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Kenji Hashimoto - One of the best experts on this subject based on the ideXlab platform.
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rapid acting antidepressant ketamine its metabolites and other candidates a historical overview and future perspective
Psychiatry and Clinical Neurosciences, 2019Co-Authors: Kenji HashimotoAbstract:Major depressive disorder (MDD) is one of the most disabling psychiatric disorders. Approximately one-third of the patients with MDD are treatment resistant to the current antidepressants. There is also a significant therapeutic time lag of weeks to months. Furthermore, depression in patients with bipolar disorder (BD) is typically poorly responsive to antidepressants. Therefore, there exists an unmet medical need for rapidly acting antidepressants with beneficial effects in treatment-resistant patients with MDD or BD. Accumulating evidence suggests that the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid and sustained antidepressant effects in treatment-resistant patients with MDD or BD. Ketamine is a racemic mixture comprising equal parts of (R)-ketamine (or arketamine) and (S)-ketamine (or esketamine). Because (S)-ketamine has higher affinity for NMDAR than (R)-ketamine, esketamine was developed as an antidepressant. On 5 March 2019, esketamine nasal spray was approved by the US Food and Drug Administration. However, preclinical data suggest that (R)-ketamine exerts greater potency and longer-lasting antidepressant effects than (S)-ketamine in animal models of depression and that (R)-ketamine has less detrimental side-effects than (R,S)-ketamine or (S)-ketamine. In this article, the author reviews the historical overview of the antidepressant actions of enantiomers of ketamine and its major metabolites norketamine and hydroxynorketamine. Furthermore, the author discusses the other potential rapid-acting antidepressant candidates (i.e., NMDAR antagonists and modulators, low-voltage-sensitive T-type calcium channel inhibitor, potassium channel Kir4.1 inhibitor, negative modulators of γ-aminobutyric acid, and type A [GABAA ] receptors) to compare them with ketamine. Moreover, the molecular and cellular mechanisms of ketamine's antidepressant effects are discussed.
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expression of heat shock protein hsp 70 in the retrosplenial cortex of rat brain after administration of r s ketamine and s ketamine but not r ketamine
Pharmacology Biochemistry and Behavior, 2018Co-Authors: Zheng Tian, Chao Dong, Yuko Fujita, Atsuhiro Fujita, Kenji HashimotoAbstract:The N-methyl-d-aspartate receptor (NMDAR) antagonist (R,S)-ketamine has robust antidepressant effects in depressed patients although it has detrimental side effects such as psychotomimetic and dissociative symptoms. (R,S)-Ketamine is known to cause the expression of heat shock protein HSP-70 (a marker for neuronal injury) in the retrosplenial cortex of rat brain, suggesting that the neuropathological changes may play a role in the detrimental side effects of (R,S)-ketamine. This study was undertaken to examine whether (R,S)-ketamine and its two enantiomers, (R)-ketamine and (S)-ketamine, causes the expression of HSP-70 in the rat retrosplenial cortex after a single administration. The HSP-70 immunohistochemistry in the rat brain was performed 24 h after intraperitoneal administration of saline (1 ml/kg), (+)-MK-801 (or dizocilpine: 1.0 mg/kg), (R,S)-ketamine (100 mg/kg), (S)-ketamine (25, 50, or 75, mg/kg), or (R)-ketamine (25, 50, or 75 mg/kg). Marked expression of HSP-70 immunoreactivity in the retrosplenial cortex was detected after administration of dizocilpine or (R,S)-ketamine (100 mg/kg). Higher does (50 and 75 mg/kg) of (S)-ketamine, but not low dose (25 mg/kg), caused expression of HSP-70 in this region. In contrast, all doses of (R)-ketamine did not induce the expression of HSP-70 in this region. These findings suggest that marked expression of HSP-70 in the retrosplenial cortex after a single dose of (R,S)-ketamine or (S)-ketamine may have detrimental side effects in the rat brain. Therefore, it is likely that (R)-ketamine is a safer compound in humans than (R,S)-ketamine and (S)-ketamine.
