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Kohji Fukunaga - One of the best experts on this subject based on the ideXlab platform.
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Cognitive Enhancer st101 improves schizophrenia like behaviors in neonatal ventral hippocampus lesioned rats in association with improved camkii pkc pathway
Journal of Pharmacological Sciences, 2019Co-Authors: Yasushi Yabuki, Kohji FukunagaAbstract:Abstract Atypical antipsychotics improve positive and negative symptoms but are not effective for treating Cognitive impairments in patients with schizophrenia. We previously reported that Cognitive impairments in neonatal ventral hippocampus (NVH)-lesioned rats show resistance to atypical antipsychotics risperidone and are associated with reduced calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC) signaling in memory-related regions. The Cognitive Enhancer ST101 (spiro[imi-dazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) stimulates CaMKII activity in the hippocampus and medial prefrontal cortex (mPFC). We thus tested ST101 on Cognitive impairments in NVH-lesioned rats. Chronic ST101 administration (0.1 and/or 0.5 mg/kg, p.o.) significantly improved deficits in prepulse inhibition (PPI), social interaction, and Cognitive function in NVH-lesioned rats. ST101 administration (0.5 mg/kg, p.o.) significantly restored the decreased CaMKII autophosphorylation (Thr-286) in the mPFC and hippocampal CA1 regions of NVH-lesioned rats when assessed by immunohistochemistry. Chronic ST101 administration (0.1 mg/kg, p.o.) improved the decline in phosphorylation levels of CaMKII (Thr-286), PKCα (Ser-657), α-amino-3-hydroxy-5-methyl-4-isoxazol- propionic acid (AMPA)-type glutamate receptor subunit 1 (GluA1: Ser-831), and N-methyl- d -aspartate (NMDA) receptor subunit 1 (GluN1: Ser-896) in the mPFC and hippocampal CA1 regions. Taken together, these results suggest that ST101 improves schizophrenia-like behaviors and Cognitive impairment by enhancing CaMKII/PKCα signaling in the mPFC and hippocampus in NVH-lesioned rats.
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the novel Cognitive Enhancer st101 enhances acetylcholine release in mouse dorsal hippocampus through t type voltage gated calcium channel stimulation
Journal of Pharmacological Sciences, 2013Co-Authors: Yui Yamamoto, Norifumi Shioda, Feng Han, Shigeki Moriguchi, Kohji FukunagaAbstract:We recently developed a novel Cognitive Enhancer, ST101 (spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one), that activates T-type voltage-gated calcium channels (VGCCs). Here, we address whether T-type VGCC activation with ST101 mediates its Cognitive effects in vivo and the relevance of T-type VGCC activation to acetylcholine (ACh) release in the hippocampus. Acute intraperitoneal administration of ST101 (1 mg/kg, i.p.) improved memory-related behaviors in both olfactory bulbectomized (OBX) and scopolamine-treated mice. Effects of ST101 administration were abolished by both intraperitoneal and intracerebroventricular pre-administration of the T-type VGCC inhibitor mibefradil. Acute administration of ST101 enhanced basal and nicotine-induced ACh release in the dorsal hippocampus in both OBX and sham-treated mice. Enhanced ACh release was abolished by infusion with mibefradil (10 μM) but not with the L-type VGCC inhibitor nifedipine (10 μM). As expected, significantly reduced CaMKIIα, PKCα, and ERK phosphorylation was restored by acute ST101 administration in the OBX mouse hippocampal CA1 region. Enhancement of CaMKIIα and PKCα but not ERK phosphorylation was inhibited by mibefradil (20 mg/kg, i.p.) preadministration. Increased CaMKIIα and PKCα phosphorylation was confirmed by increased phosphorylation of GluR1, synapsin I, and NR1. Taken together, stimulation of T-type VGCCs is critical for the enhanced hippocampal ACh release and improved Cognitive function seen following ST101 administration.
