title: Sinularin from indigenous soft coral attenuates nociceptive responses and spinal neuroinflammation in carrageenan-induced inflammatory rat model.
abstract: Three decades ago, the marine-derived compound sinularin was shown to have anti-edematous effects on paw edema induced by carrageenan or adjuvant. To the best of our knowledge, no new studies were conducted to explore the bioactivity of sinularin until we reported the analgesic properties of sinularin based on in vivo experiments. In the present study, we found that sinularin significantly inhibits the upregulation of proinflammatory proteins, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) and upregulates the production of transforming growth factor-β (TGF-β) in lipopolysaccharide (LPS)-stimulated murine macrophage RAW 264.7 cells according to western blot analysis. We found that subcutaneous (s.c.) administration of sinularin (80 mg/kg) 1 h before carrageenan injection significantly inhibited carrageenan-induced nociceptive behaviors, including thermal hyperalgesia, mechanical allodynia, cold allodynia, and hindpaw weight-bearing deficits. Further, s.c. sinularin (80 mg/kg) significantly inhibited carrageenan-induced microglial and astrocyte activation as well as upregulation of iNOS in the dorsal horn of the lumbar spinal cord. Moreover, s.c. sinularin (80 mg/kg) inhibited carrageenan-induced tissue inflammatory responses, redness and edema of the paw, and leukocyte infiltration. The results of immunohistochemical studies indicate that s.c. sinularin (80 mg/kg) could upregulate production of TGF-β1 in carrageenan-induced inflamed paw tissue. The present results demonstrate that systemic sinularin exerts analgesic effects at the behavioral and spinal levels, which are associated with both inhibition of leukocyte infiltration and upregulation of TGF-β1.
authors.affiliation: Department of Marine Biotechnology and Resources, Asia-Pacific Ocean Research Center, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
authors.forename: Shi-Ying
authors.initials: SY
authors.lastname: Huang
authors.affiliation: Division of Neurosurgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan.
authors.forename: Nan-Fu
authors.initials: NF
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
authors.forename: Wu-Fu
authors.initials: WF
authors.lastname: Chen
authors.affiliation: Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
authors.forename: Han-Chun
authors.identifier: 0000-0002-0013-3247
authors.initials: HC
authors.lastname: Hung
authors.affiliation: Sections of Orthopedic Surgery, Pingtung Christian Hospital, #60 Da-Lan Road, Pingtung 900, Taiwan.
authors.forename: Hsin-Pai
authors.initials: HP
authors.lastname: Lee
authors.affiliation: Department of Marine Biotechnology and Resources, Asia-Pacific Ocean Research Center, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
authors.forename: Yen-You
authors.identifier: 0000-0002-7636-1115
authors.initials: YY
authors.lastname: Lin
authors.affiliation: Department of Fragrance and Cosmetic Science, Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
authors.forename: Hui-Min
authors.identifier: 0000-0002-5162-9752
authors.initials: HM
authors.lastname: Wang
authors.affiliation: Taiwan Coral Research Center, National Museum of Marine Biology and Aquarium, Pingtung 944, Taiwan.
authors.forename: Ping-Jyun
authors.identifier: 0000-0002-6644-9236
authors.initials: PJ
authors.lastname: Sung
authors.affiliation: Department of Marine Biotechnology and Resources, Asia-Pacific Ocean Research Center, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
authors.forename: Jyh-Horng
authors.initials: JH
authors.lastname: Sheu
authors.affiliation: Department of Marine Biotechnology and Resources, Asia-Pacific Ocean Research Center, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
authors.forename: Zhi-Hong
authors.identifier: 0000-0003-4411-044X
authors.initials: ZH
authors.lastname: Wen
mesh_terms: D000818:Animals; D037421:Anthozoa / Q000737:chemistry; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002351:Carrageenan; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004224:Diterpenes / Q000494:pharmacology*; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D008161:Lumbosacral Region; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D059226:Nociceptive Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D020671:Posterior Horn Cells / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D004224:Diterpenes; D006575:Heterocyclic Compounds, 3-Ring; D008070:Lipopolysaccharides; D053773:Transforming Growth Factor beta1; C574383:sinularin; D002351:Carrageenan; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
keywords: carrageenan; inflammatory pain; natural marine compound; sinularin; spinal neuroinflammation; transforming growth factor-β1