title: Blockade of gap junction hemichannel protects secondary spinal cord injury from activated microglia-mediated glutamate exitoneurotoxicity.
abstract: We previously demonstrated that activated microglia release excessive glutamate through gap junction hemichannels and identified a novel gap junction hemichannel blocker, INI-0602, that was proven to penetrate the blood-brain barrier and be an effective treatment in mouse models of amyotrophic lateral sclerosis and Alzheimer disease. Spinal cord injury causes tissue damage in two successive waves. The initial injury is mechanical and directly causes primary tissue damage, which induces subsequent ischemia, inflammation, and neurotoxic factor release resulting in the secondary tissue damage. These lead to activation of glial cells. Activated glial cells such as microglia and astrocytes are common pathological observations in the damaged lesion. Activated microglia release glutamate, the major neurotoxic factor released into the extracellular space after neural injury, which causes neuronal death at high concentration. In the present study, we demonstrate that reduction of glutamate-mediated exitotoxicity via intraperitoneal administration of INI-0602 in the microenvironment of the injured spinal cord elicited neurobehavioral recovery and extensive suppression of glial scar formation by reducing secondary tissue damage. Further, this intervention stimulated anti-inflammatory cytokines, and subsequently elevated brain-derived neurotrophic factor. Thus, preventing microglial activation by a gap junction hemichannel blocker, INI-0602, may be a promising therapeutic strategy in spinal cord injury.
authors.affiliation: 1 Department of Neurosurgery, Nagoya University School of Medicine , Nagoya, Japan .
authors.forename: Daisuke
authors.initials: D
authors.lastname: Umebayashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Natsume
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Masahito
authors.initials: M
authors.lastname: Hara
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Fukuyama
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Sumiyoshi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Wakabayashi
mesh_terms: D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000633:toxicity*; D005260:Female; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013119:Spinal Cord Injuries / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018846:Excitatory Amino Acids; D006576:Heterocyclic Compounds, 4 or More Rings; C000599854:INI-0602; D018696:Neuroprotective Agents; D018698:Glutamic Acid
keywords: functional recovery; gap junction hemichannel inhibitor; glutamate; microglia; spinal cord injury