| Reference | 1. J Pharmacol Exp Ther. 2016 Feb;356(2):445-55. doi: 10.1124/jpet.115.229021. Epub 2015 Nov 17.<br />
Potentiation of Acetylcholine-Mediated Facilitation of Inhibitory Synaptic Transmission by an Azaindolizione Derivative, ZSET1446 (ST101), in the Rat Hippocampus.<br />
Takeda K(1), Yamaguchi Y(2), Hino M(2), Kato F(2).<br />
Author information:<br />
(1)Central Research Laboratory, Zenyaku Kogyo Co., Ltd. (K.T., Y.Y., M.H.,) and Department of Neuroscience, Jikei University School of Medicine, Tokyo Japan (F.K.) [email protected]. (2)Central Research Laboratory, Zenyaku Kogyo Co., Ltd. (K.T., Y.Y., M.H.,) and Department of Neuroscience, Jikei University School of Medicine, Tokyo Japan (F.K.).<br />
The integrity of the hippocampal network depends on the coordination of excitatory and inhibitory signaling, which are under dynamic control by various regulatory influences such as the cholinergic systems. ZSET1446 (ST101; spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) is a newly synthesized azaindolizinone derivative that significantly improves learning deficits in various types of Alzheimer disease (AD) models in rats. We examined the effect of ZSET1446 on the nicotinic acetylcholine (ACh) receptor (nAChR)-mediated regulation of synaptic transmission in hippocampal slices of rats. ZSET1446 significantly potentiated the facilitatory effect of nicotine and ACh on the frequency of spontaneous postsynaptic currents (sPSCs) recorded in CA1 pyramidal neurons with a maximum effect at 100 pM (tested range, 10 pM-1000 pM). The basal sPSC frequency without ACh was not affected. Such potentiation by ZSET1446 was observed in both the pharmacologic isolations of inhibitory and excitatory sPSCs and markedly reduced by blockade of either α7 or α4β2 nAChRs. ZSET1446 did not affect ACh-activated inward currents or depolarization of interneurons in the stratum radiatum and the lacunosum moleculare. These results indicate that ZSET1446 potentiates the nicotine-mediated enhancement of synaptic transmission in the hippocampal neurons without affecting nAChRs themselves, providing a novel possible mechanism of procognitive action that might improve learning deficits in clinical therapy.<br />
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2. J Pharmacol Sci. 2013;123(4):347-55. Epub 2013 Nov 29.<br />
Combination effects of ZSET1446/ST101 with memantine on cognitive function and extracellular acetylcholine in the hippocampus.<br />
Yamaguchi Y(1), Takeda K, Hino M.<br />
Author information:<br />
(1)Central Research Laboratory, Zenyaku Kogyo Co., Ltd., Japan.<br />
In the novel object recognition task, ZSET1446 (also coded as ST101) enhanced object recognition memory in mice and ameliorated cognitive impairment caused by scopolamine in rats. The enhancement induced by ZSET1446 in mice was abolished by injection of mechamylamine, a nonselective antagonist of nicotinic acetylcholine (ACh) receptors, or dihydro-β-erythroidine, a selective antagonist against the α4 subunit of nicotinic ACh receptors. These results suggest that the procognitive effect of ZSET146 is probably mediated by stimulation of nicotinic receptors. Memantine was also effective in these tests and concomitant administration of subeffective doses of ZSET1446 and memantine significantly ameliorated the cognitive performance in the novel object recognition task in both mice and rats. Moreover, oral administration of ZSET1446 or memantine increased the extracellular level of ACh in the hippocampus as compared with the control. Further, concomitant administration of subeffective doses of ZSET1446 and memantine significantly increased the extracellular level of ACh as compared with the group of ZSET1446 or memantine alone. These results suggest that these two compounds have a synergistic effect on the cognitive function possibly by synergistic increase in the extracellular level of ACh in the hippocampus, and that the combination therapy of these compounds might be effective in clinical settings.<br />
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3. J Pharmacol Sci. 2012;119(2):160-6.<br />
Effects of ZSET1446/ST101 on cognitive deficits and amyloid β deposition in the senescence accelerated prone mouse brain.<br />
Yamaguchi Y(1), Saito K, Matsuno T, Takeda K, Hino M.<br />
Author information:<br />
(1)Central Research Laboratory, Zenyaku Kogyo Co, Ltd, Tokyo, Japan. [email protected]<br />
The senescence accelerated prone mouse strain 8 (SAMP8) develops age-related deficits in learning and memory. Effects of the azaindolizinone derivative ZSET1446/ST101, a newly synthesized cognitive enhancer, on cognitive impairment and deposition of amyloid β (Aβ) were assessed in the SAMP8. ZSET1446 was administered in drinking water at estimated doses of 0.002, 0.01, and 0.1 mg/kg per day from the age of 8 months. The SAMP8 at the age of 8 months showed cognitive impairment in a novel object recognition task compared with young SAMP8 at the age of 8 weeks. Further, grading scores were gradually increased from 9 to 12 months and Aβ-like immunoreactivity in the hippocampus was increased at the age of 10 months. ZSET1446 ameliorated cognitive deficits of SAMP8 after 4, 8, 12, and 16 weeks of treatment in a novel object recognition test. ZSET1446 also reduced grading scores of SAMP8 after 16 weeks of treatment. Further, 8-week treatment of ZSET1446 significantly reduced the total number of Aβ-positive granules in the hippocampus. These results suggest that ZSET1446 shows ameliorating effects on SAMP8 partly due to the suppression of an increase of Aβ-deposition in the hippocampus.<br />
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4. J Pharmacol Exp Ther. 2010 Apr;333(1):43-50. doi: 10.1124/jpet.109.163535. Epub 2010 Jan 12.<br />
A novel cognitive enhancer, ZSET1446/ST101, promotes hippocampal neurogenesis and ameliorates depressive behavior in olfactory bulbectomized mice.<br />
Shioda N(1), Yamamoto Y, Han F, Moriguchi S, Yamaguchi Y, Hino M, Fukunaga K.<br />
Author information:<br />
(1)Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan.<br />
In the adult brain, neurogenesis persistently occurs in the subgranular zone of the hippocampal dentate gyrus (DG), and impaired neurogenesis is implicated in depressive behaviors and poor learning memory. Here, we investigated the effects of oral administration of spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446/ST101), a novel cognitive enhancer stimulating acetylcholine release, on adult neurogenesis in olfactory bulbectomized (OBX) mice. OBX mice showed significant decreases in the number of newborn cells in the DG by immunohistochemical analysis of 5-bromo-2-deoxyuridine incorporation. Impaired neurogenesis observed in OBX mice was significantly improved by chronic administration with ZSET1446. We confirmed that administration with mecamylamine, a nicotinic acetylcholine receptor antagonist, inhibits ZSET1446-enhanced neurogenesis in the DG. ZSET1446 administration also restored decreased phosphorylation of Akt and extracellular signal-regulated kinase in the DG of OBX mice. Consistent with restored neurogenesis, chronic but not single ZSET1446 administration promoted significant decreases in immobility in tail suspension tests and improved cognitive behaviors in OBX mice. Taken together, chronic ZSET1446 administration antagonized impaired neurogenesis seen in OBX mice, an effect closely associated with improvement of depressive behavior.<br />
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