Resolvin D3 Promotes Inflammatory Resolution, Neuroprotection, and Functional Recovery After Spinal Cord Injury
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Resolvin D3 Promotes Inflammatory Resolution, Neuroprotection, and Functional Recovery After Spinal Cord Injury Juri Kim 1,2 & Hari Prasad Joshi 1,2 & Seung Hun Sheen 1 & Kyoung-Tae Kim 3,4 & Jae Won Kyung 1 & Hyemin Choi 1 & Ye Won Kim 1 & Su Yeon Kwon 1 & Eun Ji Roh 1,2 & Un Yong Choi 1 & Seil Sohn 1 & Yong Ho Kim 5 & Chul-Kyu Park 5 & Hemant Kumar 6 & In-Bo Han 1 Received: 1 May 2020 / Accepted: 5 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Resolvins, a new family from the endogenous specialized pro-resolving mediators (SPMs), promote the resolution of the inflammatory response. Resolvin D3 (RvD3), a docosahexaenoic acid (DHA) product, has been known to suppress the inflammatory response. However, the anti-inflammatory and neuroprotective effects of RvD3 are not known in a model of spinal cord injury (SCI). Here, we investigated the anti-inflammatory and neuroprotective effect of RvD3 in a mouse model of SCI. Processes associated with anti-inflammation and angiogenesis were studied in RAW 264.7 cells and the human brain endothelial cell line hCMEC/D3, respectively. Additionally, female C57BL/6 mice were subjected to moderate compression SCI (20-g weight compression for 1 min) followed by intrathecal injection of vehicle or RvD3 (1 μg/20 μL) at 1 h post-SCI. RvD3 decreased the lipopolysaccharide (LPS)-induced production of inflammatory mediators and nitric oxide (NO) in RAW 264.7 cells and promoted an angiogenic effect in the hCMEC/D3 cell line. Treatment with RvD3 improved locomotor recovery and reduced thermal hyperalgesia in SCI mice compared with vehicle treatment at 14 days post-SCI. Remarkably, RvD3-treated mice exhibited reduced expression of inflammatory cytokines (TNF-α, IL6, IL1β) and chemokines (CCL2, CCL3). Also, RvD3treated mice exhibited increased expression of tight junction proteins such as zonula occludens (ZO)-1 and occludin. Furthermore, immunohistochemistry showed a decreased level of gliosis (GFAP, Iba-1) and neuroinflammation (CD68, TGF-β) and enhanced neuroprotection. These data provide evidence that intrathecal injection of RvD3 represents a promising therapeutic strategy to promote inflammatory resolution, neuroprotection, and neurological functional recovery following SCI. Keywords Spinal cord injury . Secondary injury . Inflammatory response . Resolvins . Resolvin D3 . Pain
Juri Kim, Hari Prasad Joshi and Seung Hun Sheen contributed equally to this work. * In-Bo Han [email protected] 1
Department of Neurosurgery, CHA University School of Medicine, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do 13496, Republic of Korea
2
Department of Biomedical Science, CHA University School of Medicine, Seongnam-si, Gyeonggi-do, Republic of Korea
3
Department of Neurosurgery, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
4
Department of Neurosurgery, Kyungpook National University Hospital, Daegu, Republic of Korea
5
Gachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheo
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