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mechanistic target of rapamycin independent antidepressant effects of r ketamine in a social defeat stress model
Biological Psychiatry, 2018Co-Authors: Chun Yang, Chao Dong, Jichun Zhang, Qian Ren, Kenji HashimotoAbstract:Abstract Background The role of the mechanistic target of rapamycin (mTOR) signaling in the antidepressant effects of ketamine is controversial. In addition to mTOR, extracellular signal-regulated kinase (ERK) is a key signaling molecule in prominent pathways that regulate protein synthesis. ( R )-Ketamine has a greater potency and longer-lasting antidepressant effects than ( S )-ketamine. Here we investigated whether mTOR signaling and ERK signaling play a role in the antidepressant effects of two enantiomers. Methods The effects of mTOR inhibitors (rapamycin and AZD8055) and an ERK inhibitor (SL327) on the antidepressant effects of ketamine enantiomers in the chronic social defeat stress (CSDS) model ( n = 7 or 8) and on those of ketamine enantiomers in these signaling pathways in mouse brain regions were examined. Results The intracerebroventricular infusion of rapamycin or AZD8055 blocked the antidepressant effects of ( S )-ketamine, but not ( R )-ketamine, in the CSDS model. Furthermore, ( S )-ketamine, but not ( R )-ketamine, significantly attenuated the decreased phosphorylation of mTOR and its downstream effector, ribosomal protein S6 kinase, in the prefrontal cortex of susceptible mice after CSDS. Pretreatment with SL327 blocked the antidepressant effects of ( R )-ketamine but not ( S )-ketamine. Moreover, ( R )-ketamine, but not ( S )-ketamine, significantly attenuated the decreased phosphorylation of ERK and its upstream effector, mitogen-activated protein kinase/ERK kinase, in the prefrontal cortex and hippocampal dentate gyrus of susceptible mice after CSDS. Conclusions This study suggests that mTOR plays a role in the antidepressant effects of ( S )-ketamine, but not ( R )-ketamine, and that ERK plays a role in ( R )-ketamine’s antidepressant effects. Thus, it is unlikely that the activation of mTOR signaling is necessary for antidepressant actions of ( R )-ketamine.
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possible role of the gut microbiota brain axis in the antidepressant effects of r ketamine in a social defeat stress model
Translational Psychiatry, 2017Co-Authors: Chao Dong, Yuko Fujita, Chun Yang, Qian Ren, Kenji HashimotoAbstract:Accumulating evidence suggests that the gut microbiota-brain axis plays a role in the pathogenesis of depression, thereby contributing to the antidepressant actions of certain compounds. (R)-ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here, we investigated whether the gut microbiota plays a role in the antidepressant effects of these two ketamine enantiomers. The role of the gut microbiota in the antidepressant effects of ketamine enantiomers in a chronic social defeat stress (CSDS) model of depression was examined using 16S ribosomal RNA gene sequencing of fecal samples. At the phylum level, CSDS-susceptible mice showed alterations in the levels of Tenericutes and Actinobacteria; however, neither ketamine enantiomers influenced these alterations. At the class level, both ketamine enantiomers significantly attenuated the increase in the levels of Deltaproteobacteria in the susceptible mice after CSDS. Furthermore, (R)-ketamine, but not (S)-ketamine, significantly attenuated the reduction in the levels of Mollicutes in the susceptible mice. At the genus level, both ketamine enantiomers significantly attenuated the decrease in the levels of Butyricimonas in the susceptible mice. Notably, (R)-ketamine was more potent than (S)-ketamine at reducing the levels of Butyricimonas in the susceptible mice. In conclusion, this study suggests that the antidepressant effects of two enantiomers of ketamine in CSDS model may be partly mediated by the restoration of the gut microbiota. Furthermore, the specific effect of (R)-ketamine on the levels of Mollicutes and Butyricimonas may explain its robust antidepressant action.
