Ketamine Inhibits Glutamate-, N-Methyl-D-Aspartate-, and Quisqualate-stimulated cGMP Production in Cultured Cerebral Neurons

Gonzales, Jerry M.; Loeb, Alex L.; Reichard, Peter S.; Irvine, Steven

doi:10.1097/00000542-199501000-00025

Cited by 67 publications

(14 citation statements)

References 61 publications

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“…Exposure of cultured hippocampal neurons to ketamine induced HDAC5 phosphorylation in a concentration-dependent manner, which reached peak levels at ∼100 nM (Fig. 1A), a concentration lower than comparable plasma concentrations required to produce anesthesia in humans (5-10 μM) (15). The response to ketamine displayed an inverted U, as higher doses had no effect on HDAC5 phosphorylation.…”

Section: Resultsmentioning

confidence: 93%

Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

Choi

Lee

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Ketamine produces rapid antidepressant-like effects in animal assays for depression, although the molecular mechanisms underlying these behavioral actions remain incomplete. Here, we demonstrate that ketamine rapidly stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons through calcium/calmodulin kinase II-and protein kinase D-dependent pathways. Consequently, ketamine enhanced the transcriptional activity of myocyte enhancer factor 2 (MEF2), which leads to regulation of MEF2 target genes. Transfection of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 replaced by Ala259/Ala498, HDAC5-S/A), resulted in resistance to ketamineinduced nuclear export, suppression of ketamine-mediated MEF2 transcriptional activity, and decreased expression of MEF2 target genes. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked or occluded the antidepressant effects of ketamine both in unstressed and stressed animals. Taken together, our results reveal a novel role of HDAC5 in the actions of ketamine and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of ketamine.ketamine | HDAC | depression | hippocampus D epression is a multifaceted illness, characterized by somatic, cognitive, and behavioral changes. All currently available antidepressants primarily act via monoaminergic neurotransmitters, such as serotonin and/or noradrenaline (1). Currently available pharmacotherapies for depression provide some relief for patients, but these agents have significant limitations (1). In this context, new antidepressants with faster onset of action and greater efficacy are needed (2).The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown remarkable consistency in rapidly ameliorating depressive symptoms in major depressive disorder (MDD) (3). Preclinical studies have demonstrated that ketamine produces rapid antidepressant responses (within hours) (4, 5). Ketamine's antidepressant effects in rodents are associated with activation of several signaling systems including the mammalian target of rapamycin complex 1 (mTORC1) (4), brain derived neurotrophic factor (BDNF) and elongation factor 2 (EF2) kinase (5). Despite these remarkable effects, the widespread use of ketamine is limited by potential side effects and abuse. Thus, studies are necessary to further elucidate mechanistic actions of ketamine at cellular and network levels.Recent studies have generated evidence that epigenetic regulation is closely involved in the pathophysiology of depression and in the therapeutic mechanisms of typical antidepressants (6, 7). In addition, reports that sodium butyrate, a histone deacetylase (HDAC) inhibitor, has antidepressant effects indicate that HDAC inhibition is sufficient to produce an antidepressant response (8). HDACs are a family of enzymes capable of repressing gene expression by removing acetyl groups from histones to produce a less accessible chromatin structure (9).Previous studies demonstrate that the...

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Section: Resultsmentioning

confidence: 93%

Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

Choi

Lee

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, the effect of ketamine is considered to be synergic with that of intrathecal bupivacaine because combined administration demonstrates better blocking with a longer duration (13,29). Several in vitro and in vivo studies have demonstrated the potential of ketamine for producing neuroprotective effects (43)(44)(45). This ability is indicated by the observations that ketamine blocks NMDA-receptor activation, mediates beneficial changes in apoptosis-regulating proteins and interferes with the inflammatory response to injury when administered in typical sedative or anesthetic doses.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the effects of ketamine on spinal anesthesia with levobupivacaine or ropivacaine

