title: Investigation of Mechanisms for MK-801-Induced Neurotoxicity Utilizing Metabolomic Approach.
abstract: Single treatment of rats with the noncompetitive N-methyl-D-aspartate receptor antagonist MK-801 induces neuronal cell degeneration and death in the retrosplenial/posterior cingulate cortex (RS/PC) region, along with local cerebral glucose utilization. However, the relationship between this neuronal cell degeneration and death and glucose utilization remains unclear. To investigate the mechanism of MK-801-induced neurotoxicity and its relation to glucose utilization, changes in endogenous metabolites in the RS/PC region of MK-801 treated rats were assessed using metabolomics. Inverse correlation between citrulline and arginine levels suggested increased nitric oxide (NO) production. In addition, decreased levels of purine metabolites suggested enhanced xanthine oxidase activity accompanied with reactive oxygen species (ROS) production. Histopathological analysis confirmed that the production of ROS in the RS/PC region was increased by MK-801 and that the nonspecific NO synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) prevented MK-801-induced neuronal cell death. These results suggest that NO increases oxidative stress-related cell death. Increased levels of metabolites of glucose metabolism suggested enhanced energy production via glycolysis. To confirm the relationship between NO and glucose utilization, positron emission tomography (PET) imaging with [(18)F] fluoro-2-deoxy-d-glucose ([(18)F] FDG) was conducted. [(18)F] FDG-PET imaging accompanied by co-treatment of L-NAME with MK-801 demonstrated that L-NAME ameliorated MK-801-induced glucose utilization.In conclusion, MK-801 induces NO and ROS production in the RS/PC region, which might subsequently induce oxidative stress and in turn neuronal cell death. In addition, MK-801-induced NO production increased glucose utilization and affected glucose metabolism, the imbalance of which might generate additional oxidative stress related to neuronal cell death.
authors.affiliation: *Drug Safety Research Labs, Drug Discovery Research, Astellas Pharma Inc, Yodogawa-Ku, Osaka 532-8514, Japan; and.
authors.forename: Kanae
authors.initials: K
authors.lastname: Kuroda
authors.affiliation: Translational Science Research Labs, Drug Discovery Research, Astellas Pharma Inc, Tsukuba-Shi, Ibaraki 305-8585, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Suzumura
authors.affiliation: *Drug Safety Research Labs, Drug Discovery Research, Astellas Pharma Inc, Yodogawa-Ku, Osaka 532-8514, Japan; and takafumi.shirakawa@astellas.com.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Shirakawa
authors.affiliation: Translational Science Research Labs, Drug Discovery Research, Astellas Pharma Inc, Tsukuba-Shi, Ibaraki 305-8585, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hiraishi
authors.affiliation: *Drug Safety Research Labs, Drug Discovery Research, Astellas Pharma Inc, Yodogawa-Ku, Osaka 532-8514, Japan; and.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakahara
authors.affiliation: Translational Science Research Labs, Drug Discovery Research, Astellas Pharma Inc, Tsukuba-Shi, Ibaraki 305-8585, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fushiki
authors.affiliation: Translational Science Research Labs, Drug Discovery Research, Astellas Pharma Inc, Tsukuba-Shi, Ibaraki 305-8585, Japan.
authors.forename: Sokichi
authors.initials: S
authors.lastname: Honda
authors.affiliation: *Drug Safety Research Labs, Drug Discovery Research, Astellas Pharma Inc, Yodogawa-Ku, Osaka 532-8514, Japan; and.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Naraoka
authors.affiliation: Translational Science Research Labs, Drug Discovery Research, Astellas Pharma Inc, Tsukuba-Shi, Ibaraki 305-8585, Japan.
authors.forename: Sosuke
authors.initials: S
authors.lastname: Miyoshi
authors.affiliation: *Drug Safety Research Labs, Drug Discovery Research, Astellas Pharma Inc, Yodogawa-Ku, Osaka 532-8514, Japan; and.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Aoki
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000633:toxicity*; D005260:Female; D005947:Glucose / Q000378:metabolism; D055432:Metabolomics; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D016291:Dizocilpine Maleate; D005947:Glucose; D019331:NG-Nitroarginine Methyl Ester
keywords: MK-801; glucose metabolism; metabolomics; neuronal cell death; nitric oxide