The Novel Cognitive Enhancer ST101 Enhances Acetylcholine Release in Mouse Dorsal Hippocampus Through T-type Voltage-Gated Calcium Channel Stimulation

Yamamoto, Yoshiyuki; Shioda, Norifumi; Han, Feng; Moriguchi, Shigeki; Fukunaga, Kohji

doi:10.1254/jphs.12233fp

Cited by 31 publications

(26 citation statements)

References 38 publications

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“…This study provides the in vitro evidence for the synaptic mechanism underlying the effect of ZSET1446, a potent procognitive drug that significantly improves the learning and memory deficits in various rodent AD models (Yamaguchi et al, 2006;Han et al, 2008;Yamamoto et al, 2013). The main conclusion of this study is that whereas ZSET1446 does not affect basal synaptic activities, excitatory or inhibitory, in the hippocampal CA1, it enhances the facilitatory effect of nicotinic receptor activation on the frequency of spontaneous transmission, especially the inhibitory ones.…”

Section: Discussion Effect Of Zset1446 On the Inhibitory Synaptic Tramentioning

confidence: 97%

“…2, F and H) suggest an involvement of the effects on T-VDCCs in this potentiation. It is therefore likely that, together with the increase in the extracellular ACh level after administration of ZSET1446, both in naïve and AD models (Yamaguchi et al, 2006;Yamamoto et al, 2013), modulation of GABA release through interaction between nAChR and T-VDCC at the GABAergic terminal is one of the principal targets of ZSET1446.…”

Section: Targets Of Zset1446mentioning

confidence: 99%

“…For example, such enhancement of LTP by ZSET1446 does not occur in the hippocampus (Moriguchi et al, 2012), despite manifest increase in extracellular ACh level, both that occurring spontaneously and that stimulated by nicotine, by systemic injection of ZSET1446 (Yamamoto et al, 2013). Interestingly, such an enhancing effect of ZSET1446 on extracellular ACh level, in a manner sensitive to a T-VDCC inhibitor, could be observed both in naïve and OBX rodents (Yamamoto et al, 2013), which is in clear contrast to the LTP enhancement that was observed only in OBX animals (Han et al, 2008). Therefore, how ZSET1446 affects the synaptic transmission in a manner related to changes in the extracellular ACh level in the hippocampal network remains to be clarified.…”

Section: Introductionmentioning

confidence: 97%

“…injection of scopolamine, and in mice with genetically accelerated senescence (Yamaguchi et al, 2006(Yamaguchi et al, , 2012. It also improves memory deficits in other rodent dementia models, including those induced by methamphetamine administration (Ito et al, 2007) and olfactory bulbectomy (OBX) (Han et al, 2008;Yamamoto et al, 2013). In addition, ZSET1446 prevents a reduction in nicotine-induced increase in extracellular ACh level by intracerebral microinjection of Ab in the hippocampus in freely moving rats (Yamaguchi et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Potentiation of Acetylcholine-Mediated Facilitation of Inhibitory Synaptic Transmission by an Azaindolizione Derivative, ZSET1446 (ST101), in the Rat Hippocampus

Takeda¹,

Yamaguchi²,

Hino³

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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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 a7 or a4b2 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.

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Section: Discussion Effect Of Zset1446 On the Inhibitory Synaptic Tramentioning

confidence: 97%

Section: Targets Of Zset1446mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Potentiation of Acetylcholine-Mediated Facilitation of Inhibitory Synaptic Transmission by an Azaindolizione Derivative, ZSET1446 (ST101), in the Rat Hippocampus

Takeda¹,

Yamaguchi²,

Hino³

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…In addition, acetyhlcholine (ACh) release enhancement by ZSET1446 is abolished by mibefradil in the hippocampus (16). These results suggest that stimulation of T-type calcium channel is important for the ZSET1446-induced enhancement of the cognitive function and ACh release.…”

Section: Combination Effects Of Zset1446/st101 With Memantine On Cognmentioning

confidence: 88%

Combination Effects of ZSET1446/ST101 With Memantine on Cognitive Function and Extracellular Acetylcholine in the Hippocampus

2013

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Abstract. 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-berythroidine, a selective antagonist against the a4 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.

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SAK3-Induced Neuroprotection Is Mediated by Nicotinic Acetylcholine Receptors

Fukunaga

Yabuki

2018

Nicotinic Acetylcholine Receptor Signaling in Neuroprotection

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Cholinergic neurotransmission plays a critical role in neuronal plasticity and cell survival in the central nervous system (CNS). Two types of acetylcholine receptors (AChRs), muscarinic AChRs (mAChRs) and nicotinic AChRs (nAChRs), trigger intracellular signaling through G protein activity and ion influx, respectively. To assess mechanisms underlying neuroprotection through nAChRs, we developed SAK3, a novel modulator of nAChR activity. Recently, we found that SAK3 enhances T-type calcium channel activity, promoting ACh release in the hippocampal CA1 region of olfactory-bulbectomized mice. Here, we observed potent SAK3 neuroprotective activity in mice with 20-min bilateral common carotid artery occlusion (BCCAO) or hypothyroidism. Treatment of mice with the α7 nAChR-selective inhibitor methyllycaconitine (0.5 mg/kg/day, p.o.) antagonized SAK3-mediated neuroprotection and memory improvement in BCCAO mice. Single administration of the anti-Graves' disease therapeutic methimazole (MMI) to female mice disrupted olfactory bulb (OB) glomerular structure, and cholinergic neurons largely disappeared in the medial septum followed by memory loss. Chronic SAK3 (0.5-1 mg/kg, p.o.) administration significantly rescued the number of cholinergic medial septum neurons in MMI-treated mice and improved cognitive deficits seen in those mice. Overall, our study suggests that, in mice, the novel nAChR modulator SAK3 can rescue neurons impaired by transient ischemia and hypothyroidism. We also address mechanisms common to SAK3-induced neuroprotection in both conditions.

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The Novel Cognitive Enhancer ST101 Enhances Acetylcholine Release in Mouse Dorsal Hippocampus Through T-type Voltage-Gated Calcium Channel Stimulation

Cited by 31 publications

References 38 publications

Potentiation of Acetylcholine-Mediated Facilitation of Inhibitory Synaptic Transmission by an Azaindolizione Derivative, ZSET1446 (ST101), in the Rat Hippocampus

Potentiation of Acetylcholine-Mediated Facilitation of Inhibitory Synaptic Transmission by an Azaindolizione Derivative, ZSET1446 (ST101), in the Rat Hippocampus

Combination Effects of ZSET1446/ST101 With Memantine on Cognitive Function and Extracellular Acetylcholine in the Hippocampus

SAK3-Induced Neuroprotection Is Mediated by Nicotinic Acetylcholine Receptors

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