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Neurosteroids alter glutamate-induced changes in neurite morphology of NG108-15 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.
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.
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2007 (English)In: Journal of Steroid Biochemistry and Molecular Biology, ISSN 0960-0760, E-ISSN 1879-1220, Vol. 104, no 3-5, 215-219 p.Article in journal (Refereed) Published
Abstract [en]

Activation of the NMDA receptor leads to increased intracellular Ca2+ levels ([Ca2+]i) which induces outgrowth of and morphologic changes in the neurites of the NG108-15 cell line. This effect can be blocked by antagonists for this glutamate receptor subtype (e.g. ifenprodil or AP5). We have previously shown that nanomolar concentrations of various neurosteroids modulate ifenprodil binding to the NMDA receptor. To investigate whether this interaction affects the functioning of the receptor, we studied the effect of 24 and 48 h of pregnenolone sulphate (PS) or pregnanolone sulphate (3α5βS) on glutamate-stimulated NG108-15 cells.

Unexpectedly, the neurosteroids themselves had an inhibitory effect on glutamate-induced changes in neurite patterns. This effect was comparable to that of ifenprodil or AP5. Moreover, the effect of combined treatment with 3α5βS and ifenprodil on neurite morphology indicated a functional interaction between the substances. Interestingly, PS induced cell detachment over time, an effect that was further enhanced by ifenprodil. Cell detachment was also seen after 48 h of treatment with 3α5βS; however, the effect was blocked by ifenprodil and weaker than that of PS. The interaction with the NR2B-selective antagonist ifenprodil indicates that this NMDA receptor subunit may be involved in neurosteroid-induced NG108-15 cell detachment.

Place, publisher, year, edition, pages
2007. Vol. 104, no 3-5, 215-219 p.
Keyword [en]
NMDA receptor, NR2B subunit, Neurosteroids, Ifenprodil, Pregnenolone sulphate (PS), Pregnanolone sulphate (3α5βS), NG108-15, Neurite outgrowth, Cell adhesion
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96825DOI: 10.1016/j.jsbmb.2007.03.024ISI: 000248110100016PubMedID: 17512193OAI: oai:DiVA.org:uu-96825DiVA: diva2:171530
Available from: 2008-03-14 Created: 2008-03-14 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Neurosteroids Induce Allosteric Effects on the NMDA Receptor: Nanomolar Concentrations of Neurosteroids Exert Non-Genomic Effects on the NMDA Receptor Complex
Open this publication in new window or tab >>Neurosteroids Induce Allosteric Effects on the NMDA Receptor: Nanomolar Concentrations of Neurosteroids Exert Non-Genomic Effects on the NMDA Receptor Complex
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The neurosteroids constitute a group of powerful hormones synthesized and acting in the central nervous system. They participate in a number of important central processes, such as memory and learning, mood and neuroprotection. Their effects emerge from rapid interactions with membrane bound receptors, such as the N-methyl-D-aspartate (NMDA) receptor, the gamma-amino-butyric acid receptor and the sigma 1 receptor. The mechanisms of action are separate from classical genomic interactions.

The aims of this thesis were to identify and characterize the molecular mechanisms underlying the effects of nanomolar concentrations of neurosteroids at the NMDA receptor.

The results show that the neurosteroids pregnenolone sulfate (PS) and pregnanolone sulfate 3α5βS) differently modulate the NMDA receptor, changing the kinetics for the NMDA receptor antagonist ifenprodil, through unique and separate targets at the NR2B subunit. The effects that appear to be temperature independent were further confirmed in a calcium imagining functional assay. A second functional study demonstrated that PS and 3α5βS affect glutamate-stimulated neurite outgrowth in NG108-15 cells.

Misuse of anabolic androgenic steroids (AAS) has powerful effects on emotional states. Since neurosteroids regulate processes involved in mood it can be hypothesised that AAS can interact with the action of neurosteroids in the brain. However, chronic administration of the AAS nandrolone decanoate did not alter the allosteric effects of PS or 3α5βS at the NMDA receptor, but changed the affinity for PS, 3α5βS and dehydroepiandrosterone sulfate to the sigma 1 receptor. The results also showed that the neurosteroids displace 3H-ifenprodil from the sigma 1 and 2 receptors without directly sharing the binding site for 3H-ifenprodil at the sigma 1 receptor. The decreased affinity for the neurosteroids at the sigma 1 receptor may be involved in the depressive symptoms associated with AAS misuse.

The NMDA receptor system is deeply involved in neurodegeneration and the NMDA receptor antagonist ifenprodil exert neuroprotective actions. The findings that neurosteroids interact with ifenprodil at the NMDA receptor may be an opportunity to obtain synergistic effects in neuroprotective treatment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 69
Keyword
Pharmaceutical pharmacology, Pharmacology, neurosteroids, NMDA receptor, NR2B subunit, ifenprodil, sigma receptor, anabolic androgenic steroids, allosteric modulation, non-genomic, Farmaceutisk farmakologi
Identifiers
urn:nbn:se:uu:diva-8503 (URN)978-91-554-7114-9 (ISBN)
Public defence
2008-04-04, B22, BMC, Husargatan, Uppsala, 09:15
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Available from: 2008-03-14 Created: 2008-03-14Bibliographically approved

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