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t type voltage gated calcium channel activated by st101 is a novel molecular target as Cognitive Enhancer
Alzheimers & Dementia, 2012Co-Authors: Shigeki Moriguchi, Kohji FukunagaAbstract:an increase. Accordingly, Western blotting revealed decreases in C83 and the constitutive a -secretase ADAM10, suggesting that blockade of T-type channels downregulates the non-amyloidogenic processing pathway of APP. Notably, no significant changes in tau pathology were observed. However, the cleavage of p35 to p25, which is carried out by calpains, was dramatically reduced with treatment. Further investigation revealed that calpain 1 and 2 protein levels were decreased with drug treatment. Another substrate of calpains, spectrin, was also analyzed in these samples and was found to be similarly decreased in drug-treated mice compared to controls, suggesting that T-type calcium currents contribute substantially to the regulation of calpains.Conclusions: From our results, we conclude that age-related reductions in T-type calcium channels may have the potential to push APP processing toward the amyloidogenic pathway. This could, in turn, predispose the aging brain to develop Alzheimer’s disease.
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the t type voltage gated calcium channel as a molecular target of the novel Cognitive Enhancer st101 enhancement of long term potentiation and camkii autophosphorylation in rat cortical slices
Journal of Neurochemistry, 2012Co-Authors: Shigeki Moriguchi, Norifumi Shioda, Yui Yamamoto, Hideaki Tagashira, Kohji FukunagaAbstract:J. Neurochem. (2012) 121, 44–53. Abstract In this study, we report that spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ST101; previously coded as ZSET1446) targets T-type voltage-gated calcium channels in mediating improved cognition in the CNS. We prepared rat somatosensory cortical and hippocampal slices, treated them with 0.01 to 100 nM ST101, and performed immunoblotting and electrophysiological analyses using various voltage-gated calcium channel (VGCC) inhibitors. Treatment of rat cortical slices with a range of ST101 concentrations significantly increased calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation following a bell-shaped dose–response curve, with 0.1 nM ST101 representing the maximally effective concentration. protein kinase Cα autophosphorylation was also significantly increased by 0.1 nM ST101 treatment. ST101 treatment had a moderate effect on CaMKII autophosphorylation but no effect on hippocampal protein kinase Cα autophosphorylation in slice preparations. Consistent with increased cortical CaMKII autophosphorylation, AMPA-type glutamate receptor subunit 1 (Ser-831) phosphorylation as a CaMKII post-synaptic substrate was significantly increased by treatment with 0.1–1 nM ST101, whereas phosphorylation of the pre-synaptic substrate synapsin I (Ser-603) remained unchanged. Notably, enhanced CaMKII autophosphorylation seen following 0.1 nM ST101 treatment was significantly inhibited by pre-treatment with 1 μM mibefradil, a T-type VGCC inhibitor, but not with N-type (ω-conotoxin), P/Q-type (ω-agatoxin) or L-type (nifedipine) VGCC inhibitors. Similarly, 0.1 nM ST101 significantly potentiated long-term potentiation in cortical but not hippocampal slices. Enhanced long-term potentiation in cortical slices was totally inhibited by 1 μM mibefadil treatment. Finally, whole-cell patch-clamp analysis of Neuro2A cells over-expressing recombinant human CaV3.1 (α1G) T-channels and treated with 0.1 nM ST101 showed significant increases in T-type VGCC currents. These results indicate that T-type VGCCs are direct molecular targets for the novel Cognitive Enhancer ST101, a potential Alzheimer disease therapeutic.
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a novel Cognitive Enhancer zset1446 st101 promotes hippocampal neurogenesis and ameliorates depressive behavior in olfactory bulbectomized mice
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Norifumi Shioda, Yoshimasa Yamaguchi, Yui Yamamoto, Feng Han, Shigeki Moriguchi, Masataka Hino, Kohji FukunagaAbstract: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.
Shigeki Moriguchi - One of the best experts on this subject based on the ideXlab platform.
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the novel Cognitive Enhancer st101 enhances acetylcholine release in mouse dorsal hippocampus through t type voltage gated calcium channel stimulation
Journal of Pharmacological Sciences, 2013Co-Authors: Yui Yamamoto, Norifumi Shioda, Feng Han, Shigeki Moriguchi, Kohji FukunagaAbstract:We recently developed a novel Cognitive Enhancer, ST101 (spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one), that activates T-type voltage-gated calcium channels (VGCCs). Here, we address whether T-type VGCC activation with ST101 mediates its Cognitive effects in vivo and the relevance of T-type VGCC activation to acetylcholine (ACh) release in the hippocampus. Acute intraperitoneal administration of ST101 (1 mg/kg, i.p.) improved memory-related behaviors in both olfactory bulbectomized (OBX) and scopolamine-treated mice. Effects of ST101 administration were abolished by both intraperitoneal and intracerebroventricular pre-administration of the T-type VGCC inhibitor mibefradil. Acute administration of ST101 enhanced basal and nicotine-induced ACh release in the dorsal hippocampus in both OBX and sham-treated mice. Enhanced ACh release was abolished by infusion with mibefradil (10 μM) but not with the L-type VGCC inhibitor nifedipine (10 μM). As expected, significantly reduced CaMKIIα, PKCα, and ERK phosphorylation was restored by acute ST101 administration in the OBX mouse hippocampal CA1 region. Enhancement of CaMKIIα and PKCα but not ERK phosphorylation was inhibited by mibefradil (20 mg/kg, i.p.) preadministration. Increased CaMKIIα and PKCα phosphorylation was confirmed by increased phosphorylation of GluR1, synapsin I, and NR1. Taken together, stimulation of T-type VGCCs is critical for the enhanced hippocampal ACh release and improved Cognitive function seen following ST101 administration.
