title: Blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer's disease.
abstract: BACKGROUND
  Glutamate released by activated microglia induces excitotoxic neuronal death, which likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for these neurodegenerative diseases, glutamate receptor blockers also perturbed physiological and essential glutamate signals, and inhibitors of microglial activation suppressed both neurotoxic/neuroprotective roles of microglia and hardly affected disease progression. We previously demonstrated that activated microglia release a large amount of glutamate specifically through gap junction hemichannel. Hence, blockade of gap junction hemichannel may be potentially beneficial in treatment of neurodegenerative diseases.
  
  
  RESULTS
  In this study, we generated a novel blood-brain barrier permeable gap junction hemichannel blocker based on glycyrrhetinic acid. We found that pharmacologic blockade of gap junction hemichannel inhibited excessive glutamate release from activated microglia in vitro and in vivo without producing notable toxicity. Blocking gap junction hemichannel significantly suppressed neuronal loss of the spinal cord and extended survival in transgenic mice carrying human superoxide dismutase 1 with G93A or G37R mutation as an amyotrophic lateral sclerosis mouse model. Moreover, blockade of gap junction hemichannel also significantly improved memory impairments without altering amyloid β deposition in double transgenic mice expressing human amyloid precursor protein with K595N and M596L mutations and presenilin 1 with A264E mutation as an Alzheimer's disease mouse model.
  
  
  CONCLUSIONS
  Our results suggest that gap junction hemichannel blockers may represent a new therapeutic strategy to target neurotoxic microglia specifically and prevent microglia-mediated neuronal death in various neurodegenerative diseases.
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Japan. htake@riem.nagoya-u.ac.jp
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizoguchi
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Doi
authors.forename: Shijie
authors.initials: S
authors.lastname: Jin
authors.forename: Mariko
authors.initials: M
authors.lastname: Noda
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liang
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Rarami
authors.initials: R
authors.lastname: Mori
authors.forename: Satoko
authors.initials: S
authors.lastname: Yasuoka
authors.forename: Endong
authors.initials: E
authors.lastname: Li
authors.forename: Bijay
authors.initials: B
authors.lastname: Parajuli
authors.forename: Jun
authors.initials: J
authors.lastname: Kawanokuchi
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Sonobe
authors.forename: Jun
authors.initials: J
authors.lastname: Sato
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanaka
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mizuno
authors.forename: Akio
authors.initials: A
authors.lastname: Suzumura
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology*; D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D001522:Behavior, Animal / Q000502:physiology; D002229:Carbenoxolone / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D018450:Disease Progression; D005260:Female; D017629:Gap Junctions / Q000378:metabolism*; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D007473:Ion Channels; C470429:SOD1 G37R protein, mouse; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D002229:Carbenoxolone; D006034:Glycyrrhetinic Acid