突变性的抗氧化剂和抗炎剂。在胚胎第17天给怀孕的ICR小鼠腹腔注射脂多糖（LPS），以建立产前炎症引起的围产期脑损伤模型。在该模型中，还评估了母体给予氢水（HW）对幼崽的影响。测定了胎儿脑中促炎细胞因子的水平、氧化损伤和小胶质细胞的活化情况。H2降低了LPS诱导的胎儿脑中促炎细胞因子的表达、氧化损伤和小胶质细胞活化。接下来，我们使用原代培养的小胶质细胞和神经元，重点研究了H2如何通过小胶质细胞对神经保护发挥作用。H2可预防LPS或细胞因子诱导的小胶质细胞产生活性氧化物质，并降低LPS诱导的小胶质细胞神经毒性。最后，我们鉴定了几种受H2影响的分子，它们参与了小胶质细胞的活化过程。这些结果表明，H2有望预防与围产期脑损伤相关的炎症。
