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Structurally different anabolic androgenic steroids reduce neurite outgrowth and neuronal viability in primary rat cortical cell cultures
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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2021 (English)In: Journal of Steroid Biochemistry and Molecular Biology, ISSN 0960-0760, E-ISSN 1879-1220, Vol. 210, article id 105863Article in journal (Refereed) Published
Abstract [en]

The illicit use of anabolic androgenic steroids (AAS) among adolescents and young adults is a major concern due to the unknown and unpredictable impact of AAS on the developing brain and the consequences of this on mental health, cognitive function and behaviour. The present study aimed to investigate the effects of supra-physiological doses of four structurally different AAS (testosterone, nandrolone, stanozolol and trenbolone) on neurite development and cell viability using an in vitro model of immature primary rat cortical cell cultures. A high-throughput screening image-based approach, measuring the neurite length and number of neurons, was used for the analysis of neurite outgrowth. In addition, cell viability and expression of the Tubb3 gene (encoding the protein beta-III tubulin) were investigated. Testosterone, nandrolone, and trenbolone elicited adverse effects on neurite outgrowth as deduced from an observed reduced neurite length per neuron. Trenbolone was the only AAS that reduced the cell viability as indicated by a decreased number of neurons and declined mitochondrial function. Moreover, trenbolone downregulated the Tubb3 mRNA expression. The adverse impact on neurite development was neither inhibited nor supressed by the selective androgen receptor (AR) antagonist, flutamide, suggesting that the observed effects result from another mechanism or mechanisms of action that are operating apart from AR activation. The results demonstrate a possible AAS-induced detrimental effect on neuronal development and regenerative functions. An impact on these events, that are essential mechanisms for maintaining normal brain function, could possibly contribute to behavioural alterations seen in AAS users.

Place, publisher, year, edition, pages
2021. Vol. 210, article id 105863
Keywords [en]
Anabolic androgenic steroids, Neurite outgrowth, Neurotoxicity, Primary cortical cell culture, Rat
National Category
Basic Medicine Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-439046DOI: 10.1016/j.jsbmb.2021.105863ISI: 000652020500001PubMedID: 33677017OAI: oai:DiVA.org:uu-439046DiVA, id: diva2:1540582
Funder
Kjell and Marta Beijer FoundationThe Swedish Brain FoundationSwedish Research Council, 9459Available from: 2021-03-29 Created: 2021-03-29 Last updated: 2022-08-03Bibliographically approved
In thesis
1. Anabolic Androgenic Steroids: Neurobiological Effects of Nandrolone, Testosterone, Trenbolone, and Stanozolol
Open this publication in new window or tab >>Anabolic Androgenic Steroids: Neurobiological Effects of Nandrolone, Testosterone, Trenbolone, and Stanozolol
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The use of anabolic androgenic steroids (AAS) for recreational purposes is a health concern, as long-term AAS-use in supraphysiological doses is associated with severe physical and psychological adverse effects. Several behavioral and cognitive problems are reported after long-term AAS-use, and alterations in brain morphology as well as neurotransmitter systems have been reported. The AAS-induced negative impact on the brain may depend on the type of AAS used, but the rationale behind the adverse effects observed is still not clear.

The aim of the present thesis was to investigate the neurobiological impact of supraphysiological doses of structurally diverse AAS; testosterone, nandrolone, stanozolol, and trenbolone, as well as of the prodrugs nandrolone decanoate, testosterone undecanoate, testosterone decanoate, and trenbolone decanoate. Wistar rats were used to study the influence on behavior, effects on the brain, and additional somatic effects. Furthermore, in vitro models of immature and mature primary rat cortical cell cultures were used to examine the potential toxic properties of the AAS administered. In the in vitro studies, nandrolone and trenbolone were identified as the most toxic of the AAS investigated, due to their adverse impact on mitochondrial function, membrane integrity, apoptosis, and neurite outgrowth. In vivo, the AAS demonstrated diverse somatic outcomes affecting body weight development, and organ weights to different degrees. In addition, nandrolone decanoate caused a reduced general activity, an effect possibly induced by increased stress vulnerability and alterations in the oxytocinergic system. Furthermore, nandrolone decanoate induced impaired memory in the novel object recognition test. Overall, nandrolone decanoate was identified as the most harmful steroid investigated due to its prominent impact on body weight development, affecting multiple organs, and being the only AAS causing impaired cognitive function. 

In conclusion, the structurally different AAS exerted diverse effects on cell viability, neurite development as well as regarding physical impairments and impact on behavior, suggesting that harmful physiological, neurological, and psychological outcomes may be expected after AAS-use. These findings highlight that the severity and type of adverse effects depend on the type of AAS used, which is valuable information to consider in order to provide good healthcare and treatment options to AAS-users.    

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2022. p. 87
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 315
Keywords
Anabolic androgenic steroids, testosterone, nandrolone, trenbolone, stanozolol, central nervous system, primary cortical cell cultures, rats, multivariate concentric square field, novel object recognition.
National Category
Basic Medicine
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-480857 (URN)978-91-513-1560-7 (ISBN)
Public defence
2022-09-23, B42, Biomedical center, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2022-09-02 Created: 2022-08-03 Last updated: 2022-09-02

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Zelleroth, SofiaNylander, ErikStam, FridaNyberg, FredGrönbladh, AlfhildHallberg, Mathias

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