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Possible role of the gut microbiota–brain axis in the antidepressant effects of (R)-ketamine in a social defeat stress model
Nature Publishing Group, 2017Co-Authors: Chun Yang, Chao Dong, Yuko Fujita, Qian Ren, Kenji HashimotoAbstract:Abstract Accumulating evidence suggests that the gut microbiota–brain axis plays a role in the pathogenesis of depression, thereby contributing to the antidepressant actions of certain compounds. (R)-ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here, we investigated whether the gut microbiota plays a role in the antidepressant effects of these two ketamine enantiomers. The role of the gut microbiota in the antidepressant effects of ketamine enantiomers in a chronic social defeat stress (CSDS) model of depression was examined using 16S ribosomal RNA gene sequencing of fecal samples. At the phylum level, CSDS-susceptible mice showed alterations in the levels of Tenericutes and Actinobacteria; however, neither ketamine enantiomers influenced these alterations. At the class level, both ketamine enantiomers significantly attenuated the increase in the levels of Deltaproteobacteria in the susceptible mice after CSDS. Furthermore, (R)-ketamine, but not (S)-ketamine, significantly attenuated the reduction in the levels of Mollicutes in the susceptible mice. At the genus level, both ketamine enantiomers significantly attenuated the decrease in the levels of Butyricimonas in the susceptible mice. Notably, (R)-ketamine was more potent than (S)-ketamine at reducing the levels of Butyricimonas in the susceptible mice. In conclusion, this study suggests that the antidepressant effects of two enantiomers of ketamine in CSDS model may be partly mediated by the restoration of the gut microbiota. Furthermore, the specific effect of (R)-ketamine on the levels of Mollicutes and Butyricimonas may explain its robust antidepressant action
Chun Yang - One of the best experts on this subject based on the ideXlab platform.
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mechanistic target of rapamycin independent antidepressant effects of r ketamine in a social defeat stress model
Biological Psychiatry, 2018Co-Authors: Chun Yang, Chao Dong, Jichun Zhang, Qian Ren, Kenji HashimotoAbstract:Abstract Background The role of the mechanistic target of rapamycin (mTOR) signaling in the antidepressant effects of ketamine is controversial. In addition to mTOR, extracellular signal-regulated kinase (ERK) is a key signaling molecule in prominent pathways that regulate protein synthesis. ( R )-Ketamine has a greater potency and longer-lasting antidepressant effects than ( S )-ketamine. Here we investigated whether mTOR signaling and ERK signaling play a role in the antidepressant effects of two enantiomers. Methods The effects of mTOR inhibitors (rapamycin and AZD8055) and an ERK inhibitor (SL327) on the antidepressant effects of ketamine enantiomers in the chronic social defeat stress (CSDS) model ( n = 7 or 8) and on those of ketamine enantiomers in these signaling pathways in mouse brain regions were examined. Results The intracerebroventricular infusion of rapamycin or AZD8055 blocked the antidepressant effects of ( S )-ketamine, but not ( R )-ketamine, in the CSDS model. Furthermore, ( S )-ketamine, but not ( R )-ketamine, significantly attenuated the decreased phosphorylation of mTOR and its downstream effector, ribosomal protein S6 kinase, in the prefrontal cortex of susceptible mice after CSDS. Pretreatment with SL327 blocked the antidepressant effects of ( R )-ketamine but not ( S )-ketamine. Moreover, ( R )-ketamine, but not ( S )-ketamine, significantly attenuated the decreased phosphorylation of ERK and its upstream effector, mitogen-activated protein kinase/ERK kinase, in the prefrontal cortex and hippocampal dentate gyrus of susceptible mice after CSDS. Conclusions This study suggests that mTOR plays a role in the antidepressant effects of ( S )-ketamine, but not ( R )-ketamine, and that ERK plays a role in ( R )-ketamine’s antidepressant effects. Thus, it is unlikely that the activation of mTOR signaling is necessary for antidepressant actions of ( R )-ketamine.
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possible role of the gut microbiota brain axis in the antidepressant effects of r ketamine in a social defeat stress model
Translational Psychiatry, 2017Co-Authors: Chao Dong, Yuko Fujita, Chun Yang, Qian Ren, Kenji HashimotoAbstract:Accumulating evidence suggests that the gut microbiota-brain axis plays a role in the pathogenesis of depression, thereby contributing to the antidepressant actions of certain compounds. (R)-ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here, we investigated whether the gut microbiota plays a role in the antidepressant effects of these two ketamine enantiomers. The role of the gut microbiota in the antidepressant effects of ketamine enantiomers in a chronic social defeat stress (CSDS) model of depression was examined using 16S ribosomal RNA gene sequencing of fecal samples. At the phylum level, CSDS-susceptible mice showed alterations in the levels of Tenericutes and Actinobacteria; however, neither ketamine enantiomers influenced these alterations. At the class level, both ketamine enantiomers significantly attenuated the increase in the levels of Deltaproteobacteria in the susceptible mice after CSDS. Furthermore, (R)-ketamine, but not (S)-ketamine, significantly attenuated the reduction in the levels of Mollicutes in the susceptible mice. At the genus level, both ketamine enantiomers significantly attenuated the decrease in the levels of Butyricimonas in the susceptible mice. Notably, (R)-ketamine was more potent than (S)-ketamine at reducing the levels of Butyricimonas in the susceptible mice. In conclusion, this study suggests that the antidepressant effects of two enantiomers of ketamine in CSDS model may be partly mediated by the restoration of the gut microbiota. Furthermore, the specific effect of (R)-ketamine on the levels of Mollicutes and Butyricimonas may explain its robust antidepressant action.
