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Neuroprotective Effects of Testosterone in Male Wobbler Mouse, a Model of Amyotrophic Lateral Sclerosis

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Abstract

Patients suffering of amyotrophic lateral sclerosis (ALS) present motoneuron degeneration leading to muscle atrophy, dysphagia, and dysarthria. The Wobbler mouse, an animal model of ALS, shows a selective loss of motoneurons, astrocytosis, and microgliosis in the spinal cord. The incidence of ALS is greater in men; however, it increases in women after menopause, suggesting a role of sex steroids in ALS. Testosterone is a complex steroid that exerts its effects directly via androgen (AR) or Sigma-1 receptors and indirectly via estrogen receptors (ER) after aromatization into estradiol. Its reduced-metabolite 5α-dihydrotestosterone acts via AR. This study analyzed the effects of testosterone in male symptomatic Wobblers. Controls or Wobblers received empty or testosterone-filled silastic tubes for 2 months. The cervical spinal cord from testosterone-treated Wobblers showed (1) similar androgen levels to untreated control and (2) increased levels of testosterone, and its 5α-reduced metabolites, 5α- dihydrotestosterone, and 3β-androstanediol, but (3) undetectable levels of estradiol compared to untreated Wobblers. Testosterone-treated controls showed comparable steroid concentrations to its untreated counterpart. In testosterone- treated Wobblers a reduction of AR, ERα, and aromatase and high levels of Sigma-1 receptor mRNAs was demonstrated. Testosterone treatment increased ChAT immunoreactivity and the antiinflammatory mediator TGFβ, while it lessened vacuolated motoneurons, GFAP+ astrogliosis, the density of IBA1+ microgliosis, proinflammatory mediators, and oxidative/nitrosative stress. Clinically, testosterone treatment in Wobblers slowed the progression of paw atrophy and improved rotarod performance. Collectively, our findings indicate an antiinflammatory and protective effect of testosterone in the degenerating spinal cord. These results coincided with a high concentration of androgen-reduced derivatives after testosterone treatment suggesting that the steroid profile may have a beneficial role on disease progression.

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Data Availability

The data supporting the results of this investigation are available from the corresponding author upon request.

Abbreviations

ALS:

Amyotrophic lateral sclerosis

AR:

Androgen receptor

CAIS:

Complete androgen insensitivity syndrome

ChAT:

Choline acetyltransferase

ER:

Estrogen receptor

FSH:

Follicle stimulating hormone

GFAP:

Glial fibrillary acidic protein

GnRH:

Gonadotropin-releasing hormone

HPG:

Hypothalamic–pituitary–gonadal axis

IBA1:

Ionized calcium–binding adaptor molecule 1

LH:

Luteinizing hormone

MAM:

Mitochondrion-associated endoplasmic reticulum membrane

NADPH-d:

NADPH diaphorase

NOS:

Nitric oxide synthase

PAIS:

Partial androgen insensitivity syndrome

SBMA:

Spinal and bulbar muscular atrophy

TGF β1 :

Transforming growth factor-beta1

3-NT:

3-Nitrotyrosine

3βHSOR:

3β-Hydroxysteroid oxidoreductase

3α-HSD:

3α-Hydroxysteroid dehydrogenase

5α-DHT:

5α-Dihydrotestosterone

17β-HSD:

17β-Hydroxysteroid dehydrogenase

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Acknowledgments

The authors kindly acknowledge the laboratory assistance of Mrs. Analia Lima and Paulina Roig.

Funding

We thank the financial support of the National Research Council of Argentina [CONICET, PIP 2017-2019 #11220170100002CO and PIP 2017-2019 #11220170100301CO], the Ministry of Health and Technology of Argentina (PICT 2017 No. 1150), Roemmers, René Barón and Williams Foundations, and the University of Buenos Aires [Ubacyt # 20020170100224BA]. Agustina Lara was the recipient of a Salvador Mazza Fellowship from the Faculty of Medicine, UBA (2015-2018).

Author information

Author notes

  1. Agustina Lara and Iván Esperante contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina

    Agustina Lara, Iván Esperante, Maria Meyer, Gisella Gargiulo-Monachelli, Alejandro Federico De Nicola & Maria Claudia Gonzalez Deniselle

  2. U1195 Inserm and University Paris-Sud and University Paris-Saclay, 80 rue du Général Leclerc, Le Kremlin-Bicêtre, 94276, France

    Philippe Liere, Michael Schumacher & Rachida Guennoun

  3. Laboratory of Neuroendocrinology, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, Buenos Aires, 1428, Argentina

    Noelia Di Giorgio

  4. Department of Human Biochemistry, Faculty of Medicine, University of Buenos Aires, Paraguay 2155, 1121, Buenos Aires, Argentina

    Alejandro Federico De Nicola

  5. Department of Physiology, Faculty of Medicine, University of Buenos Aires, Paraguay 2155, Buenos Aires, 1121, Argentina

    Maria Claudia Gonzalez Deniselle

Authors
  1. Agustina Lara
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  2. Iván Esperante
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  3. Maria Meyer
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  4. Philippe Liere
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  5. Noelia Di Giorgio
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  6. Michael Schumacher
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  7. Rachida Guennoun
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  8. Gisella Gargiulo-Monachelli
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  9. Alejandro Federico De Nicola
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  10. Maria Claudia Gonzalez Deniselle
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Contributions

Lara A., Esperante I and Meyer M carried out the experiments. Philippe L. performed steroid determination by gas chromatography and mass spectrometry (GC/MS). Di Giorgio N carried out FSH and LH determination. Gonzalez Deniselle MC planned and supervised the experiments. Guennoun R. supervised GC/MS experiments. Gargiulo-Monachelli G helped in the supervision of experiments. Schumacher M. contributed with the testosterone silastic preparation. Gonzalez Deniselle MC, Gargiulo-Monachelli G, De Nicola AF, Schumacher M and Guennoun R. contributed to discuss the project and interpretation of results. Gonzalez Deniselle MC wrote the manuscript with the support from De Nicola AF and Guennoun R. All authors discussed the results.

Corresponding author

Correspondence to Maria Claudia Gonzalez Deniselle.

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Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. The experiments were approved by the local IACUC, following the Guide for the Care and Use of Laboratory Animals (Animal Welfare Assurance, NIH certificate # F16-00065 A5072-01). The experiments are reported in accordance with the ARRIVE guidelines (www.nc3rs.org.uk).

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Not applicable.

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All authors were informed of the changes introduced to the manuscript and agreed with submission of the revised version.

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These funding sources did not have a role in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

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Lara, A., Esperante, I., Meyer, M. et al. Neuroprotective Effects of Testosterone in Male Wobbler Mouse, a Model of Amyotrophic Lateral Sclerosis. Mol Neurobiol 58, 2088–2106 (2021). https://doi.org/10.1007/s12035-020-02209-5

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