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t type voltage gated calcium channel activated by st101 is a novel molecular target as Cognitive Enhancer
Alzheimers & Dementia, 2012Co-Authors: Shigeki Moriguchi, Kohji FukunagaAbstract:an increase. Accordingly, Western blotting revealed decreases in C83 and the constitutive a -secretase ADAM10, suggesting that blockade of T-type channels downregulates the non-amyloidogenic processing pathway of APP. Notably, no significant changes in tau pathology were observed. However, the cleavage of p35 to p25, which is carried out by calpains, was dramatically reduced with treatment. Further investigation revealed that calpain 1 and 2 protein levels were decreased with drug treatment. Another substrate of calpains, spectrin, was also analyzed in these samples and was found to be similarly decreased in drug-treated mice compared to controls, suggesting that T-type calcium currents contribute substantially to the regulation of calpains.Conclusions: From our results, we conclude that age-related reductions in T-type calcium channels may have the potential to push APP processing toward the amyloidogenic pathway. This could, in turn, predispose the aging brain to develop Alzheimer’s disease.
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the t type voltage gated calcium channel as a molecular target of the novel Cognitive Enhancer st101 enhancement of long term potentiation and camkii autophosphorylation in rat cortical slices
Journal of Neurochemistry, 2012Co-Authors: Shigeki Moriguchi, Norifumi Shioda, Yui Yamamoto, Hideaki Tagashira, Kohji FukunagaAbstract:J. Neurochem. (2012) 121, 44–53. Abstract In this study, we report that spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ST101; previously coded as ZSET1446) targets T-type voltage-gated calcium channels in mediating improved cognition in the CNS. We prepared rat somatosensory cortical and hippocampal slices, treated them with 0.01 to 100 nM ST101, and performed immunoblotting and electrophysiological analyses using various voltage-gated calcium channel (VGCC) inhibitors. Treatment of rat cortical slices with a range of ST101 concentrations significantly increased calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation following a bell-shaped dose–response curve, with 0.1 nM ST101 representing the maximally effective concentration. protein kinase Cα autophosphorylation was also significantly increased by 0.1 nM ST101 treatment. ST101 treatment had a moderate effect on CaMKII autophosphorylation but no effect on hippocampal protein kinase Cα autophosphorylation in slice preparations. Consistent with increased cortical CaMKII autophosphorylation, AMPA-type glutamate receptor subunit 1 (Ser-831) phosphorylation as a CaMKII post-synaptic substrate was significantly increased by treatment with 0.1–1 nM ST101, whereas phosphorylation of the pre-synaptic substrate synapsin I (Ser-603) remained unchanged. Notably, enhanced CaMKII autophosphorylation seen following 0.1 nM ST101 treatment was significantly inhibited by pre-treatment with 1 μM mibefradil, a T-type VGCC inhibitor, but not with N-type (ω-conotoxin), P/Q-type (ω-agatoxin) or L-type (nifedipine) VGCC inhibitors. Similarly, 0.1 nM ST101 significantly potentiated long-term potentiation in cortical but not hippocampal slices. Enhanced long-term potentiation in cortical slices was totally inhibited by 1 μM mibefadil treatment. Finally, whole-cell patch-clamp analysis of Neuro2A cells over-expressing recombinant human CaV3.1 (α1G) T-channels and treated with 0.1 nM ST101 showed significant increases in T-type VGCC currents. These results indicate that T-type VGCCs are direct molecular targets for the novel Cognitive Enhancer ST101, a potential Alzheimer disease therapeutic.
