title: Orally active glutamate carboxypeptidase II inhibitor 2-MPPA attenuates dizocilpine-induced prepulse inhibition deficits in mice.
abstract: Glutamate carboxypeptidase II (GCP II) is a glial enzyme responsible for the hydrolysis of N-acetylaspartylglutamate (NAAG) into glutamate and N-acetylaspartate (NAA). Abnormalities in glutamate neurotransmission are implicated in the pathophysiology of schizophrenia. In this study, we examined the effects of a novel, orally active GCP II inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), on the prepulse inhibition (PPI) deficits after administration of the N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine. Oral administration of 2-MPPA (10, 30 or 100mg/kg) significantly attenuated dizocilpine (0.1mg/kg)-induced PPI deficits in mice, in a dose dependent manner. Furthermore, the efficacy of 2-MPPA on dizocilpine-induced PPI deficits was significantly antagonized by pretreatment with the selective group II metabotropic glutamate receptor (mGluR) antagonist LY341495 (1.0mg/kg). In the same model, however, the selective group II mGluR agonist LY354740 (3, 10 or 30 mg/kg) significantly attenuated dizocilpine-induced PPI deficits at only one dose and prepulse intensity. Our findings suggest that GCP II inhibition may be useful therapeutic strategy for schizophrenia. From a mechanistic perspective, while increased NAAG and activation of group II mGluRs may contribute to the therapeutic efficacy of 2-MPPA, it is likely that additional pharmacological activities are also involved.
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan.
authors.forename: Yuto
authors.initials: Y
authors.lastname: Takatsu
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujita
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000284:Administration, Oral; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D004151:Dipeptides / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D005977:Glutarates / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009433:Neural Inhibition / Q000187:drug effects*; D012559:Schizophrenia / Q000188:drug therapy; D055139:Sensory Gating / Q000187:drug effects* / Q000502:physiology; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D014966:Xanthenes / Q000494:pharmacology
chemical_list: C474576:2-(3-mercaptopropyl)pentanedioic acid; D000596:Amino Acids; D014150:Antipsychotic Agents; D001643:Bridged Bicyclo Compounds; D004151:Dipeptides; D018691:Excitatory Amino Acid Antagonists; D005977:Glutarates; C114624:LY 341495; D013438:Sulfhydryl Compounds; D014966:Xanthenes; C027172:isospaglumic acid; D016291:Dizocilpine Maleate; D043425:Glutamate Carboxypeptidase II; C104753:eglumetad