title: T-817MA, a novel neurotrophic agent, ameliorates loss of GABAergic parvalbumin-positive neurons and sensorimotor gating deficits in rats transiently exposed to MK-801 in the neonatal period.
abstract: T-817MA [1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}azetidin-3-ol maleate] is a newly synthesized neuroprotective agent for the treatment of psychiatric disorders characterized by cognitive disturbances, such as Alzheimer's disease. Cognitive impairment has also been suggested to be a cardinal feature of schizophrenia. We sought to determine whether T-817MA would ameliorate sensorimotor gating deficits and loss of parvalbumin (PV)-positive γ-aminobutyric acid (GABA) neurons in the brain of rats transiently exposed to MK-801, an N-methyl-d-aspartate receptor blocker, in the neonatal stage, as an animal model of schizophrenia. Prepulse inhibition (PPI) was examined in rats treated neonatally with MK-801 (postnatal day; PD 7-10, 0.2 mg/kg/day, s.c.) or vehicle at PD 35 and PD 63. The number of PV-positive GABAergic neurons in the medial prefrontal cortex (mPFC) and the hippocampus was measured after the behavioral assessments. T-817MA (10 or 20 mg/kg) or vehicle was administered for 14 days (on PD 49-62). Administration of T-817MA at 20 mg/kg, but not 10 mg/kg, ameliorated PPI deficits and completely reversed the decrease in the number of PV-positive GABAergic neurons in rats given MK-801. These results indicate that T-817MA may provide a novel therapeutic approach for the treatment of cognitive deficits of schizophrenia.
authors.affiliation: Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan. uehara@med.u-toyama.ac.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Uehara
authors.forename: Tomiki
authors.initials: T
authors.lastname: Sumiyoshi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hattori
authors.forename: Hiroko
authors.initials: H
authors.lastname: Itoh
authors.forename: Tadasu
authors.initials: T
authors.lastname: Matsuoka
authors.forename: Noboru
authors.initials: N
authors.lastname: Iwakami
authors.forename: Michio
authors.initials: M
authors.lastname: Suzuki
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kurachi
mesh_terms: D000161:Acoustic Stimulation; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology*; D016291:Dizocilpine Maleate / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D005260:Female; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism*; D020233:Gait Disorders, Neurologic / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008298:Maleates / Q000627:therapeutic use*; D009414:Nerve Growth Factors / Q000627:therapeutic use*; D009433:Neural Inhibition / Q000187:drug effects; D010320:Parvalbumins / Q000378:metabolism*; D011247:Pregnancy; D011571:Psychoacoustics; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013216:Reflex, Startle / Q000187:drug effects; D013876:Thiophenes / Q000627:therapeutic use*
chemical_list: C503102:1-(3-(2-(1-benzothiophen-5-yl) ethoxy) propyl)-3-azetidinol maleate; D018691:Excitatory Amino Acid Antagonists; D008298:Maleates; D009414:Nerve Growth Factors; D010320:Parvalbumins; D013876:Thiophenes; D016291:Dizocilpine Maleate