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a novel Cognitive Enhancer zset1446 st101 promotes hippocampal neurogenesis and ameliorates depressive behavior in olfactory bulbectomized mice
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Norifumi Shioda, Yoshimasa Yamaguchi, Yui Yamamoto, Feng Han, Shigeki Moriguchi, Masataka Hino, Kohji FukunagaAbstract: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.
Yui Yamamoto - One of the best experts on this subject based on the ideXlab platform.
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the novel Cognitive Enhancer st101 enhances acetylcholine release in mouse dorsal hippocampus through t type voltage gated calcium channel stimulation
Journal of Pharmacological Sciences, 2013Co-Authors: Yui Yamamoto, Norifumi Shioda, Feng Han, Shigeki Moriguchi, Kohji FukunagaAbstract:We recently developed a novel Cognitive Enhancer, ST101 (spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one), that activates T-type voltage-gated calcium channels (VGCCs). Here, we address whether T-type VGCC activation with ST101 mediates its Cognitive effects in vivo and the relevance of T-type VGCC activation to acetylcholine (ACh) release in the hippocampus. Acute intraperitoneal administration of ST101 (1 mg/kg, i.p.) improved memory-related behaviors in both olfactory bulbectomized (OBX) and scopolamine-treated mice. Effects of ST101 administration were abolished by both intraperitoneal and intracerebroventricular pre-administration of the T-type VGCC inhibitor mibefradil. Acute administration of ST101 enhanced basal and nicotine-induced ACh release in the dorsal hippocampus in both OBX and sham-treated mice. Enhanced ACh release was abolished by infusion with mibefradil (10 μM) but not with the L-type VGCC inhibitor nifedipine (10 μM). As expected, significantly reduced CaMKIIα, PKCα, and ERK phosphorylation was restored by acute ST101 administration in the OBX mouse hippocampal CA1 region. Enhancement of CaMKIIα and PKCα but not ERK phosphorylation was inhibited by mibefradil (20 mg/kg, i.p.) preadministration. Increased CaMKIIα and PKCα phosphorylation was confirmed by increased phosphorylation of GluR1, synapsin I, and NR1. Taken together, stimulation of T-type VGCCs is critical for the enhanced hippocampal ACh release and improved Cognitive function seen following ST101 administration.
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the t type voltage gated calcium channel as a molecular target of the novel Cognitive Enhancer st101 enhancement of long term potentiation and camkii autophosphorylation in rat cortical slices
Journal of Neurochemistry, 2012Co-Authors: Shigeki Moriguchi, Norifumi Shioda, Yui Yamamoto, Hideaki Tagashira, Kohji FukunagaAbstract:J. Neurochem. (2012) 121, 44–53. Abstract In this study, we report that spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ST101; previously coded as ZSET1446) targets T-type voltage-gated calcium channels in mediating improved cognition in the CNS. We prepared rat somatosensory cortical and hippocampal slices, treated them with 0.01 to 100 nM ST101, and performed immunoblotting and electrophysiological analyses using various voltage-gated calcium channel (VGCC) inhibitors. Treatment of rat cortical slices with a range of ST101 concentrations significantly increased calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation following a bell-shaped dose–response curve, with 0.1 nM ST101 representing the maximally effective concentration. protein kinase Cα autophosphorylation was also significantly increased by 0.1 nM ST101 treatment. ST101 treatment had a moderate effect on CaMKII autophosphorylation but no effect on hippocampal protein kinase Cα autophosphorylation in slice preparations. Consistent with increased cortical CaMKII autophosphorylation, AMPA-type glutamate receptor subunit 1 (Ser-831) phosphorylation as a CaMKII post-synaptic substrate was significantly increased by treatment with 0.1–1 nM ST101, whereas phosphorylation of the pre-synaptic substrate synapsin I (Ser-603) remained unchanged. Notably, enhanced CaMKII autophosphorylation seen following 0.1 nM ST101 treatment was significantly inhibited by pre-treatment with 1 μM mibefradil, a T-type VGCC inhibitor, but not with N-type (ω-conotoxin), P/Q-type (ω-agatoxin) or L-type (nifedipine) VGCC inhibitors. Similarly, 0.1 nM ST101 significantly potentiated long-term potentiation in cortical but not hippocampal slices. Enhanced long-term potentiation in cortical slices was totally inhibited by 1 μM mibefadil treatment. Finally, whole-cell patch-clamp analysis of Neuro2A cells over-expressing recombinant human CaV3.1 (α1G) T-channels and treated with 0.1 nM ST101 showed significant increases in T-type VGCC currents. These results indicate that T-type VGCCs are direct molecular targets for the novel Cognitive Enhancer ST101, a potential Alzheimer disease therapeutic.