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Possible role of the gut microbiota–brain axis in the antidepressant effects of (R)-ketamine in a social defeat stress model
Nature Publishing Group, 2017Co-Authors: Chun Yang, Chao Dong, Yuko Fujita, Qian Ren, Kenji HashimotoAbstract:Abstract Accumulating evidence suggests that the gut microbiota–brain axis plays a role in the pathogenesis of depression, thereby contributing to the antidepressant actions of certain compounds. (R)-ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here, we investigated whether the gut microbiota plays a role in the antidepressant effects of these two ketamine enantiomers. The role of the gut microbiota in the antidepressant effects of ketamine enantiomers in a chronic social defeat stress (CSDS) model of depression was examined using 16S ribosomal RNA gene sequencing of fecal samples. At the phylum level, CSDS-susceptible mice showed alterations in the levels of Tenericutes and Actinobacteria; however, neither ketamine enantiomers influenced these alterations. At the class level, both ketamine enantiomers significantly attenuated the increase in the levels of Deltaproteobacteria in the susceptible mice after CSDS. Furthermore, (R)-ketamine, but not (S)-ketamine, significantly attenuated the reduction in the levels of Mollicutes in the susceptible mice. At the genus level, both ketamine enantiomers significantly attenuated the decrease in the levels of Butyricimonas in the susceptible mice. Notably, (R)-ketamine was more potent than (S)-ketamine at reducing the levels of Butyricimonas in the susceptible mice. In conclusion, this study suggests that the antidepressant effects of two enantiomers of ketamine in CSDS model may be partly mediated by the restoration of the gut microbiota. Furthermore, the specific effect of (R)-ketamine on the levels of Mollicutes and Butyricimonas may explain its robust antidepressant action
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r ketamine a rapid onset and sustained antidepressant without psychotomimetic side effects
Translational Psychiatry, 2015Co-Authors: Chun Yang, Chao Dong, Qian Ren, Yukihiko Shirayama, Jiancheng Zhang, W Yao, Kenji HashimotoAbstract:Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clinical use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examined the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)–TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamine (esketamine). Furthermore, R-ketamine induced a more potent beneficial effect on decreased dendritic spine density, BDNF–TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S-ketamine, but not R-ketamine, precipitated behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addition, a single dose of S-ketamine, but not R-ketamine, caused a loss of parvalbumin (PV)-positive cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S-ketamine, R-ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF–TrkB signaling and synaptogenesis in the PFC, DG and CA3. R-ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S-ketamine, as R-ketamine appears to be free of psychotomimetic side effects and abuse liability.
Chao Dong - One of the best experts on this subject based on the ideXlab platform.
