Ketamine and Calcium Signaling—A Crosstalk for Neuronal Physiology and Pathology

Lisek, Malwina; Żylińska, Ludmiła; Boczek, Tomasz

doi:10.3390/ijms21218410

Cited by 24 publications

(22 citation statements)

References 162 publications

(211 reference statements)

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“…Excessive activation of the excitatory glutamate pathway by methoxphenidine administration would increase calcium influx, resulting in an increase in calcium‐related kinases, such as CAMK2 and PKC. This is consistent with previous studies that have shown that administration of dissociative drug increases these kinases (Lisek et al, 2020; Strong et al, 2017), which are closely involved in the phosphorylation of DAT (Foster & Vaughan, 2017). DAT acts as a reuptake transporter that removes excess dopamine from the synaptic cleft, whereas p‐DAT acts as an efflux transporter that increases dopamine into the synaptic cleft.…”

Section: Discussionsupporting

confidence: 93%

Methoxphenidine (MXP) induced abnormalities: Addictive and schizophrenia‐related behaviours based on an imbalance of neurochemicals in the brain

Jang

Kim

Shi

et al. 2021

British J Pharmacology

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Background and Purpose Methoxphenidine is a dissociative‐based novel psychoactive designer drug. Although fatal accidents from methoxphenidine abuse have been reported, recreational use of the drug continues. We aim to provide scientific supportfor legal regulation of recreational abuse of methoxphenidine by demonstrating its the pharmacological action. Experimental Approach Addictive potential of methoxphenidine was examined using intravenous self‐administration test with rats and conditioned place preference test with mice. Further, a series of behavioural tests (open field test, elevated plus maze test, novel object recognition test, social interaction test and tail suspension test) performed to assess whether methoxphenidine caused schizophrenia‐related symptoms in mice. Additionally, neurotransmitter enzyme‐linked immunosorbent assay and western blot were used to confirm methoxphenidine‐induced neurochemical changes in specific brain regions related to abnormal behaviours. Key Results Methoxphenidine caused addictive behaviours via reinforcing and rewarding effects. Consistently, methoxphenidine induced over‐activation of dopamine pathways in the nuclear accumbens, indicating activation of the brain reward circuit. Also, methoxphenidine caused all categories of schizophrenia‐related symptoms, including positive symptoms (hyperactivity, impulsivity), negative symptoms (anxiety, social withdrawal, depression) and cognitive impairment. Consistently, methoxphenidine led to the disruption of the hippocampal–prefrontal cortex pathway that is considered to be pathological involved in schizophrenia. Conclusions and Implications We demonastrate that methoxphenidine causes addictive and schizophrenia‐like behaviours and induces neurochemical changes in brain regions associated with these behaviours. We propose that methoxphenidine could be used in developing useful animal disease models and that it also requires legal restrictions on its recreational use.

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Section: Discussionsupporting

confidence: 93%

Methoxphenidine (MXP) induced abnormalities: Addictive and schizophrenia‐related behaviours based on an imbalance of neurochemicals in the brain

Jang

Kim

Shi

et al. 2021

British J Pharmacology

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“…Ketamine not only significantly inhibited platelet aggregation on the construct surface but also inhibited their activation within the surrounding platelet suspension, as demonstrated by the aggregation state of platelets before and after exposure to the TEML ( Figure 6 II). This is likely due to the known effect of ketamine inhibiting platelet Ca 2+ signalling [ 34 , 35 ]. This would prevent dense granule secretion, which would in turn prevent the activation of these cells in the perfused platelet suspension.…”

Section: Resultsmentioning

confidence: 99%

The Combination of Tissue-Engineered Blood Vessel Constructs and Parallel Flow Chamber Provides a Potential Alternative to In Vivo Drug Testing Models

et al. 2021

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Cardiovascular disease is a major cause of death globally. This has led to significant efforts to develop new anti-thrombotic therapies or re-purpose existing drugs to treat cardiovascular diseases. Due to difficulties of obtaining healthy human blood vessel tissues to recreate in vivo conditions, pre-clinical testing of these drugs currently requires significant use of animal experimentation, however, the successful translation of drugs from animal tests to use in humans is poor. Developing humanised drug test models that better replicate the human vasculature will help to develop anti-thrombotic therapies more rapidly. Tissue-engineered human blood vessel (TEBV) models were fabricated with biomimetic matrix and cellular components. The pro- and anti-aggregatory properties of both intact and FeCl3-injured TEBVs were assessed under physiological flow conditions using a modified parallel-plate flow chamber. These were perfused with fluorescently labelled human platelets and endothelial progenitor cells (EPCs), and their responses were monitored in real-time using fluorescent imaging. An endothelium-free TEBV exhibited the capacity to trigger platelet activation and aggregation in a shear stress-dependent manner, similar to the responses observed in vivo. Ketamine is commonly used as an anaesthetic in current in vivo models, but this drug significantly inhibited platelet aggregation on the injured TEBV. Atorvastatin was also shown to enhance EPC attachment on the injured TEBV. The TEBV, when perfused with human blood or blood components under physiological conditions, provides a powerful alternative to current in vivo drug testing models to assess their effects on thrombus formation and EPC recruitment.