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a novel Cognitive Enhancer zset1446 st101 promotes hippocampal neurogenesis and ameliorates depressive behavior in olfactory bulbectomized mice
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Norifumi Shioda, Yoshimasa Yamaguchi, Yui Yamamoto, Feng Han, Shigeki Moriguchi, Masataka Hino, Kohji FukunagaAbstract: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.
Norifumi Shioda - One of the best experts on this subject based on the ideXlab platform.
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the novel Cognitive Enhancer st101 enhances acetylcholine release in mouse dorsal hippocampus through t type voltage gated calcium channel stimulation
Journal of Pharmacological Sciences, 2013Co-Authors: Yui Yamamoto, Norifumi Shioda, Feng Han, Shigeki Moriguchi, Kohji FukunagaAbstract:We recently developed a novel Cognitive Enhancer, ST101 (spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one), that activates T-type voltage-gated calcium channels (VGCCs). Here, we address whether T-type VGCC activation with ST101 mediates its Cognitive effects in vivo and the relevance of T-type VGCC activation to acetylcholine (ACh) release in the hippocampus. Acute intraperitoneal administration of ST101 (1 mg/kg, i.p.) improved memory-related behaviors in both olfactory bulbectomized (OBX) and scopolamine-treated mice. Effects of ST101 administration were abolished by both intraperitoneal and intracerebroventricular pre-administration of the T-type VGCC inhibitor mibefradil. Acute administration of ST101 enhanced basal and nicotine-induced ACh release in the dorsal hippocampus in both OBX and sham-treated mice. Enhanced ACh release was abolished by infusion with mibefradil (10 μM) but not with the L-type VGCC inhibitor nifedipine (10 μM). As expected, significantly reduced CaMKIIα, PKCα, and ERK phosphorylation was restored by acute ST101 administration in the OBX mouse hippocampal CA1 region. Enhancement of CaMKIIα and PKCα but not ERK phosphorylation was inhibited by mibefradil (20 mg/kg, i.p.) preadministration. Increased CaMKIIα and PKCα phosphorylation was confirmed by increased phosphorylation of GluR1, synapsin I, and NR1. Taken together, stimulation of T-type VGCCs is critical for the enhanced hippocampal ACh release and improved Cognitive function seen following ST101 administration.
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the t type voltage gated calcium channel as a molecular target of the novel Cognitive Enhancer st101 enhancement of long term potentiation and camkii autophosphorylation in rat cortical slices
Journal of Neurochemistry, 2012Co-Authors: Shigeki Moriguchi, Norifumi Shioda, Yui Yamamoto, Hideaki Tagashira, Kohji FukunagaAbstract:J. Neurochem. (2012) 121, 44–53. Abstract In this study, we report that spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ST101; previously coded as ZSET1446) targets T-type voltage-gated calcium channels in mediating improved cognition in the CNS. We prepared rat somatosensory cortical and hippocampal slices, treated them with 0.01 to 100 nM ST101, and performed immunoblotting and electrophysiological analyses using various voltage-gated calcium channel (VGCC) inhibitors. Treatment of rat cortical slices with a range of ST101 concentrations significantly increased calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation following a bell-shaped dose–response curve, with 0.1 nM ST101 representing the maximally effective concentration. protein kinase Cα autophosphorylation was also significantly increased by 0.1 nM ST101 treatment. ST101 treatment had a moderate effect on CaMKII autophosphorylation but no effect on hippocampal protein kinase Cα autophosphorylation in slice preparations. Consistent with increased cortical CaMKII autophosphorylation, AMPA-type glutamate receptor subunit 1 (Ser-831) phosphorylation as a CaMKII post-synaptic substrate was significantly increased by treatment with 0.1–1 nM ST101, whereas phosphorylation of the pre-synaptic substrate synapsin I (Ser-603) remained unchanged. Notably, enhanced CaMKII autophosphorylation seen following 0.1 nM ST101 treatment was significantly inhibited by pre-treatment with 1 μM mibefradil, a T-type VGCC inhibitor, but not with N-type (ω-conotoxin), P/Q-type (ω-agatoxin) or L-type (nifedipine) VGCC inhibitors. Similarly, 0.1 nM ST101 significantly potentiated long-term potentiation in cortical but not hippocampal slices. Enhanced long-term potentiation in cortical slices was totally inhibited by 1 μM mibefadil treatment. Finally, whole-cell patch-clamp analysis of Neuro2A cells over-expressing recombinant human CaV3.1 (α1G) T-channels and treated with 0.1 nM ST101 showed significant increases in T-type VGCC currents. These results indicate that T-type VGCCs are direct molecular targets for the novel Cognitive Enhancer ST101, a potential Alzheimer disease therapeutic.
