l-Carnitine rescues ketamine-induced attenuated heart rate and MAPK (ERK) activity in zebrafish embryos

Kanungo, Jyotshnabala; Cuevas, Elvis; Ali, Syed F.; Paule, Merle G.

doi:10.1016/j.reprotox.2011.10.004

Cited by 36 publications

(86 citation statements)

References 62 publications

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“…The rationale behind this experiment was based on the notion that being younger by 20 h than the 48 hpf embryos, the skin of the 28 hpf embryos will be less complex and more permeable to ketamine, thus facilitating enhanced diffusion. The dose and duration were selected on the basis of our previous report on ketamine-induced cardiotoxicity in zebrafish embryos (Kanungo et al, 2012). In our studies, although ketamine dose was high in the embryo water, the real exposure turned out to be significantly lower; at 2.0 mM ketamine dose, each embryo only accumulated 8.4 μM.…”

Section: Discussionmentioning

confidence: 98%

“…Importantly, in another study we also showed that acetyl L-carnitine counteracts ketamine's negative effects on heart rate and ERK (MAPK) activity in zebrafish embryos (Kanungo et al, 2012). In order to quantitate the effect of ketamine on motor neurons in vivo, hb9:green fluorescent protein (hb9:GFP) transgenic zebrafish embryos were used, in which the promoter of the transcription factor hb9 that is found in developing motor neurons of both mammals (William et al, 2003) and zebrafish (Cheesman et al, 2004;Park et al, 2004), drives GFP expression specifically in motor neurons (Flanagan-Steet et al, 2005;Nakano et al, 2005).…”

Section: Introductionmentioning

confidence: 83%

“…Beneficial effects of acetyl L-carnitine on cognitive and mitochondrial dysfunction have been shown in aging rats (Hagen et al, 2002a;Liu et al, 2002), as well. In our earlier study, we speculated that acetyl L-carnitine's reversal of ketamine-induced decrease in heart rate and ERK/MAPK activity could be mediated by calcium-modulated signaling (Kanungo et al, 2012). Moreover, acetyl L-carnitine has been shown to protect hippocampal neurons from hypoxia-induced apoptosis by activating NGF receptors that resulted in ERK/MAPK activation (Barhwal et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…A similar preventive effect of acetyl L-carnitine on ketamine's effects was also observed for the RB primary sensory neurons. Ketamine-induced attenuation of heart rate in zebrafish embryos has been shown to be normalized in the presence of acetyl Lcarnitine (Kanungo et al, 2012). Whether a single specific signaling pathway culminating in different tissue-specific effectors or completely distinct pathways regulating specific/ common effectors are triggered by acetyl L-carnitine remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…Embryos were incubated at 28.5 °C. Based on our earlier studies (Kanungo et al, 2012), acetyl L-carnitine (Sigma, St Louis, MO) was used at 0.5 mM for co-treatment with ketamine.…”

Section: Treatment Of Zebrafish Embryos With Ketamine and Acetyl L-camentioning

confidence: 99%

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Acetyl l-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos

Cuevas

Trickler

Guo

et al. 2013

Neurotoxicology and Teratology

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Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) type glutamate receptors is commonly used as a pediatric anesthetic. Multiple studies have shown ketamine to be neurotoxic, particularly when administered during the brain growth spurt. Previously, we have shown that ketamine is detrimental to motor neuron development in the zebrafish embryos. Here, using both wild type (WT) and transgenic (hb9:GFP) zebrafish embryos, we demonstrate that ketamine is neurotoxic to both motor and sensory neurons. Drug absorption studies showed that in the WT embryos, ketamine accumulation was approximately 0.4% of the original dose added to the exposure medium. The transgenic embryos express green fluorescent protein (GFP) localized in the motor neurons making them ideal for evaluating motor neuron development and toxicities in vivo. The hb9:GFP zebrafish embryos (28 h post fertilization) treated with 2 mM ketamine for 20 h demonstrated significant reductions in spinal motor neuron numbers, while co-treatment with acetyl L-carnitine proved to be neuroprotective. In whole mount immunohistochemical studies using WT embryos, a similar effect was observed for the primary sensory neurons. In the ketamine-treated WT embryos, the number of primary sensory Rohon-Beard (RB) neurons was significantly reduced compared to that in controls. However, acetyl L-carnitine co-treatment prevented ketamine-induced adverse effects on the RB neurons. These results suggest that acetyl L-carnitine protects both motor and sensory neurons from ketamine-induced neurotoxicity.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Embryos were incubated at 28.5 °C. Based on our earlier studies (Kanungo et al, 2012), acetyl L-carnitine (Sigma, St Louis, MO) was used at 0.5 mM for co-treatment with ketamine.…”

