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Stroke-Induced Peripheral Immune Dysfunction in Vitamin D–Deficient Conditions: Modulation by Progesterone and Vitamin D

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Abstract

Vitamin D deficiency (Ddef) alters morphology and outcomes after a stroke. We investigated the interaction of Ddef following post-stroke systemic inflammation and evaluated whether administration of progesterone (P) or vitamin D (D) will improve outcomes. Ddef rats underwent stroke with lipopolysaccharide (LPS)-induced systemic inflammation. Rats were randomly divided into 9 groups and treated with P, D, or vehicle for 4 days. At day 4, rats were tested on different behavioral parameters. Markers of neuronal inflammation, endoplasmic reticulum stress, oxidative stress, white matter integrity, and apoptosis were measured along with immune cell populations from the spleen, thymus, and blood. Severely altered outcomes were observed in the Ddef group compared to the D-sufficient (Dsuf) group. Stroke caused peripheral immune dysfunction in the Dsuf group which was worse in the Ddef group. Systemic inflammation exacerbated injury outcomes in the Dsuf group and these were worse in the Ddef group. Monotherapy with P/D showed beneficial functional effects but the combined treatment showed better outcomes than either alone. Ddef as a comorbid condition with stroke worsens stroke outcomes and can delay functional recovery. Combination treatment with P and D might be promising for future stroke therapeutics in Ddef.

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Funding

The research was supported by gifts from Allen and Company and the Marcus Foundation. Allen and Company is a banking firm with no commercial interests in pharmacology or any other matters relating to our research. The Marcus Foundation is a philanthropic foundation supporting research in developmental psychobiology and other related areas.

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Authors and Affiliations

  1. Department of Emergency Medicine, Brain Research Laboratory, Emory University, 615 Michael Street, Room 655A, Atlanta, GA, 30322, USA

    Seema Yousuf, Fahim Atif & Donald G. Stein

  2. Department of Pharmacology, Emory University, Atlanta, GA, 30322, USA

    Claudia Espinosa-Garcia

  3. School of Medicine, Department of Hematology-Oncology, Emory University, Atlanta, GA, 30322, USA

    Wayne Harris

  4. Department of Neurology, School of Medicine, Tufts University, Boston, MA, 0211, USA

    Nefize Turan

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  1. Seema Yousuf
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  2. Fahim Atif
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  5. Nefize Turan
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SY, FA: made a substantial contribution to the concept and design, acquisition of data or analysis and interpretation of data, drafted the article; CEG, NT: made a substantial contribution to the acquisition of data and interpretation of data, approved the version to be published; WH: acquisition of flow cytometric data or analysis and interpretation of data, approved the version to be published; DGS: made a substantial contribution to the concept and design, acquisition of data or analysis and revised it critically for important intellectual content, approved the version to be published.

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Yousuf, S., Atif, F., Espinosa-Garcia, C. et al. Stroke-Induced Peripheral Immune Dysfunction in Vitamin D–Deficient Conditions: Modulation by Progesterone and Vitamin D. Mol Neurobiol 58, 950–963 (2021). https://doi.org/10.1007/s12035-020-02129-4

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