Zhang

Lin

Wen-bo

2016

Experimental and Therapeutic Medicine

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Abstract. Spinal anesthesia or regional anesthesia is a potent anesthetic procedure. Additional modalities have been sought to increase the duration of block in spinal anesthesia. Ketamine is an N-methyl-D-aspartate (NMDA) receptor blocker that has an anesthetic effect when injected intrathecally and has a synergic effect with bupivacaine. Ketamine also has potent analgesic properties. The present study investigated the effect of intrathecally administered ketamine on spinal anesthesia with levobupivacaine or ropivacaine. Sprague-Dawley rats at post-natal day 21 were exposed to spinal anesthesia with 0.5% levobupivacaine or 0.5% ropivacaine. Separate groups of rats were treated with intrathecal ketamine at a 5 or 10 mg/kg bodyweight dose along with ropivacaine or levobupivacaine. The thermal and mechanical withdrawal latencies of the animals were determined using hot plate and von Frey filaments, respectively. A rotarod apparatus was employed to assess the capacity of the rats to rotate the spindle at 24 h following anesthesia. The gait of the rat pups was also assessed. Intrathecal administration of ketamine resulted in dense blocks and extended the duration of spinal blocks as evidenced by thermal latencies and responses to von Frey filaments. The latency to fall was shorter in rats exposed to ketamine along with ropivacaine or levobupivacaine spinal anesthesia. The gait parameters were also more disturbed upon ketamine administration. In conclusion, ketamine administration with ropivacaine or levobupivacaine increased the intensity and duration of spinal blockade, thereby increasing the anesthetic effects.

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“…This analogue probably acts through a mechanism different from L-glutamate (Gonzales et al, 1995), as the inhibitory effect of kainate, but not L-glutamate, could be abolished by the non-NMDA receptor antagonist CNQX (Watkins et al, 1990). These results suggest that the inhibitory effect of kainate on the EFS vas deferens contraction is mediated by non-NMDA receptors.…”

Section: Discussionmentioning

confidence: 99%

Presynaptic modulation by L‐glutamate and GABA of sympathetic co‐transmission in rat isolated vas deferens

Kwan

Ngan

Tsang

et al. 1996

British J Pharmacology

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1 The modulatory effects of L-glutamate and its structural analogues, and of y-aminobutyric acid (GABA), on sympathetic co-transmission were studied in the rat isolated vas deferens exposed to electrical field stimulation (EFS). 2 Application of exogenous L-glutamate caused a concentration-dependent (1 /M -3 mM) inhibition of the rapid twitch component of the biphasic EFS contraction. However, L-glutamate (1 MM-3 mM) had a minimal effect on the phasic contraction induced by exogenous adenosine 5'-triphosphate (ATP, 150 MM) and noradrenaline (50 Mm). Unlike L-glutamate, D-glutamate had no effect on the EFS contraction. 3 The L-glutamate-induced inhibition of the EFS contractions was significantly attenuated by the glutamate decarboxylase (GAD) inhibitor 3-mercapto-propionic acid (150 Mm) and was abolished in the presence of the GABA transaminase (GABA-T) inhibitor, 2-aminoethyl hydrogen sulphate (500 gM).4 The L-glutamate-induced inhibition of the electrically evoked contraction was not affected by the adenosine Al-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX)(30 nM), reactive blue 2 (30 Mm) or the GABAA receptor antagonist bicuculline (50 gM). However, the GABAB receptor antagonist 2-hydroxysaclofen (50 uM) significantly inhibited the L-glutamate effect. 5 Similar to L-glutamate, GABA also caused a concentration-dependent (0.1 -100 Mm) inhibition of the EFS contractions. This GABA-induced inhibition was not affected by either the GABAA receptor antagonist bicuculline (50 gM) or reactive blue 2 (30 gM). However, a significant attenuation of the GABA-mediated effect was recorded with the GABAB receptor antagonist 2-hydroxysaclofen (50 gM).Contractions of the vas deferens induced by exogenous ATP and noradrenaline were not affected by GABA (0.1-100 gM).6 The L-glutamate analogues, N-methyl-D-aspartate (NMDA) (1 MM-I mM) and quisqualate (Quis 0.1 Mm -0.3 mM) had no effect, whilst kainate (Kain, 1 MM-I mM) caused an inhibition of the EFSinduced contractions. Effects of Kain could be abolished by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dioxine (CNQX, 10 gM). NMDA, Quis and Kain had no effect on the exogenous ATP-or noradrenaline-induced contractions. 7 It is concluded that the excitatory amino acid L-glutamate modulates the electrically evoked vas deferens contraction through conversion to the inhibitory amino acid GABA by a specific GABA transaminase. The GABA formed may then act on GABAB receptors and cause inhibition of the contraction through a presynaptic mechanism.

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Ketamine Inhibits Glutamate-, N-Methyl-D-Aspartate-, and Quisqualate-stimulated cGMP Production in Cultured Cerebral Neurons

Abstract: The authors' data demonstrate that ketamine inhibited NO synthesis stimulated by NMDA- and non-NMDA-receptor specific analogs. Our findings indicate that blockade of QUIS- as well as NMDA-subtypes of GLU- receptor may be important in the development of ketamine-induced anesthesia.

Cited by 67 publications

References 61 publications

Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

Evaluation of the effects of ketamine on spinal anesthesia with levobupivacaine or ropivacaine

Presynaptic modulation by L‐glutamate and GABA of sympathetic co‐transmission in rat isolated vas deferens

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