Section: Treatment Of Zebrafish Embryos With Ketamine and Acetyl L-camentioning

confidence: 99%

See 3 more Smart Citations

Acetyl l-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos

Cuevas

Trickler

Guo

et al. 2013

Neurotoxicology and Teratology

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Effects of ketamine‐induced H3K9 hypoacetylation during pregnancy on cardiogenesis of mouse offspring

Quan

Zou

et al. 2023

Birth Defects Research

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Background: Prenatal exposure to adverse factors can cause congenital heart defects. Ketamine, a widely used anesthetic drug, produces several adverse reactions such as tachycardia, hypertension, and laryngospasm, especially in pediatric patients. This study aimed to detect the effects of ketamine exposure during pregnancy on the cardiogenesis of mouse offspring and the potential mechanisms.Methods: In this study, ketamine at an addictive dose (5 mg/kg) was administered to mice during early gestation to explore the epigenetic mechanism of its causing cardiac dysplasia. The cardiac morphology of the mouse offspring was observed through hematoxylin-eosin staining and transmission electron microscopy. The heart function of one-month-old neonates was detected by echocardiography. The expression of cardiomyogenesis-related genes was detected by western blot and RT-qPCR. The acetylation level of histone H3K9 at the Mlc2 promoter and its deacetylase level and activity were detected by CHIP-qPCR, RT-qPCR, and ELISA, respectively. Results: Our data revealed that ketamine exposure during pregnancy could cause cardiac enlargement, myocardial sarcomere disorganization, and decreased cardiac contractile function in mouse offspring. Moreover, ketamine reduced the expression of Myh6, Myh7, Mlc2, Mef2c, and cTnI. The histone H3K9 acetylation level at the Mlc2 promoter was down-regulated by increasing the histone deacetylase activity and HDAC3 level upon ketamine administration.Conclusions: Our work indicates that H3K9 acetylation is a vital player in cardiac dysplasia in offspring caused by prenatal ketamine exposure and HDAC3 is a key regulatory factor.

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Ketamine attenuates cytochrome p450 aromatase gene expression and estradiol‐17β levels in zebrafish early life stages

Trickler

Guo

Cuevas

et al. 2013

J of Applied Toxicology

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Ketamine, a dissociative anesthetic, is a noncompetitive antagonist of N-methyl-D-aspartate-type glutamate receptors. In rodents and non-human primates as well as in zebrafish embryos, ketamine has been shown to be neurotoxic. In cyclic female rats, ketamine has been shown to decrease serum estradiol-17β(E2) levels. E2 plays critical roles in neurodevelopment and neuroprotection. Cytochrome p450 (CYP) aromatase catalyzes E2 synthesis from androgens. Although ketamine down-regulates a number of CYP enzymes in rodents, its effect on the CYP aromatase (CYP19) is not known. Zebrafish have been used as a model system for examining mechanisms underlying drug effects. Here, using wild-type (WT) zebrafish (Danio rerio) embryos, we demonstrate that ketamine significantly reduced E2 levels compared with the control. However, the testosterone level was elevated in ketamine-treated embryos. These results are concordant with data from mammalian studies. Ketamine also attenuated the expression of the ovary form of CYP aromatase (cyp19a1a) at the transcriptional level but not the brain form of aromatase, cyp19a1b. Exogenous E2 potently induced the expression of cyp19a1b and vtg 1, both validated biomarkers of estrogenicity and endocrine disruption, but not cyp19a1a expression. Attenuation of activated ERK/MAPK levels, reportedly responsible for reduced human cyp19 transcription, was also observed in ketamine-treated embryos. These results suggest that reduced E2 levels in ketaminetreated embryos may have resulted from the suppression of cyp19a1a transcription. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

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l-Carnitine rescues ketamine-induced attenuated heart rate and MAPK (ERK) activity in zebrafish embryos

Cited by 36 publications

References 62 publications

Acetyl l-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos

Acetyl l-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos

Effects of ketamine‐induced H3K9 hypoacetylation during pregnancy on cardiogenesis of mouse offspring

Ketamine attenuates cytochrome p450 aromatase gene expression and estradiol‐17β levels in zebrafish early life stages

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