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Sinularin from indigenous soft coral attenuates nociceptive responses and spinal neuroinflammation in carrageenan-induced inflammatory rat model.

Huang SY, Chen NF, Chen WF, Hung HC, Lee HP, Lin YY, Wang HM, Sung PJ, Sheu JH, Wen ZH - Mar Drugs (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Marine Biotechnology and Resources, Asia-Pacific Ocean Research Center, National Sun Yat-sen University, Kaohsiung 80424, Taiwan. johnjohnkings@gmail.com

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.

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Inhibitive effect of subcutaneous (s.c.) sinularin on intraplantar (i.p.l.) carrageenan-induced leukocyte infiltration in paw tissue. Paw sections (2 μm) at 24 h after i.p.l. saline or carrageenan injection were from (A) i.p.l. saline plus s.c. vehicle (dimethyl sulfoxide [DMSO]), (B) i.p.l. carrageenan plus s.c. vehicle, and (C) i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) groups. (D) Quantification of the number of leukocytes (arrows) in the paw tissue, and each bar represents the mean ± standard error of the mean (SEM) of 6 rats per group. S.c. sinularin significantly reduced carrageenan-induced leukocyte infiltration. Scale bars: 300 μm for all images (A–C). * P < 0.05 compared with the i.p.l. saline plus s.c. vehicle group; #P < 0.05 compared with the i.p.l. carrageenan plus s.c. vehicle group.
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marinedrugs-10-01899-f006: Inhibitive effect of subcutaneous (s.c.) sinularin on intraplantar (i.p.l.) carrageenan-induced leukocyte infiltration in paw tissue. Paw sections (2 μm) at 24 h after i.p.l. saline or carrageenan injection were from (A) i.p.l. saline plus s.c. vehicle (dimethyl sulfoxide [DMSO]), (B) i.p.l. carrageenan plus s.c. vehicle, and (C) i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) groups. (D) Quantification of the number of leukocytes (arrows) in the paw tissue, and each bar represents the mean ± standard error of the mean (SEM) of 6 rats per group. S.c. sinularin significantly reduced carrageenan-induced leukocyte infiltration. Scale bars: 300 μm for all images (A–C). * P < 0.05 compared with the i.p.l. saline plus s.c. vehicle group; #P < 0.05 compared with the i.p.l. carrageenan plus s.c. vehicle group.

Mentions: Histopathological examination was conducted to evaluate tissue inflammatory responses. Biopsies of paws were taken from the following groups: i.p.l. saline plus s.c. vehicle, i.p.l. carrageenan plus s.c. vehicle, and i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) groups at 24 h after i.p.l. carrageenan injection. No inflammation or tissue destruction was observed in the paws of i.p.l. saline plus s.c. vehicle-treated rats (Figure 6A In contrast, as previously reported [1], we observed that i.p.l. carrageenan caused infiltrating cells (leukocytes) populated enlarged cavities resulting from tissue erosion (Figure 6B). Treatment with sinularin (80 mg/kg) clearly inhibited carrageenan-induced leukocyte infiltration (Figure 6C,D). To detect TGF-β1 protein expression in paws, we used paw sections at 24 h after i.p.l. saline or carrageenan injection from i.p.l. saline plus s.c. vehicle, i.p.l. carrageenan plus s.c. vehicle, and i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) groups. At 24 h after i.p.l. carrageenan injection, we found that numerous TGF-β1 immunoreactive cells in the paw tissue (Figure 7B). Administration of sinularin (80 mg/kg) 1 h prior to the injection of carrageenan markedly increased TGF-β1 immunoreactivity in paws (Figure 7C,E).


Sinularin from indigenous soft coral attenuates nociceptive responses and spinal neuroinflammation in carrageenan-induced inflammatory rat model.

Huang SY, Chen NF, Chen WF, Hung HC, Lee HP, Lin YY, Wang HM, Sung PJ, Sheu JH, Wen ZH - Mar Drugs (2012)

Inhibitive effect of subcutaneous (s.c.) sinularin on intraplantar (i.p.l.) carrageenan-induced leukocyte infiltration in paw tissue. Paw sections (2 μm) at 24 h after i.p.l. saline or carrageenan injection were from (A) i.p.l. saline plus s.c. vehicle (dimethyl sulfoxide [DMSO]), (B) i.p.l. carrageenan plus s.c. vehicle, and (C) i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) groups. (D) Quantification of the number of leukocytes (arrows) in the paw tissue, and each bar represents the mean ± standard error of the mean (SEM) of 6 rats per group. S.c. sinularin significantly reduced carrageenan-induced leukocyte infiltration. Scale bars: 300 μm for all images (A–C). * P < 0.05 compared with the i.p.l. saline plus s.c. vehicle group; #P < 0.05 compared with the i.p.l. carrageenan plus s.c. vehicle group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3475263&req=5

marinedrugs-10-01899-f006: Inhibitive effect of subcutaneous (s.c.) sinularin on intraplantar (i.p.l.) carrageenan-induced leukocyte infiltration in paw tissue. Paw sections (2 μm) at 24 h after i.p.l. saline or carrageenan injection were from (A) i.p.l. saline plus s.c. vehicle (dimethyl sulfoxide [DMSO]), (B) i.p.l. carrageenan plus s.c. vehicle, and (C) i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) groups. (D) Quantification of the number of leukocytes (arrows) in the paw tissue, and each bar represents the mean ± standard error of the mean (SEM) of 6 rats per group. S.c. sinularin significantly reduced carrageenan-induced leukocyte infiltration. Scale bars: 300 μm for all images (A–C). * P < 0.05 compared with the i.p.l. saline plus s.c. vehicle group; #P < 0.05 compared with the i.p.l. carrageenan plus s.c. vehicle group.
Mentions: Histopathological examination was conducted to evaluate tissue inflammatory responses. Biopsies of paws were taken from the following groups: i.p.l. saline plus s.c. vehicle, i.p.l. carrageenan plus s.c. vehicle, and i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) groups at 24 h after i.p.l. carrageenan injection. No inflammation or tissue destruction was observed in the paws of i.p.l. saline plus s.c. vehicle-treated rats (Figure 6A In contrast, as previously reported [1], we observed that i.p.l. carrageenan caused infiltrating cells (leukocytes) populated enlarged cavities resulting from tissue erosion (Figure 6B). Treatment with sinularin (80 mg/kg) clearly inhibited carrageenan-induced leukocyte infiltration (Figure 6C,D). To detect TGF-β1 protein expression in paws, we used paw sections at 24 h after i.p.l. saline or carrageenan injection from i.p.l. saline plus s.c. vehicle, i.p.l. carrageenan plus s.c. vehicle, and i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) groups. At 24 h after i.p.l. carrageenan injection, we found that numerous TGF-β1 immunoreactive cells in the paw tissue (Figure 7B). Administration of sinularin (80 mg/kg) 1 h prior to the injection of carrageenan markedly increased TGF-β1 immunoreactivity in paws (Figure 7C,E).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Marine Biotechnology and Resources, Asia-Pacific Ocean Research Center, National Sun Yat-sen University, Kaohsiung 80424, Taiwan. johnjohnkings@gmail.com

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.

Show MeSH
Related in: MedlinePlus