T-817MA, a novel neurotrophic compound, ameliorates phencyclidine-induced disruption of sensorimotor gating.
BACKGROUND
Neurodegenerative changes have been suggested to provide a basis for the pathophysiology of schizophrenia. T-817MA (1-{3-[2-(1-benzothiophen-5-yl) ethoxy] propyl} azetidin-3-ol maleate) is a novel compound with neuroprotective and neurite-outgrowth effects, as elicited in rat primary cultured neurons.


OBJECTIVE
We examined the effect of T-817MA on phencyclidine (PCP)-induced disruption of prepulse inhibition (PPI), a measure of sensorimotor gating, in male Wistar rats.


METHODS
In chronic experiments, male Wistar rats were injected intermittently with PCP (2.0 mg/kg, i.p., three times per week) or vehicle (saline, 2.0 ml/kg) for 1 month. T-817MA (0.21 or 0.07 mg/ml, p.o.) or distilled water was administered throughout the study period. In an acute experiment, T-817MA (8.4 mg/kg, p.o.) or distilled water was administered, followed by treatment with PCP (2.0 mg/kg, i.p.) or vehicle (saline, 2.0 ml/kg), before PPI measurements.


RESULTS
Intermittent administration of PCP for 1 month induced persistent disruption of PPI. Coadministration of T-817MA at 0.21 mg/ml but not 0.07 mg/ml completely blocked PCP-induced disruption of PPI, whereas T-817MA (0.21 mg/ml) by itself did not show a significant effect on PPI in control rats. On the other hand, single administration of T-817MA did not affect PPI disruption by acute treatment with PCP.


CONCLUSIONS
These results suggest that T-817MA is effective in ameliorating sensorimotor gating deficits caused by chronic PCP treatment, possibly via neuroprotective actions. Our findings provide a novel therapeutic approach for patients with schizophrenia.
Seo
Tomonori
T
Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan.
Sumiyoshi
Tomiki
T
Tsunoda
Masahiko
M
Tanaka
Kodai
K
Uehara
Takashi
T
Matsuoka
Tadasu
T
Itoh
Hiroko
H
Kurachi
Masayoshi
M
D000161:Acoustic Stimulation; D000818:Animals; D001288:Attention / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D007266:Inhibition, Psychological; D007274:Injections, Intraperitoneal; D008297:Male; D008298:Maleates / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010622:Phencyclidine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013216:Reflex, Startle / Q000187:drug effects*; D013876:Thiophenes / Q000494:pharmacology*
C503102:1-(3-(2-(1-benzothiophen-5-yl) ethoxy) propyl)-3-azetidinol maleate; D018691:Excitatory Amino Acid Antagonists; D008298:Maleates; D018696:Neuroprotective Agents; D013876:Thiophenes; D010622:Phencyclidine