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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 spinal neuroinflammatory markers in the dorsal horn of the lumbar spinal cord. These spinal cord sections (10 μm) at 24 h after i.p.l. saline or carrageenan injection were from i.p.l. saline plus s.c. vehicle (dimethyl sulfoxide [DMSO]) (A, D, G), i.p.l. carrageenan plus s.c. vehicle (B, E, H), and i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) (C, F, I) groups. Immunostaining images show cells labeled with OX-42 (green) (A–C), glial fibrillary acidic protein (GFAP) (green) (D–F), and iNOS (red) (G–I) in the spinal cord. Quantification of OX-42 (J), GFAP (K), and iNOS (L) immunoreactivity on the ipsilateral dorsal horn of the lumbar spinal gray matter, and each bar in images J–L represents the mean ± standard error of the mean (SEM) of 6 rats per group. S.c. sinularin significantly inhibited carrageenan-induced upregulation of spinal OX-42, GFAP, and iNOS immunoreactivity. Scale bars: 200 μm for all images (A–I). * 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-f005: Inhibitive effect of subcutaneous (s.c.) sinularin on intraplantar (i.p.l.) carrageenan-induced spinal neuroinflammatory markers in the dorsal horn of the lumbar spinal cord. These spinal cord sections (10 μm) at 24 h after i.p.l. saline or carrageenan injection were from i.p.l. saline plus s.c. vehicle (dimethyl sulfoxide [DMSO]) (A, D, G), i.p.l. carrageenan plus s.c. vehicle (B, E, H), and i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) (C, F, I) groups. Immunostaining images show cells labeled with OX-42 (green) (A–C), glial fibrillary acidic protein (GFAP) (green) (D–F), and iNOS (red) (G–I) in the spinal cord. Quantification of OX-42 (J), GFAP (K), and iNOS (L) immunoreactivity on the ipsilateral dorsal horn of the lumbar spinal gray matter, and each bar in images J–L represents the mean ± standard error of the mean (SEM) of 6 rats per group. S.c. sinularin significantly inhibited carrageenan-induced upregulation of spinal OX-42, GFAP, and iNOS immunoreactivity. Scale bars: 200 μm for all images (A–I). * 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: Spinal tissue was collected at 24 h after carrageenan injection from the lumbar enlargement (L2–L4) for a spinal immunohistofluorescence assay of neuroinflammatory markers. OX-42-, GFAP-, or iNOS-immunoreactive cells were scattered throughout the ipsilateral dorsal horn of the lumbar spinal gray matter of i.p.l. saline plus s.c. vehicle (Figure 5A,D,G), i.p.l. carrageenan plus s.c. vehicle (Figure 5B,E,H), and i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) (Figure 5C,F,I) groups. Compared with i.p.l. saline plus s.c. vehicle group, the immunoreactivity of OX-42 (Figure 5B), GFAP (Figure 5E), and iNOS (Figure 5H) of i.p.l. carrageenan plus s.c. vehicle group were upregulated 24 h after carrageenan injection. Carrageenan-induced upregulation of OX-42 (Figure 5C and iNOS (Figure 5I) were significantly inhibited by s.c. sinularin (80 mg/kg). Quantification results of OX-42 (Figure 5J), GFAP (Figure 5K), and iNOS (Figure 5L supported that inhibition of carrageenan-induced upregulation of spinal neuroinflammatory markers are consistent with the antinociceptive effects of sinularin. To explore the possible effects of sinularin on carrageenan-induced peripheral inflammatory responses, we then focused on the site of rat’s inflamed paw by histopathological examination and immunohistochemistry assay.


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 spinal neuroinflammatory markers in the dorsal horn of the lumbar spinal cord. These spinal cord sections (10 μm) at 24 h after i.p.l. saline or carrageenan injection were from i.p.l. saline plus s.c. vehicle (dimethyl sulfoxide [DMSO]) (A, D, G), i.p.l. carrageenan plus s.c. vehicle (B, E, H), and i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) (C, F, I) groups. Immunostaining images show cells labeled with OX-42 (green) (A–C), glial fibrillary acidic protein (GFAP) (green) (D–F), and iNOS (red) (G–I) in the spinal cord. Quantification of OX-42 (J), GFAP (K), and iNOS (L) immunoreactivity on the ipsilateral dorsal horn of the lumbar spinal gray matter, and each bar in images J–L represents the mean ± standard error of the mean (SEM) of 6 rats per group. S.c. sinularin significantly inhibited carrageenan-induced upregulation of spinal OX-42, GFAP, and iNOS immunoreactivity. Scale bars: 200 μm for all images (A–I). * 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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Show All Figures
getmorefigures.php?uid=PMC3475263&req=5

marinedrugs-10-01899-f005: Inhibitive effect of subcutaneous (s.c.) sinularin on intraplantar (i.p.l.) carrageenan-induced spinal neuroinflammatory markers in the dorsal horn of the lumbar spinal cord. These spinal cord sections (10 μm) at 24 h after i.p.l. saline or carrageenan injection were from i.p.l. saline plus s.c. vehicle (dimethyl sulfoxide [DMSO]) (A, D, G), i.p.l. carrageenan plus s.c. vehicle (B, E, H), and i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) (C, F, I) groups. Immunostaining images show cells labeled with OX-42 (green) (A–C), glial fibrillary acidic protein (GFAP) (green) (D–F), and iNOS (red) (G–I) in the spinal cord. Quantification of OX-42 (J), GFAP (K), and iNOS (L) immunoreactivity on the ipsilateral dorsal horn of the lumbar spinal gray matter, and each bar in images J–L represents the mean ± standard error of the mean (SEM) of 6 rats per group. S.c. sinularin significantly inhibited carrageenan-induced upregulation of spinal OX-42, GFAP, and iNOS immunoreactivity. Scale bars: 200 μm for all images (A–I). * 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: Spinal tissue was collected at 24 h after carrageenan injection from the lumbar enlargement (L2–L4) for a spinal immunohistofluorescence assay of neuroinflammatory markers. OX-42-, GFAP-, or iNOS-immunoreactive cells were scattered throughout the ipsilateral dorsal horn of the lumbar spinal gray matter of i.p.l. saline plus s.c. vehicle (Figure 5A,D,G), i.p.l. carrageenan plus s.c. vehicle (Figure 5B,E,H), and i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) (Figure 5C,F,I) groups. Compared with i.p.l. saline plus s.c. vehicle group, the immunoreactivity of OX-42 (Figure 5B), GFAP (Figure 5E), and iNOS (Figure 5H) of i.p.l. carrageenan plus s.c. vehicle group were upregulated 24 h after carrageenan injection. Carrageenan-induced upregulation of OX-42 (Figure 5C and iNOS (Figure 5I) were significantly inhibited by s.c. sinularin (80 mg/kg). Quantification results of OX-42 (Figure 5J), GFAP (Figure 5K), and iNOS (Figure 5L supported that inhibition of carrageenan-induced upregulation of spinal neuroinflammatory markers are consistent with the antinociceptive effects of sinularin. To explore the possible effects of sinularin on carrageenan-induced peripheral inflammatory responses, we then focused on the site of rat’s inflamed paw by histopathological examination and immunohistochemistry assay.

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