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expression of heat shock protein hsp 70 in the retrosplenial cortex of rat brain after administration of r s ketamine and s ketamine but not r ketamine
Pharmacology Biochemistry and Behavior, 2018Co-Authors: Zheng Tian, Chao Dong, Yuko Fujita, Atsuhiro Fujita, Kenji HashimotoAbstract:The N-methyl-d-aspartate receptor (NMDAR) antagonist (R,S)-ketamine has robust antidepressant effects in depressed patients although it has detrimental side effects such as psychotomimetic and dissociative symptoms. (R,S)-Ketamine is known to cause the expression of heat shock protein HSP-70 (a marker for neuronal injury) in the retrosplenial cortex of rat brain, suggesting that the neuropathological changes may play a role in the detrimental side effects of (R,S)-ketamine. This study was undertaken to examine whether (R,S)-ketamine and its two enantiomers, (R)-ketamine and (S)-ketamine, causes the expression of HSP-70 in the rat retrosplenial cortex after a single administration. The HSP-70 immunohistochemistry in the rat brain was performed 24 h after intraperitoneal administration of saline (1 ml/kg), (+)-MK-801 (or dizocilpine: 1.0 mg/kg), (R,S)-ketamine (100 mg/kg), (S)-ketamine (25, 50, or 75, mg/kg), or (R)-ketamine (25, 50, or 75 mg/kg). Marked expression of HSP-70 immunoreactivity in the retrosplenial cortex was detected after administration of dizocilpine or (R,S)-ketamine (100 mg/kg). Higher does (50 and 75 mg/kg) of (S)-ketamine, but not low dose (25 mg/kg), caused expression of HSP-70 in this region. In contrast, all doses of (R)-ketamine did not induce the expression of HSP-70 in this region. These findings suggest that marked expression of HSP-70 in the retrosplenial cortex after a single dose of (R,S)-ketamine or (S)-ketamine may have detrimental side effects in the rat brain. Therefore, it is likely that (R)-ketamine is a safer compound in humans than (R,S)-ketamine and (S)-ketamine.
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mechanistic target of rapamycin independent antidepressant effects of r ketamine in a social defeat stress model
Biological Psychiatry, 2018Co-Authors: Chun Yang, Chao Dong, Jichun Zhang, Qian Ren, Kenji HashimotoAbstract:Abstract Background The role of the mechanistic target of rapamycin (mTOR) signaling in the antidepressant effects of ketamine is controversial. In addition to mTOR, extracellular signal-regulated kinase (ERK) is a key signaling molecule in prominent pathways that regulate protein synthesis. ( R )-Ketamine has a greater potency and longer-lasting antidepressant effects than ( S )-ketamine. Here we investigated whether mTOR signaling and ERK signaling play a role in the antidepressant effects of two enantiomers. Methods The effects of mTOR inhibitors (rapamycin and AZD8055) and an ERK inhibitor (SL327) on the antidepressant effects of ketamine enantiomers in the chronic social defeat stress (CSDS) model ( n = 7 or 8) and on those of ketamine enantiomers in these signaling pathways in mouse brain regions were examined. Results The intracerebroventricular infusion of rapamycin or AZD8055 blocked the antidepressant effects of ( S )-ketamine, but not ( R )-ketamine, in the CSDS model. Furthermore, ( S )-ketamine, but not ( R )-ketamine, significantly attenuated the decreased phosphorylation of mTOR and its downstream effector, ribosomal protein S6 kinase, in the prefrontal cortex of susceptible mice after CSDS. Pretreatment with SL327 blocked the antidepressant effects of ( R )-ketamine but not ( S )-ketamine. Moreover, ( R )-ketamine, but not ( S )-ketamine, significantly attenuated the decreased phosphorylation of ERK and its upstream effector, mitogen-activated protein kinase/ERK kinase, in the prefrontal cortex and hippocampal dentate gyrus of susceptible mice after CSDS. Conclusions This study suggests that mTOR plays a role in the antidepressant effects of ( S )-ketamine, but not ( R )-ketamine, and that ERK plays a role in ( R )-ketamine’s antidepressant effects. Thus, it is unlikely that the activation of mTOR signaling is necessary for antidepressant actions of ( R )-ketamine.
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possible role of the gut microbiota brain axis in the antidepressant effects of r ketamine in a social defeat stress model
Translational Psychiatry, 2017Co-Authors: Chao Dong, Yuko Fujita, Chun Yang, Qian Ren, Kenji HashimotoAbstract:Accumulating evidence suggests that the gut microbiota-brain axis plays a role in the pathogenesis of depression, thereby contributing to the antidepressant actions of certain compounds. (R)-ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here, we investigated whether the gut microbiota plays a role in the antidepressant effects of these two ketamine enantiomers. The role of the gut microbiota in the antidepressant effects of ketamine enantiomers in a chronic social defeat stress (CSDS) model of depression was examined using 16S ribosomal RNA gene sequencing of fecal samples. At the phylum level, CSDS-susceptible mice showed alterations in the levels of Tenericutes and Actinobacteria; however, neither ketamine enantiomers influenced these alterations. At the class level, both ketamine enantiomers significantly attenuated the increase in the levels of Deltaproteobacteria in the susceptible mice after CSDS. Furthermore, (R)-ketamine, but not (S)-ketamine, significantly attenuated the reduction in the levels of Mollicutes in the susceptible mice. At the genus level, both ketamine enantiomers significantly attenuated the decrease in the levels of Butyricimonas in the susceptible mice. Notably, (R)-ketamine was more potent than (S)-ketamine at reducing the levels of Butyricimonas in the susceptible mice. In conclusion, this study suggests that the antidepressant effects of two enantiomers of ketamine in CSDS model may be partly mediated by the restoration of the gut microbiota. Furthermore, the specific effect of (R)-ketamine on the levels of Mollicutes and Butyricimonas may explain its robust antidepressant action.