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a novel Cognitive Enhancer zset1446 st101 promotes hippocampal neurogenesis and ameliorates depressive behavior in olfactory bulbectomized mice
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Norifumi Shioda, Yoshimasa Yamaguchi, Yui Yamamoto, Feng Han, Shigeki Moriguchi, Masataka Hino, Kohji FukunagaAbstract: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.
Sanyogita Ram - One of the best experts on this subject based on the ideXlab platform.
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attitudes toward Cognitive Enhancer use among new zealand tertiary students
Substance Use & Misuse, 2017Co-Authors: Sanyogita Ram, Safeera Yasmeen Hussainy, Marcus A Henning, Maree Jensen, Kay Stewart, Bruce R RussellAbstract:ABSTRACTBackground: Cognitive enhancement is the use of prescription stimulant medicines by healthy individuals for nonmedical use in academic settings. Commonly used Cognitive Enhancers (CEs) include methylphenidate, amphetamines, and modafinil. To understand the motivation to use CEs, it is important to look beyond prevalence and explore the extent to which attitudes, beliefs, and intentions predict the decision to use CEs. Objective: The study aimed to investigate what factors explain the decision to use CEs among tertiary students in New Zealand, using the Theory of Planned Behaviour (TPB). Methods: Students from the Schools of Pharmacy, Nursing, Medicine, Law, and Accounting at a university in New Zealand were invited to complete a paper-based questionnaire. The questionnaire elicited students' attitudes, subjective norms, and perceived control toward illicit use of CEs using TPB. An exploratory factor analysis was conducted. Results: Response rate was 88.6% (442/499). Students who perceived CE use t...
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prevalence of Cognitive Enhancer use among new zealand tertiary students
Drug and Alcohol Review, 2016Co-Authors: Sanyogita Ram, Safeera Yasmeen Hussainy, Marcus A Henning, Maree Jensen, Bruce R RussellAbstract:Introduction and Aims Cognitive Enhancers (CE) such as methylphenidate, amphetamines and modafinil are becoming more commonly used in non-medical situations. This study explored the prevalence and motivations for CE use in a New Zealand university. Design and Methods Students from the Schools of Pharmacy, Nursing, Medicine, Law and Accounting at a university in New Zealand were invited to complete a paper-based questionnaire that elicited their views on the prevalence, reasons for use and attitudes towards use of CEs. Questionnaires were distributed at the end of a third-year lecture (August–October 2012). Reasons for use and attitudes towards use was measured using a 7-point Likert scale from strongly agree (1) to strongly disagree (7). Descriptive and prevalence statistics were calculated. Inferential statistics were generated to explore the overall associations between CE use and how the respondents had first learnt about CEs, and to investigate reasons for CE use. Results The response fraction was 88.6 % (442/499) and the prevalence of CE use was 6.6% (95% confidence interval 4.5–9.0). Commonly cited reasons for use were to get high [M = 4.43, standard deviation (SD) 2.36], experimentation (M = 4.17, SD 2.36), increase alertness (M = 3.55, SD 2.48), to help concentrate (M = 3.48, SD 2.42), to help stay awake (M = 3.20, SD 2.33), to help study (M = 3.10, SD 2.47) and to concentrate better while studying (M = 3.00, SD 2.43). Discussion and Conclusions Use of CEs was uncommon in contrast to the prevalence reported in the USA. The reasons for use also varied depending on which CE was used. Students who use CEs have differing attitudes towards their acceptability, which warrants further research about how these attitudes influence their use and attitudes towards academic performance. [Ram S(S), Hussainy S, Henning M, Jensen M, Russell B. Prevalence of Cognitive Enhancer use among New Zealand tertiary students. Drug Alcohol Rev 2015]