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Stress-induced Neuroinflammation of the Spinal Cord is Restrained by Cort113176 (Dazucorilant), A Specific Glucocorticoid Receptor Modulator

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Abstract

Glucocorticoids exert antiinflammatory, antiproliferative and immunosupressive effects. Paradoxically they may also enhance inflammation particularly in the nervous system, as shown in Cushing´ syndrome and neurodegenerative disorders of humans and models of human diseases. .”The Wobbler mouse model of amyotrophic lateral sclerosis shows hypercorticoidism and neuroinflammation which subsided by treatment with the glucocorticoid receptor (GR) modulator Dazucorilant (CORT113176). This effect suggests that GR mediates the chronic glucocorticoid unwanted effects. We now tested this hypothesis using a chronic stress model resembling the condition of the Wobbler mouse Male NFR/NFR mice remained as controls or were subjected to a restraining / rotation stress protocol for 3 weeks, with a group of stressed mice receiving CORT113176 also for 3 weeks. We determined the mRNAS or reactive protein for the proinflamatory factors HMGB1, TLR4, NFkB, TNFα, markers of astrogliosis (GFAP, SOX9 and acquaporin 4), of microgliosis (Iba, CD11b, P2RY12 purinergic receptor) as well as serum IL1β and corticosterone. We showed that chronic stress produced high levels of serum corticosterone and IL1β, decreased body and spleen weight, produced microgliosis and astrogliosis and increased proinflammatory mediators. In stressed mice, modulation of the GR with CORT113176 reduced Iba + microgliosis, CD11b and P2RY12 mRNAs, immunoreactive HMGB1 + cells, GFAP + astrogliosis, SOX9 and acquaporin expression and TLR4 and NFkB mRNAs vs. stress-only mice. The effects of CORT113176 indicate that glucocorticoids are probably involved in neuroinflammation. Thus, modulation of the GR would become useful to dampen the inflammatory component of neurodegenerative disorders.

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Data Availability

All data presented in this study are included in the Materials and Methods section, in the corresponding References section and are available from the corresponding author on request.

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Finantial support was received from the National Research Council of Argentina (PIP 2017 2019 #11220170100002CO, PIP 2022–2024 # 11220210100091CO), the Ministry of Health and Technology of Argentina (PICT 2021 00389), the University of Buenos Aires (Ubacyt 20020170100224BA) and Corcept Therapeutics, Menlo Park, Ca. USA. The Rene Baron, Williams, Allende and Roemmers Foundations of Argentina contributed to the basic functions of the Institute. These funding sources did not have a role in the collection, analysis or interpretation of data, in the writing and in the decision to publish the results of the present investigation.

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Authors and Affiliations

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

    Maria Meyer, Analia Lima, Maria Claudia Gonzalez Deniselle & Alejandro F. De Nicola

  2. Dept. of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands

    Onno Meijer & E. Ronald de Kloet

  3. Corcept Therapeutics, Menlo Park, Ca, USA

    Hazel Hunt & Joseph Belanoff

  4. Dept. of Physiology, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina

    Maria Claudia Gonzalez Deniselle

  5. Dept. of Human Biochemiistry, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina

    Alejandro F. De Nicola

Authors
  1. Maria Meyer
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  2. Onno Meijer
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  3. Hazel Hunt
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  4. Joseph Belanoff
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  5. Analia Lima
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  6. E. Ronald de Kloet
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  7. Maria Claudia Gonzalez Deniselle
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  8. Alejandro F. De Nicola
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Contributions

Maria Meyer and Maria Claudia Gonzalez Deniselle analyzed data and performed the experiments; Analia Lima perform cell immunolabelling; Onno Meijer and E.Ronald de Kloet corrected the manuscript, emphasized the agonist/antagonist nature of glucocorticoid receptor modulators and advised regarding the selection of cell markers; Hazel.Hunt. and Joseph Belanoff made valuable comments and corrected the manuscript; Maria Claudia Gonzalez Deniselle and Alejandro F. De Nicola wrote the final version. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Alejandro F. De Nicola.

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Ethics approval

All animal procedures were evaluated and approved by the Institutional Animal Care and Use Committee following the Guide for the Care and Use of Laboratory Animals (Animal Welfare Assurance, NIH certificate granted to our Institute is # F16-00065 A5072-01).

Consent to participate

All listed authors agreed to participate in this study. All listed authors gave explicit consent to submit. The work had the consent from the responsible authorities at the institutions where the work has been carried out.

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All listed authors have approved the final manuscript before submission, including the names and order of authors.

Competing interests

The authors have no competing interests to declare that are relevant to the content of this article.

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The present report did not include human subjects.

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Meyer, M., Meijer, O., Hunt, H. et al. Stress-induced Neuroinflammation of the Spinal Cord is Restrained by Cort113176 (Dazucorilant), A Specific Glucocorticoid Receptor Modulator. Mol Neurobiol 61, 1–14 (2024). https://doi.org/10.1007/s12035-023-03554-x

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