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Possible role of the gut microbiota–brain axis in the antidepressant effects of (R)-ketamine in a social defeat stress model
Nature Publishing Group, 2017Co-Authors: Chun Yang, Chao Dong, Yuko Fujita, Qian Ren, Kenji HashimotoAbstract:Abstract Accumulating evidence suggests that the gut microbiota–brain axis plays a role in the pathogenesis of depression, thereby contributing to the antidepressant actions of certain compounds. (R)-ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here, we investigated whether the gut microbiota plays a role in the antidepressant effects of these two ketamine enantiomers. The role of the gut microbiota in the antidepressant effects of ketamine enantiomers in a chronic social defeat stress (CSDS) model of depression was examined using 16S ribosomal RNA gene sequencing of fecal samples. At the phylum level, CSDS-susceptible mice showed alterations in the levels of Tenericutes and Actinobacteria; however, neither ketamine enantiomers influenced these alterations. At the class level, both ketamine enantiomers significantly attenuated the increase in the levels of Deltaproteobacteria in the susceptible mice after CSDS. Furthermore, (R)-ketamine, but not (S)-ketamine, significantly attenuated the reduction in the levels of Mollicutes in the susceptible mice. At the genus level, both ketamine enantiomers significantly attenuated the decrease in the levels of Butyricimonas in the susceptible mice. Notably, (R)-ketamine was more potent than (S)-ketamine at reducing the levels of Butyricimonas in the susceptible mice. In conclusion, this study suggests that the antidepressant effects of two enantiomers of ketamine in CSDS model may be partly mediated by the restoration of the gut microbiota. Furthermore, the specific effect of (R)-ketamine on the levels of Mollicutes and Butyricimonas may explain its robust antidepressant action
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r ketamine a rapid onset and sustained antidepressant without psychotomimetic side effects
Translational Psychiatry, 2015Co-Authors: Chun Yang, Chao Dong, Qian Ren, Yukihiko Shirayama, Jiancheng Zhang, W Yao, Kenji HashimotoAbstract:Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clinical use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examined the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)–TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamine (esketamine). Furthermore, R-ketamine induced a more potent beneficial effect on decreased dendritic spine density, BDNF–TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S-ketamine, but not R-ketamine, precipitated behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addition, a single dose of S-ketamine, but not R-ketamine, caused a loss of parvalbumin (PV)-positive cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S-ketamine, R-ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF–TrkB signaling and synaptogenesis in the PFC, DG and CA3. R-ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S-ketamine, as R-ketamine appears to be free of psychotomimetic side effects and abuse liability.
Donghui Wei - One of the best experts on this subject based on the ideXlab platform.
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insights into n heterocyclic carbene catalyzed oxidative α c sp3 h activation of aliphatic aldehydes and cascade 2 2 cycloaddition with Ketimines
Journal of Organic Chemistry, 2019Co-Authors: Ruihong Duan, Yanyan Wang, Donghui WeiAbstract:Predicting the chemoselectivity of [2 + 2] cyclizations is an important challenge in organic chemistry. Herein, we provided a valuable case for this issue. Density functional theory calculations were performed to systematically study the possible mechanisms and origin of selectivities for the N-heterocyclic carbene (NHC)-catalyzed oxidative α-C(sp3)–H activation of aliphatic aldehydes and the cascade [2 + 2] cycloaddition with Ketimines. The [2 + 2] cycloaddition of azolium enolate intermediates to the C═N bond, rather than the C═O bond of Ketimine, is revealed to be determined by chemo- and stereoselectivity. By comparing the energy gap between the frontier molecular orbitals (FMOs) of the two reacting parts involved in the [2 + 2] cycloaddition transition states, we propose a new strategy to determine the origin of the reaction chemoselectivity. Moreover, the local nucleophilic index can efficiently predict the active site of Ketimines. Further analyses illustrate that NHC can increase the nucleophilici...
