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CORM-2-Solid Lipid Nanoparticles Maintain Integrity of Blood-Spinal Cord Barrier After Spinal Cord Injury in Rats

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Abstract

Spinal cord injury (SCI) is a devastating condition of the central nervous system that can lead to permanent motor and sensory deficits. Carbon monoxide–releasing molecule-2 (CORM-2) has been shown to have anti-inflammatory, anti-apoptotic, and angiogenic properties that may be useful for the treatment of SCI. However, it has a short carbon monoxide (CO) release half-life (approximately 1 min). To address this challenge, we developed a CORM-2-incorporated solid lipid nanoparticle (CORM-2-SLN) and evaluated its ameliorating effects for preventing blood-spinal cord barrier (BSCB) disruption and endothelial cell death following SCI. After a moderate compression injury of the spinal cord (compression with a 35-g impounder for 5 min), groups of rats were treated with a CORM-2-solution and CORM-2-SLNs at an equal dose of 10 mg/kg each via an intraperitoneal injection for 8 consecutive days. Behavior analysis was performed and animals were later sacrificed at different time points and evaluated for whether the CORM-2-SLNs prevented BSCB disruption and rescued endothelial cell damage following SCI. The CORM-2-SLN-treated group showed significantly diminished extravasation of Evans Blue dye with enhanced expression of tight junction proteins following SCI. Likewise, significantly diminished endothelial cell markers after SCI were optimally stabilized at 21 days. Additionally, lipopolysaccharide (LPS)-induced loss of tight junction integrity was significantly preserved after CORM-2-SLN treatment in human cerebral microvascular endothelial cell line (hCMEC/D3). Clinically, CORM-2-SLNs were associated with a significantly improved functional recovery, as compared with the CORM-2-solution. CORM-2-SLNs may help potentially to maintain BSCB integrity following SCI.

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  • 08 December 2020

    A Correction to this paper has been published: <ExternalRef><RefSource>https://doi.org/10.1007/s12035-020-02233-5</RefSource><RefTarget Address="10.1007/s12035-020-02233-5" TargetType="DOI"/></ExternalRef>

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Acknowledgements

This study was supported by a grant of the Korea Healthcare Technology Research & Development Project, Ministry of Health and Welfare, Republic of Korea (HR16C0002), and the National Research Foundation of Korea (NRF-2017R1C1B1011397, NRF-2017R1A2B4006458).

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  1. Hari Prasad Joshi, Hemant Kumar and Un Yong Choi contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, CHA University School of medicine, CHA Bundang Medical Center, 59 Yaptap-ro, Bundang-gu, Seongnam-si, 13496, Gyeonggi-do, Republic of Korea

    Hari Prasad Joshi, Un Yong Choi, Hyemin Choi, Juri Kim, Jae Won Kyung, Seil Sohn & In-Bo Han

  2. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India

    Hemant Kumar

  3. Department of Neurosurgery, Ajou University Hospital, Suwon, South Korea

    Yong Cheol Lim

  4. Department of Neurosurgery, School of Medicine, Kyungpook National University, Daegu, South Korea

    Kyoung-Tae Kim

  5. Department of Neurosurgery, Kyungpook National University Hospital, Daegu, South Korea

    Kyoung-Tae Kim

  6. College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, 15588, Gyeonggi-do, Republic of Korea

    Jin-Ki Kim

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Contributions

All authors contributed and critically reviewed and approved the manuscript. IBH and HK conceived and directed the project. IBH, HK, HPJ designed the whole experimental plan. HPJ, UYC, YCL, HC, JK, JWK, and YCK performed the experiment. SS and KK analyzed the data and interpreted the result. JKK formulate and characterized the in vitro CO release properties of CORM-2-SLNs. HPJ, UYC, and IBH prepared the manuscript.

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Correspondence to In-Bo Han.

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Joshi, H.P., Kumar, H., Choi, U.Y. et al. CORM-2-Solid Lipid Nanoparticles Maintain Integrity of Blood-Spinal Cord Barrier After Spinal Cord Injury in Rats. Mol Neurobiol 57, 2671–2689 (2020). https://doi.org/10.1007/s12035-020-01914-5

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