title: Neuroprotection by JM-1232(-) against oxygen-glucose deprivation-induced injury in rat hippocampal slice culture.
abstract: JM-1232(-) (JM) is a novel isoindoline derivative with sedative and hypnotic activities that are mediated by binding to the benzodiazepine site of the Gamma-aminobutyric acid type A (GABAA) receptor. Although the neuroprotective effects of other GABAA receptor agonists are well known, there is no published report regarding JM. Thus, we examined the effects of JM on neurons exposed to oxygen-glucose deprivation (OGD) using rat hippocampal slice cultures. Hippocampal slices were assigned to either control or JM-administered groups. To assess the neuroprotective effects of JM from necrotic changes, we measured the fluorescence of propidium iodide and compared the cell mortality 24h following OGD between the control and JM-administered groups. We also verified that the effects of JM were mediated by GABAA receptors by adding flumazenil, a benzodiazepine receptor antagonist, in the same experimental settings. JM, at concentrations of 250 and 500 µM, significantly reduced cell mortality in pyramidal neurons after OGD; however, flumazenil did not inhibit this effect. To analyze more immediate effects of JM, we next measured the fluorescence of Oregon Green 488 BAPTA-1 during the OGD and re-oxygenation periods, and evaluated changes in intracellular Ca(2+) in single CA1 pyramidal neurons. JM reduced the elevation of intracellular Ca(2+) concentration during OGD, and this effect was antagonized by flumazenil. These findings indicate that JM suppressed the elevation of intracellular Ca(2+) concentration during OGD through GABAA receptors, but its neuroprotective effects from necrotic changes also involve other unknown mechanisms.
authors.affiliation: Department of Anesthesiology, National Defense Medical College, Tokorozawa, Japan. Electronic address: dr21032@ndmc.ac.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ogura
authors.affiliation: Department of Anatomy and Neurobiology, National Defense Medical College, Tokorozawa, Japan. Electronic address: thamada@ndmc.ac.jp.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hamada
authors.affiliation: Department of Anatomy and Neurobiology, National Defense Medical College, Tokorozawa, Japan. Electronic address: matsuto@ndmc.ac.jp.
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Department of Cellular Neurobiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Electronic address: tanakasj@m.u-tokyo.ac.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Cellular Neurobiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Electronic address: okabe@m.u-tokyo.ac.jp.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Okabe
authors.affiliation: Department of Anesthesiology, National Defense Medical College, Tokorozawa, Japan. Electronic address: kazama@ndmc.ac.jp.
authors.forename: Tomiei
authors.initials: T
authors.lastname: Kazama
authors.affiliation: Department of Anatomy and Neurobiology, National Defense Medical College, Tokorozawa, Japan. Electronic address: yasushi@ndmc.ac.jp.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects*; D004195:Disease Models, Animal; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D054833:Isoindoles / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C534223:3-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-2-phenyl-3,5,6,7-tetrahydrocyclopenta(f)isoindol-1(2H)-one; D054833:Isoindoles; D018696:Neuroprotective Agents; D010879:Piperazines; D005947:Glucose; D002118:Calcium
keywords: Benzodiazepine; Hippocampal slice culture; JM-1232(−); Neuroprotective effects; Oxygen–glucose deprivation