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Insights into N‑Heterocyclic Carbene-Catalyzed Oxidative α‑C(sp3)–H Activation of Aliphatic Aldehydes and Cascade [2 + 2] Cycloaddition with Ketimines
2019Co-Authors: Ruihong Duan, Yanyan Wang, Donghui WeiAbstract:Predicting the chemoselectivity of [2 + 2] cyclizations is an important challenge in organic chemistry. Herein, we provided a valuable case for this issue. Density functional theory calculations were performed to systematically study the possible mechanisms and origin of selectivities for the N-heterocyclic carbene (NHC)-catalyzed oxidative α-C(sp3)–H activation of aliphatic aldehydes and the cascade [2 + 2] cycloaddition with Ketimines. The [2 + 2] cycloaddition of azolium enolate intermediates to the CN bond, rather than the CO bond of Ketimine, is revealed to be determined by chemo- and stereoselectivity. By comparing the energy gap between the frontier molecular orbitals (FMOs) of the two reacting parts involved in the [2 + 2] cycloaddition transition states, we propose a new strategy to determine the origin of the reaction chemoselectivity. Moreover, the local nucleophilic index can efficiently predict the active site of Ketimines. Further analyses illustrate that NHC can increase the nucleophilicity of aldehydes and the acidity of the α-C(sp3)–H bond, and 3,3′,5,5′-tetra-tert-butyl diphenoquinone (DQ) acts as an oxidant and promotes α-C(sp3)–H bond deprotonation. This work is useful not only for understanding the NHC-catalyzed oxidative [2 + 2] annulation but also for developing new applications of the FMO theory in organocatalytic cyclizations
Qian Ren - One of the best experts on this subject based on the ideXlab platform.
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mechanistic target of rapamycin independent antidepressant effects of r ketamine in a social defeat stress model
Biological Psychiatry, 2018Co-Authors: Chun Yang, Chao Dong, Jichun Zhang, Qian Ren, Kenji HashimotoAbstract:Abstract Background The role of the mechanistic target of rapamycin (mTOR) signaling in the antidepressant effects of ketamine is controversial. In addition to mTOR, extracellular signal-regulated kinase (ERK) is a key signaling molecule in prominent pathways that regulate protein synthesis. ( R )-Ketamine has a greater potency and longer-lasting antidepressant effects than ( S )-ketamine. Here we investigated whether mTOR signaling and ERK signaling play a role in the antidepressant effects of two enantiomers. Methods The effects of mTOR inhibitors (rapamycin and AZD8055) and an ERK inhibitor (SL327) on the antidepressant effects of ketamine enantiomers in the chronic social defeat stress (CSDS) model ( n = 7 or 8) and on those of ketamine enantiomers in these signaling pathways in mouse brain regions were examined. Results The intracerebroventricular infusion of rapamycin or AZD8055 blocked the antidepressant effects of ( S )-ketamine, but not ( R )-ketamine, in the CSDS model. Furthermore, ( S )-ketamine, but not ( R )-ketamine, significantly attenuated the decreased phosphorylation of mTOR and its downstream effector, ribosomal protein S6 kinase, in the prefrontal cortex of susceptible mice after CSDS. Pretreatment with SL327 blocked the antidepressant effects of ( R )-ketamine but not ( S )-ketamine. Moreover, ( R )-ketamine, but not ( S )-ketamine, significantly attenuated the decreased phosphorylation of ERK and its upstream effector, mitogen-activated protein kinase/ERK kinase, in the prefrontal cortex and hippocampal dentate gyrus of susceptible mice after CSDS. Conclusions This study suggests that mTOR plays a role in the antidepressant effects of ( S )-ketamine, but not ( R )-ketamine, and that ERK plays a role in ( R )-ketamine’s antidepressant effects. Thus, it is unlikely that the activation of mTOR signaling is necessary for antidepressant actions of ( R )-ketamine.
