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Protective effects of 27-and 24-hydroxycholesterol against staurosporine-induced cell death in undifferentiated neuroblastoma SH-SY5Y cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2012 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 525, no 1, 44-48 p.Article in journal (Refereed) Published
Abstract [en]

Alterations in cholesterol metabolism have been linked to several neurodegenerative disorders, including Alzheimer's disease, multiple sclerosis and Parkinson's disease. Brain cholesterol is metabolized to the oxysterols 24-hydroxycholesterol and 27-hydroxycholesterol. Disturbed levels of these oxysterols are found in neurodegenerative conditions. In the current study we examined the effects of 27- and 24-hydroxycholesterol on viability of human neuroblastoma SH-SY5Y cells treated with staurosporine, a toxic substance that induces apoptosis. Analyses using MTT assay and measurement of lactate dehydrogenase release showed that presence of 27-hydroxycholesterol counteracted the toxic effects of staurosporine on these cells. Also, 27-hydroxycholesterol significantly decreased the staurosporine-mediated induction of caspase-3 and -7, known to be important in apoptotic events. 24-Hydroxycholesterol had similar effects on viability as 27-hydroxycholesterol in low concentrations, although in higher concentrations this oxysterol exacerbated the toxic effects of staurosporine. From these findings it may be concluded that effects of oxysterols on cellular viability are strongly dependent on the concentration and on the type of oxysterol. Previous studies on oxysterols have reported that these compounds are pro-apoptotic or trigger pathological changes that result in neurodegeneration. The present data indicate that, during some conditions, oxysterols may have neuroprotective effects.

Place, publisher, year, edition, pages
2012. Vol. 525, no 1, 44-48 p.
Keyword [en]
Oxysterol, Cholesterol metabolism, Cell viability, Neuroprotection, Neurodegeneration, Apoptosis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-183219DOI: 10.1016/j.neulet.2012.07.057ISI: 000308520900009OAI: oai:DiVA.org:uu-183219DiVA: diva2:562780
Available from: 2012-10-26 Created: 2012-10-23 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Steroids and steroid-metabolizing enzymes in the nervous system: Special focus on cell survival and sex hormone synthesis
Open this publication in new window or tab >>Steroids and steroid-metabolizing enzymes in the nervous system: Special focus on cell survival and sex hormone synthesis
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Some steroids in the brain and peripheral nervous system have been shown to have neuroprotective effects but the knowledge is limited. The present study examines the effects of steroids including oxysterols, vitamin D and vitamin D analogs on cell viability/growth and steroidogenesis in the nervous system.

Both 24- and 27-hydroxycholesterol reduced staurosporine-induced toxicity in human neuroblastoma SH-SY5Y cells. In addition, 27-hydroxycholesterol decreased the staurosporine-mediated induction of caspases, known to be important in apoptotic events. From the findings it may be concluded that effects of oxysterols on cellular viability are dependent on the concentration and on the type of oxysterol. 24-Hydroxycholesterol was also found to attenuate oxidative stress both in SH-SY5Y cells and astrocytes. The results indicate that during some conditions, oxysterols may have neuroprotective effects.

The vitamin D analogs tacalcitol and calcipotriol strongly reduced proliferation, cell viability and migration of human glioblastoma T98G cells, similarly as 1,25(OH)2D3 , the physiological form of vitamin D. Glioblastoma is the most lethal type of primary tumors in the CNS. These findings suggest that vitamin D analogs are potential candidates in treatment of brain tumors, most likely in combination with other therapies.

Astrocytes were found to be a major site for expression of 3β-hydroxysteroid dehydrogenase (3β-HSD) whereas expression of CYP17A1 was found in both astrocytes and neurons. 3β-HSD and CYP17A1 are important steroidogenic enzymes. Vitamin D inhibited both CYP17A1- and 3β-HSD -mediated activity and mRNA levels, with a stronger effect on mRNA expression than on enzyme activity. This indicates that 1,25(OH)2D3 could affect the production of sex hormones in the brain.

In summary, results from this thesis contribute to the knowledge on the effects of oxysterols on cell viability and oxidative stress in cells from the CNS. Also the results provide data on the effects of vitamin D in the brain and suggest that vitamin D analogs may be promising candidates for treatment of certain brain tumors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 236
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-328767 (URN)978-91-513-0056-6 (ISBN)
Public defence
2017-10-20, A1:107, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2017-09-28 Created: 2017-08-31 Last updated: 2017-10-17

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Emanuelsson, IdaNorlin, Maria

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