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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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Chemical structure of sinularin (5,15-dioxatricyclo[12.3.1.0(4,6)]octadec-9-en-16-one).
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marinedrugs-10-01899-f001: Chemical structure of sinularin (5,15-dioxatricyclo[12.3.1.0(4,6)]octadec-9-en-16-one).

Mentions: Marine-derived compounds obtained from soft corals are believed to yield many potential candidate compounds for treating inflammatory diseases, particularly for treating pain [1,2,3,4]. The natural marine compound sinularin (Figure 1) has been well-studied and was shown by Weinheimer et al. in 1977 to have anticancer activity against the human epidermoid carcinoma cell line (KB) and the murine P388 lymphocytic leukemia cell line (PS) cell line from the soft coral Sinularia flexibilis [5]. In 1978, Kazlauskas et al. isolated sinularin from the same soft coral, but referred to the compound as flexibilide [6]. Later, in 1980, Buckle et al. reported that oral administration of sinularin reduced carrageenan-induced paw edema 3 h after carrageenan injection and that chronic oral sinularin inhibited adjuvant-induced paw swelling (periarthritis model) over a 21-day period after adjuvant administration [7]. After Buckle et al. used rat models to show the anti-inflammatory activity of sinularin [7], scientists explored other bioactivities of sinularin, such as its cardiovascular [8] and antimicrobial [9] activities. Sinularin was originally isolated from the soft coral Sinularia flexibilis collected from Hayman Island on the Great Barrier Reef of Australia [5]. Using an in vitro anti-inflammatory assay system, we found that sinularin, isolated from the same genus but from a different species of soft coral, Sinularia querciformis collected from Dongsha Islands off Taiwan, significantly inhibited upregulation of proinflammatory proteins, particularly inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in lipopolysaccharide (LPS)-stimulated murine macrophage RAW 264.7 cells. However, there are two important points regarding the bioactivity of sinularin that remain unclear. First, no previous studies have explored the analgesic activity of sinularin. Second, potential mechanisms of sinularin’s anti-inflammatory activity remain unclear.


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)

Chemical structure of sinularin (5,15-dioxatricyclo[12.3.1.0(4,6)]octadec-9-en-16-one).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475263&req=5

marinedrugs-10-01899-f001: Chemical structure of sinularin (5,15-dioxatricyclo[12.3.1.0(4,6)]octadec-9-en-16-one).
Mentions: Marine-derived compounds obtained from soft corals are believed to yield many potential candidate compounds for treating inflammatory diseases, particularly for treating pain [1,2,3,4]. The natural marine compound sinularin (Figure 1) has been well-studied and was shown by Weinheimer et al. in 1977 to have anticancer activity against the human epidermoid carcinoma cell line (KB) and the murine P388 lymphocytic leukemia cell line (PS) cell line from the soft coral Sinularia flexibilis [5]. In 1978, Kazlauskas et al. isolated sinularin from the same soft coral, but referred to the compound as flexibilide [6]. Later, in 1980, Buckle et al. reported that oral administration of sinularin reduced carrageenan-induced paw edema 3 h after carrageenan injection and that chronic oral sinularin inhibited adjuvant-induced paw swelling (periarthritis model) over a 21-day period after adjuvant administration [7]. After Buckle et al. used rat models to show the anti-inflammatory activity of sinularin [7], scientists explored other bioactivities of sinularin, such as its cardiovascular [8] and antimicrobial [9] activities. Sinularin was originally isolated from the soft coral Sinularia flexibilis collected from Hayman Island on the Great Barrier Reef of Australia [5]. Using an in vitro anti-inflammatory assay system, we found that sinularin, isolated from the same genus but from a different species of soft coral, Sinularia querciformis collected from Dongsha Islands off Taiwan, significantly inhibited upregulation of proinflammatory proteins, particularly inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in lipopolysaccharide (LPS)-stimulated murine macrophage RAW 264.7 cells. However, there are two important points regarding the bioactivity of sinularin that remain unclear. First, no previous studies have explored the analgesic activity of sinularin. Second, potential mechanisms of sinularin’s anti-inflammatory activity remain unclear.

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