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possible role of the gut microbiota brain axis in the antidepressant effects of r ketamine in a social defeat stress model
Translational Psychiatry, 2017Co-Authors: Chao Dong, Yuko Fujita, Chun Yang, Qian Ren, Kenji HashimotoAbstract:Accumulating evidence suggests that the gut microbiota-brain axis plays a role in the pathogenesis of depression, thereby contributing to the antidepressant actions of certain compounds. (R)-ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here, we investigated whether the gut microbiota plays a role in the antidepressant effects of these two ketamine enantiomers. The role of the gut microbiota in the antidepressant effects of ketamine enantiomers in a chronic social defeat stress (CSDS) model of depression was examined using 16S ribosomal RNA gene sequencing of fecal samples. At the phylum level, CSDS-susceptible mice showed alterations in the levels of Tenericutes and Actinobacteria; however, neither ketamine enantiomers influenced these alterations. At the class level, both ketamine enantiomers significantly attenuated the increase in the levels of Deltaproteobacteria in the susceptible mice after CSDS. Furthermore, (R)-ketamine, but not (S)-ketamine, significantly attenuated the reduction in the levels of Mollicutes in the susceptible mice. At the genus level, both ketamine enantiomers significantly attenuated the decrease in the levels of Butyricimonas in the susceptible mice. Notably, (R)-ketamine was more potent than (S)-ketamine at reducing the levels of Butyricimonas in the susceptible mice. In conclusion, this study suggests that the antidepressant effects of two enantiomers of ketamine in CSDS model may be partly mediated by the restoration of the gut microbiota. Furthermore, the specific effect of (R)-ketamine on the levels of Mollicutes and Butyricimonas may explain its robust antidepressant action.
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Possible role of the gut microbiota–brain axis in the antidepressant effects of (R)-ketamine in a social defeat stress model
Nature Publishing Group, 2017Co-Authors: Chun Yang, Chao Dong, Yuko Fujita, Qian Ren, Kenji HashimotoAbstract:Abstract Accumulating evidence suggests that the gut microbiota–brain axis plays a role in the pathogenesis of depression, thereby contributing to the antidepressant actions of certain compounds. (R)-ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here, we investigated whether the gut microbiota plays a role in the antidepressant effects of these two ketamine enantiomers. The role of the gut microbiota in the antidepressant effects of ketamine enantiomers in a chronic social defeat stress (CSDS) model of depression was examined using 16S ribosomal RNA gene sequencing of fecal samples. At the phylum level, CSDS-susceptible mice showed alterations in the levels of Tenericutes and Actinobacteria; however, neither ketamine enantiomers influenced these alterations. At the class level, both ketamine enantiomers significantly attenuated the increase in the levels of Deltaproteobacteria in the susceptible mice after CSDS. Furthermore, (R)-ketamine, but not (S)-ketamine, significantly attenuated the reduction in the levels of Mollicutes in the susceptible mice. At the genus level, both ketamine enantiomers significantly attenuated the decrease in the levels of Butyricimonas in the susceptible mice. Notably, (R)-ketamine was more potent than (S)-ketamine at reducing the levels of Butyricimonas in the susceptible mice. In conclusion, this study suggests that the antidepressant effects of two enantiomers of ketamine in CSDS model may be partly mediated by the restoration of the gut microbiota. Furthermore, the specific effect of (R)-ketamine on the levels of Mollicutes and Butyricimonas may explain its robust antidepressant action
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r ketamine a rapid onset and sustained antidepressant without psychotomimetic side effects
Translational Psychiatry, 2015Co-Authors: Chun Yang, Chao Dong, Qian Ren, Yukihiko Shirayama, Jiancheng Zhang, W Yao, Kenji HashimotoAbstract:Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clinical use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examined the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)–TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamine (esketamine). Furthermore, R-ketamine induced a more potent beneficial effect on decreased dendritic spine density, BDNF–TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S-ketamine, but not R-ketamine, precipitated behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addition, a single dose of S-ketamine, but not R-ketamine, caused a loss of parvalbumin (PV)-positive cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S-ketamine, R-ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF–TrkB signaling and synaptogenesis in the PFC, DG and CA3. R-ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S-ketamine, as R-ketamine appears to be free of psychotomimetic side effects and abuse liability.
