title: Neuroprotective potential of molecular hydrogen against perinatal brain injury via suppression of activated microglia.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: itoto@med.nagoya-u.ac.jp.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kotani
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuda
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Mano
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ushida
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Laboratory of Bell Research Centre-Department of Obstetrics and Gynecology Collaborative Research, Bell Research Centre for Reproductive Health and Cancer, Department of Reproduction, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Miki
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Sumigama
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Iwase
authors.affiliation: Biostatistics Section, Center for Advanced Medicine and Clinical Research Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hirakawa
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Kinji
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takeuchi
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mizuno
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Suzumura
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kikkawa
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D001930:Brain Injuries / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006859:Hydrogen / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008813:Mice, Inbred ICR; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress; D011247:Pregnancy; D011248:Pregnancy Complications / Q000276:immunology / Q000517:prevention & control*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D006859:Hydrogen
keywords: FIRS; IL-6; Inflammation; ROS