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Mar. Drugs 2012, 10(9), 1899-1919; doi:10.3390/md10091899
Article

Sinularin from Indigenous Soft Coral Attenuates Nociceptive Responses and Spinal Neuroinflammation in Carrageenan-Induced Inflammatory Rat Model

1,†
, 2,†
, 3
, 4
, 5
, 1
, 6
, 7
, 1
 and 1,*
1 Department of Marine Biotechnology and Resources, Asia-Pacific Ocean Research Center, National Sun Yat-sen University, Kaohsiung 80424, Taiwan 2 Division of Neurosurgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan 3 Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan 4 Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan 5 Sections of Orthopedic Surgery, Pingtung Christian Hospital, #60 Da-Lan Road, Pingtung 900, Taiwan 6 Department of Fragrance and Cosmetic Science, Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan 7 Taiwan Coral Research Center, National Museum of Marine Biology and Aquarium, Pingtung 944, Taiwan These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 12 June 2012 / Revised: 2 August 2012 / Accepted: 15 August 2012 / Published: 24 August 2012
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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.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.
Keywords: sinularin; carrageenan; inflammatory pain; spinal neuroinflammation; transforming growth factor-β1; natural marine compound sinularin; carrageenan; inflammatory pain; spinal neuroinflammation; transforming growth factor-β1; natural marine compound
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Huang, S.-Y.; Chen, N.-F.; Chen, W.-F.; Hung, H.-C.; Lee, H.-P.; Lin, Y.-Y.; Wang, H.-M.; Sung, P.-J.; Sheu, J.-H.; Wen, Z.-H. Sinularin from Indigenous Soft Coral Attenuates Nociceptive Responses and Spinal Neuroinflammation in Carrageenan-Induced Inflammatory Rat Model. Mar. Drugs 2012, 10, 1899-1919.

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