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

Abstract

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.

17β-estradiol attenuates ketamine-induced neuroapoptosis and persistent cognitive deficits in the developing brain

“…These results indicated that the neurotoxicity of ketamine might be related to reduced endogenous 17β-estradiol secretion. Trickler et al (2013) recently reported that ketamine attenuates cytochrome p450 aromatase gene expression and 17β-estradiol levels in the early life stages of zebrafish , and ketamine has been shown to be neurotoxic to zebrafish embryos (Kanungo et al, 2013). Significant evidence points towards a trophic effect of endogenous 17β-estradiol in the developing brain during brain development.…”

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

“…These data are concordant with the results in multiple reports (cited above) on mammalian studies (neurotoxicity induced by ketamine in rodents and monkeys). Based on our continuing studies showing ketamine accumulation in 72 hpf embryos (48 hpf embryos exposed for 24 h to 2 mM ketamine) is much less (~7 μM/ embryo) compared to the 2.0 mM treatment dose (Trickler et al, 2013), we tested whether a similar phenomenon occurred in 28 hpf embryos that were treated for 20 h with 2.0 mM ketamine. 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.…”

Disruption of endocrine function in H295R cell in vitro and in zebrafish in vivo by naphthenic acids

“…In this context, zebrafish embryos/larvae are suitable alternatives since they are considered less susceptible to distress and pain than adults [27]. More important, zebrafish embryos/larvae express endocrine markers such as aromatase and vitellogenin that are affected by endocrine compounds, allowing them to be tested by monitoring the transcriptome [31,32]. Therefore, zebrafish embryos/larvae were employed to investigate the endocrine disruption of NAs in vivo in this study.…”

“…The zebrafish embryo/larvae has become a systematic, sensitive and easily operated mode animal for identify endocrine disruption [27]. Several zebrafish genes, such as CYP19a, CYP19b, ER␣, and VTG are wellknown biomarker genes responsive to environmental endocrine disruptors [28][29][30][31][32]. Therefore, a combined in vitro and in vivo approach is an efficient way to gain a complete understanding of the properties of endocrine disruptors.…”