17α-Estradiol down-regulates glutathione synthesis in serum deprived PC-12 cells

Rakkestad, Kirsten Eline; Sørvik, Irene Beate; Øverby, G. R.; Debernard, Karen A. Boldingh; Mathisen, Gro Haarklou; Paulsen, Ragnhild E.

doi:10.3109/10715762.2014.930455

Cited by 7 publications

(6 citation statements)

References 183 publications

(243 reference statements)

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“…One of the estradiol-derivatives, E-3py, also reduced GCL activity at 1 nM. Literature findings suggest that estradiols elicit their neuroprotection is an ER-mediated [269], [270] manner, but previous findings in our own group suggest that PC12s do not express the classical ERs [271]. As the Nrf2-mediated p38 MATK pathway is implicated in the regulation of GSH, we evaluated the effects of the test compounds in the expression levels of these proteins, and found that only 2ME-11f-db increased levels of Nrf2, and this at 10 µM concentration, whereas levels of p38 were increased by 17αE, only at 10 µM.…”

Section: Estrogens As Neuroprotectantsmentioning

confidence: 64%

Differential effects of some novel synthetic oestrogen analogs on oxidative PC12 cell death caused by serum deprivation

Sørvik

Solum

Labba

et al. 2018

Free Radical Research

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Oestrogens with no or reduced oestrogen receptor (ER) binding properties are reported to have neuroprotective functions. However, we have previously shown that the hormonally inactive isomer of 17β-estradiol (17β-E), 17α-estradiol (17α-E), down-regulates glutathione (GSH) synthesis, and fails to rescue serum deprivation-induced cell death in the rat pheochromocytoma cell line PC12 in micromolar concentration. The present study examined cellular protective effects of new 17β-E analogs and 2-methoxyestradiol (2-ME) analogs with no or little oestrogen activity. 17β-E, 17α-E, 2-ME, and an antagonist of the G protein-coupled oestrogen receptor (GPER), G36, were also included. Both 17α-E and 2-ME protected against deprivation-induced cell death in PC12 cells at 1 nM, but they enhanced the deprivation-induced cell death accompanied by caspase 3 activity and decreased intracellular GSH levels during deprivation at 10 µM. In addition, 10 μM 17α-E activated the p38 mitogen activated protein kinase pathway, which was linked to the enhanced death and reduced GSH levels. Analogs of 2-ME modified with a 6-isoquinoline moiety (6iq) protected against deprivation-induced cell death at 1 nM and did not interfere with the GSH levels nor increase p38 protein levels at 10 µM. The promoter activity of the catalytic subunit of the rate-limiting enzyme, glutamate cysteine ligase (GCLC) in GSH synthesis as well as protein levels of GCLC and Nrf2, increased with the 2-ME analogs at 10 µM. In conclusion, the steroids have differential protective effects, and modifying 2-ME may give the steroid more favourable properties than 17α-E, 2-ME, and G36 in regard to GSH regulation.

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Section: Estrogens As Neuroprotectantsmentioning

confidence: 64%

Differential effects of some novel synthetic oestrogen analogs on oxidative PC12 cell death caused by serum deprivation

Sørvik

Solum

Labba

et al. 2018

Free Radical Research

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“…PC‐12 cells were cultivated as described previously , seeded at a density of 7.0 × 10 4 cells/ml and exposed after transfection on DIV1 to 0.1 μ m DEX, 1 μ m mifepristone, 0.1 μ m DEX + 1 μ m mifepristone, or ethanol 0.01‰.…”

Section: Methodsmentioning

confidence: 99%

Glucocorticoid Effects on Cerebellar Development in a Chicken Embryo Model: Exploring Changes in PAX6 and Metalloproteinase‐9 After Exposure to Dexamethasone

Austdal

Bjørnstad

Mathisen

et al. 2016

J Neuroendocrinology

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The developing cerebellum is vulnerable to effects of glucocorticoids and cerebellar dysfunction is associated with neurodevelopmental disorders (e.g. autism). Transcription factor PAX6 and matrix metalloproteinase-9 (MMP-9) are critical for normal cerebellar development and are highly expressed in migrating neurones. Alterations in MMP-9 and PAX6 are associated with altered cerebellar development. In the present study, we characterised the growth rate and development of the cortical layers, and further investigated how the levels of PAX6 and MMP-9, as well as glucocorticoid receptor (GR) and proliferating cell nuclear antigen (PCNA), change in the cerebellum during the foetal period [embryonic day (E)12-21] in chicken, which corresponds to the human perinatal period. Dexamethasone (DEX) was administered in ovo at E13 and E16, aiming to investigate how prenatal exposure to glucocorticoids interferes with normal development. DEX reduced foetal and cerebellar weight at E17 in a dose-dependent manner linked to a reduced level of PCNA and, over time, down-regulation of GR. We report that promoter activity of PAX6 and MMP-9 increased as a result of GR-stimulation in vitro. Prenatal DEX increased the protein level of PAX6 in a transient manner. PAX6 is reduced in mature granule neurones, and this occurred earlier in embryos exposed to DEX than in non-exposed controls. DEX exposure also led to a slow-onset down-regulation of MMP-9. Taken together, these findings indicate that excess prenatal glucocorticoid stimulation disturbs normal development of the cerebellum through mechanisms associated with reduced proliferation and accelerated maturation where PAX6 and MMP-9 play important roles.

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“…The quality of ANDA's ability to quantify neuronal differentiation metrics was assessed using outlines of identified structures in freshly plated and in vitro day 3 CGN cells (Figure 2), as well as freshly plated and differentiated PC12N (Supplementary Figure 2) and NT2N (Supplementary Figure 3). Details of the cultivation of these three cell types are described in supplementary information [18,33]. To obtain phase contrast images of the cells we used the live-cell imaging platforms IncuCyte® ZOOM for the CGN and PC12N cells, and IncuCyte® S3 for the NT2N cells (Supplementary methods).…”

Section: Qualitative Measurement Assessmentmentioning

confidence: 99%

ANDA: An open-source tool for automated image analysis of neuronal differentiation

Waehler

Labba

Paulsen

et al. 2023

Preprint

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Background Imaging of in vitro neuronal differentiation and measurements of cell morphologies has led to novel insights into neuronal development. Live-cell imaging techniques and large datasets of images has increased the demand for automated pipelines for quantitative analysis of neuronal morphological metrics. Results We present ANDA, an analysis workflow for quantification of various aspects of neuronal morphology from high-throughput live-cell imaging screens. This tool automates the analysis of neuronal cell numbers, neurite lengths and neurite attachment points. We used rat, chicken and human in vitro models for neuronal differentiation and have demonstrated the accuracy, versatility, and efficiency of the tool. Conclusions ANDA is an open-source tool that is easy to use and capable of automated processing from time-course measurements of neuronal cells. The strength of this pipeline is the capability to analyse high-throughput imaging screens.

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17α-Estradiol down-regulates glutathione synthesis in serum deprived PC-12 cells

Cited by 7 publications

References 183 publications

Differential effects of some novel synthetic oestrogen analogs on oxidative PC12 cell death caused by serum deprivation

Differential effects of some novel synthetic oestrogen analogs on oxidative PC12 cell death caused by serum deprivation

Glucocorticoid Effects on Cerebellar Development in a Chicken Embryo Model: Exploring Changes in PAX6 and Metalloproteinase‐9 After Exposure to Dexamethasone

ANDA: An open-source tool for automated image analysis of neuronal differentiation

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