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Protective Effects of Estrogen via Nanoparticle Delivery to Attenuate Myelin Loss and Neuronal Death after Spinal Cord Injury

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Abstract

Spinal cord injury (SCI) is associated with devastating neurological deficits affecting more than 11,000 Americans each year. Although several therapeutic agents have been proposed and tested, no FDA-approved pharmacotherapy is available for SCI treatment. We have recently demonstrated that estrogen (E2) acts as an antioxidant and anti-inflammatory agent, attenuating gliosis in SCI. We have also demonstrated that nanoparticle-mediated focal delivery of E2 to the injured spinal cord decreases lesion size, reactive gliosis, and glial scar formation. The current study tested in vitro effects of E2 on reactive oxygen species (ROS) and calpain activity in microglia, astroglia, macrophages, and fibroblasts, which are believed to participate in the inflammatory events and glial scar formation after SCI. E2 treatment decreased ROS production and calpain activity in these glial cells, macrophages, and fibroblast cells in vitro. This study also tested the efficacy of fast- and slow–release nanoparticle-E2 constructs in a rat model of SCI. Focal delivery of E2 via nanoparticles increased tissue distribution of E2 over time, attenuated cell death, and improved myelin preservation in injured spinal cord. Specifically, the fast-release nanoparticle-E2 construct reduced the Bax/Bcl‐2 ratio in injured spinal cord tissues, and the slow-release nanoparticle-E2 construct prevented gliosis and penumbral demyelination distal to the lesion site. These data suggest this novel E2 delivery strategy to the lesion site may decrease inflammation and improve functional outcomes following SCI.

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Data Availability

The data used to support the findings of this manuscript are available from the corresponding authors upon reasonable written request.

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Acknowledgements

This work was supported in part by funding from the Veterans Administration (1IOBX001262, 1I01BX002349-01, 2I01 BX001262-05, 1I01 BX004269-01), South Carolina State Spinal Cord Injury Research Fund (SCIRF-2015P-01, SCIRF-2015P-04, SCIRF-2015-I-01, SCIRF #2016 I-03, and SCIRF #2018 I-01). Contents do not necessarily represent the policy of the SCIRF and do not imply endorsement by the funding agency. This work was also supported in part by funding from the National Institutes of Health (1R21NS118393-01).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC, 29425, USA

    Azizul Haque, Kelsey P. Drasites, Mollie Capone, Ali I. Myatich, Ramsha Shams & Naren L. Banik

  2. Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, USA

    Kelsey P. Drasites, April Cox, Mollie Capone, Ali I. Myatich, Ramsha Shams, Denise Matzelle, Donald C. Shields & Naren L. Banik

  3. Department of Health and Human Performance, The Citadel, 171 Moultrie St, Charleston, SC, 29409, USA

    Kelsey P. Drasites, Ali I. Myatich, Ramsha Shams & Dena P. Garner

  4. Ralph H. Johnson Veterans Administration Medical Center, 109 Bee St, Charleston, SC, 29401, USA

    Denise Matzelle & Naren L. Banik

  5. Department of Bioengineering, Clemson University, Clemson, SC, USA

    Mikhail Bredikhin & Alexey Vertegel

  6. Department of Neurosurgery and Neurology, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC, 29425, USA

    Naren L. Banik

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  1. Azizul Haque
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Contributions

AH conceived, designed, and wrote the manuscript, drew most of the figures, and edited the manuscript. KPD, AC, MC, AIM, and RS performed the experiments, prepared some of the figures, and edited the manuscript. DM performed spinal cord injury experiments, collected samples for analyses, and edited the manuscript. DPG and DCS edited the manuscript. MB and AV made E2-nanoparticles for the experiments. NLB conceived, designed, and edited the manuscript. All authors reviewed and approved the final version of the manuscript.

Corresponding authors

Correspondence to Azizul Haque or Naren L. Banik.

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Haque, A., Drasites, K.P., Cox, A. et al. Protective Effects of Estrogen via Nanoparticle Delivery to Attenuate Myelin Loss and Neuronal Death after Spinal Cord Injury. Neurochem Res 46, 2979–2990 (2021). https://doi.org/10.1007/s11064-021-03401-2

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