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

• Published in: Journal of psychiatric research 2012-05, Vol.46 (5), p.622-629
• Main Authors: Uehara, Takashi, Sumiyoshi, Tomiki, Hattori, Hiroshi, Itoh, Hiroko, Matsuoka, Tadasu, Iwakami, Noboru, Suzuki, Michio, Kurachi, Masayoshi
• Format: Article
• Language: English
• Subjects: Acoustic Stimulation; Adult and adolescent clinical studies; Age Factors; Analysis of Variance; Animal model; Animals; Animals, Newborn; Biological and medical sciences; Brain - pathology; Cognition; Cortex; Dizocilpine Maleate - toxicity; Excitatory Amino Acid Antagonists - toxicity; Female; GABAergic interneuron; GABAergic Neurons - drug effects; GABAergic Neurons - metabolism; Gait Disorders, Neurologic - chemically induced; Gait Disorders, Neurologic - drug therapy; Gait Disorders, Neurologic - pathology; Gamma-aminobutyric acid; Male; Maleates - therapeutic use; Medical sciences; Nerve Growth Factors - therapeutic use; Neural Inhibition - drug effects; Neurons; Parvalbumins - metabolism; Pregnancy; Prepulse inhibition; Psychiatry; Psychoacoustics; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Random Allocation; Rats; Rats, Wistar; Reflex, Startle - drug effects; Schizophrenia; T-817MA; Thiophenes - therapeutic use; Vehicles
• ISSN: 0022-3956; 1879-1379
• DOI: 10.1016/j.jpsychires.2012.01.022

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.