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“…The downregulation of PMCA4 by ketamine was seen in both the GFP and PMCA2b-GFP groups, suggesting a mechanism independent of the presence of PMCA2b. Possible explanations may be the ketamine-mediated generation of reactive oxygen species (Behrens et al, 2007 ) targeting PMCA4-rich lipid rafts, attenuation of c-Fos and c-Jun expression, and subsequent inhibition of AP-1 transcription factor (Lerea et al, 1992 ; Lisek et al, 2020 ), or the involvement of calcineurin, which was previously demonstrated during maturation of cerebellar granule cells (Guerini et al, 2000 ). Interestingly, our data did not show neuronal retraction or changes in the level of differentiation markers in the presence of ketamine.…”

Section: Discussionmentioning

confidence: 99%

“…Increased apoptotic death was demonstrated to coincide with suppression of spontaneous oscillatory activity and irreversible loss of intracellular Ca 2+ homeostasis (Sinner et al, 2011 ). An increasing body of evidence further supports the calcium hypothesis of ketamine neurotoxicity, suggesting several potential compensatory mechanisms that may lead to the accumulation of intracellular Ca 2+ to potentially toxic concentrations (Shi et al, 2010 ; Liu et al, 2013 ; Wang et al, 2017 ; Lisek et al, 2020 ). Although no reports are available for immature neurons, data from the adult brain suggest that ketamine may interfere with the assembly of local NMDAR/PSD-95/PMCA densities at the synaptic membrane, concentrating PMCA within Ca 2+ entry zones (Lisek et al, 2017 ).…”

Section: Introductionmentioning

confidence: 97%

Early Developmental PMCA2b Expression Protects From Ketamine-Induced Apoptosis and GABA Impairments in Differentiating Hippocampal Progenitor Cells

Lisek

Mackiewicz

Sobolczyk

et al. 2022

Front. Cell. Neurosci.

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PMCA2 is not expressed until the late embryonic state when the control of subtle Ca2+ fluxes becomes important for neuronal specialization. During this period, immature neurons are especially vulnerable to degenerative insults induced by the N-methyl-D-aspartate (NMDA) receptor blocker, ketamine. As H19-7 hippocampal progenitor cells isolated from E17 do not express the PMCA2 isoform, they constitute a valuable model for studying its role in neuronal development. In this study, we demonstrated that heterologous expression of PMCA2b enhanced the differentiation of H19-7 cells and protected from ketamine-induced death. PMCA2b did not affect resting [Ca2+]c in the presence or absence of ketamine and had no effect on the rate of Ca2+ clearance following membrane depolarization in the presence of the drug. The upregulation of endogenous PMCA1 demonstrated in response to PMCA2b expression as well as ketamine-induced PMCA4 depletion were indifferent to the rate of Ca2+ clearance in the presence of ketamine. Yet, co-expression of PMCA4b and PMCA2b was able to partially restore Ca2+ extrusion diminished by ketamine. The profiling of NMDA receptor expression showed upregulation of the NMDAR1 subunit in PMCA2b-expressing cells and increased co-immunoprecipitation of both proteins following ketamine treatment. Further microarray screening demonstrated a significant influence of PMCA2b on GABA signaling in differentiating progenitor cells, manifested by the unique regulation of several genes key to the GABAergic transmission. The overall activity of glutamate decarboxylase remained unchanged, but Ca2+-induced GABA release was inhibited in the presence of ketamine. Interestingly, PMCA2b expression was able to reverse this effect. The mechanism of GABA secretion normalization in the presence of ketamine may involve PMCA2b-mediated inhibition of GABA transaminase, thus shifting GABA utilization from energetic purposes to neurosecretion. In this study, we show for the first time that developmentally controlled PMCA expression may dictate the pattern of differentiation of hippocampal progenitor cells. Moreover, the appearance of PMCA2 early in development has long-standing consequences for GABA metabolism with yet an unpredictable influence on GABAergic neurotransmission during later stages of brain maturation. In contrast, the presence of PMCA2b seems to be protective for differentiating progenitor cells from ketamine-induced apoptotic death.

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Ketamine and Calcium Signaling—A Crosstalk for Neuronal Physiology and Pathology

Cited by 24 publications

References 162 publications

Methoxphenidine (MXP) induced abnormalities: Addictive and schizophrenia‐related behaviours based on an imbalance of neurochemicals in the brain

Methoxphenidine (MXP) induced abnormalities: Addictive and schizophrenia‐related behaviours based on an imbalance of neurochemicals in the brain

The Combination of Tissue-Engineered Blood Vessel Constructs and Parallel Flow Chamber Provides a Potential Alternative to In Vivo Drug Testing Models

Early Developmental PMCA2b Expression Protects From Ketamine-Induced Apoptosis and GABA Impairments in Differentiating Hippocampal Progenitor Cells

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