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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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Time-courses of analgesic effects of subcutaneous (s.c.) sinularin (80 mg/kg) or indomethacin (20 mg/kg) on intraplantar (i.p.l.) carrageenan-induced nociceptive behaviors, including thermal hyperalgesia (A) mechanical allodynia; (B) cold allodynia; (C) and hindpaw weight-bearing deficits; (D) We used 20 mg/kg indomethacin as a positive control. Carrageenan-induced nociceptive behaviors peaked at 3–6 h and persisted for at least 24 h. This phenomenon was significantly inhibited by s.c. sinularin (80 mg/kg) or indomethacin (20 mg/kg). Each point in all figures represents the mean ± standard error of the mean (SEM) of 6 rats per group. * P < 0.05 between i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) group compared with the same time points in i.p.l. carrageenan plus s.c. vehicle (dimethyl sulfoxide [DMSO]) group; #P < 0.05 between i.p.l. carrageenan plus s.c. indomethacin (20 mg/kg) group compared with the same time points in i.p.l. carrageenan plus s.c. vehicle group.
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marinedrugs-10-01899-f004: Time-courses of analgesic effects of subcutaneous (s.c.) sinularin (80 mg/kg) or indomethacin (20 mg/kg) on intraplantar (i.p.l.) carrageenan-induced nociceptive behaviors, including thermal hyperalgesia (A) mechanical allodynia; (B) cold allodynia; (C) and hindpaw weight-bearing deficits; (D) We used 20 mg/kg indomethacin as a positive control. Carrageenan-induced nociceptive behaviors peaked at 3–6 h and persisted for at least 24 h. This phenomenon was significantly inhibited by s.c. sinularin (80 mg/kg) or indomethacin (20 mg/kg). Each point in all figures represents the mean ± standard error of the mean (SEM) of 6 rats per group. * P < 0.05 between i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) group compared with the same time points in i.p.l. carrageenan plus s.c. vehicle (dimethyl sulfoxide [DMSO]) group; #P < 0.05 between i.p.l. carrageenan plus s.c. indomethacin (20 mg/kg) group compared with the same time points in i.p.l. carrageenan plus s.c. vehicle group.

Mentions: No significant differences in the baselines were observed for paw withdrawal latency (PWL), paw withdrawal threshold (PWT), acetone response score, or change in hind paw weight distribution among the experimental groups before carrageenan injection. Average baselines for PWL, PWT, acetone response score, and changes in hind paw weight distribution were 28.59 ± 0.45 s (n = 18), 12.50 ± 0.52 g (n = 18), 16.75 ± 0.66 points (n = 18), and −0.29 ± 1.10 g (n = 18), respectively. As expected, thermal hyperalgesia (PWL = 10.69 ± 1.72 s; n = 6), mechanical allodynia (PWT = 1.20 ± 0.26 g; n = 6), cold allodynia (acetone response score = 3.33 ± 0.79 points; n = 6), and hindpaw weight-bearing deficits (change in hind paw weight distribution = 84.63 ± 1.50 g; n = 6) of the carrageenan-injected paw peaked at 3–6 h after i.p.l. carrageenan injection; these nociceptive behaviors of inflammatory pain persisted for at least 24 h (Figure 4). Figure 4 presents the time course of analgesic effects of s.c. 80 mg/kg sinularin: anti-thermal hyperalgesia (Figure 4A, anti-mechanical allodynia (Figure 4B), anti-cold allodynia (Figure 4C, and anti-weight-bearing deficits (Figure 4D), respectively. Sinularin groups exhibited extended antinociceptive effects until at least 24 h after i.p.l. carrageenan injection, while s.c. injection of vehicle (100% DMSO) did not affect carrageenan-induced nociceptive behaviors. Additionally, s.c. indomethacin (20 mg/kg) also significantly inhibited these i.p.l. carrageenan-induced nociceptive behaviors until at least 24 h after i.p.l. carrageenan injection. In the present study, carrageenan plus s.c. sinularin-treated rats (20 and 80 mg/kg) did not exhibit any obvious side effects regarding external behavior, including locomotor function, during treatment. We then focused on the period of 24 h after s.c. 80 mg/kg of sinularin to determine whether inhibition of spinal neuroinflammatory processes are consistent with the antinociceptive effects of sinularin based on two primary considerations. First, these four i.p.l. carrageenan-induced nociceptive behaviors continued to 24 h after carrageenan injection. Second, s.c. administration of 80 mg/kg sinularin at 24 h after carrageenan injection retained antinociceptive efficacy.


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)

Time-courses of analgesic effects of subcutaneous (s.c.) sinularin (80 mg/kg) or indomethacin (20 mg/kg) on intraplantar (i.p.l.) carrageenan-induced nociceptive behaviors, including thermal hyperalgesia (A) mechanical allodynia; (B) cold allodynia; (C) and hindpaw weight-bearing deficits; (D) We used 20 mg/kg indomethacin as a positive control. Carrageenan-induced nociceptive behaviors peaked at 3–6 h and persisted for at least 24 h. This phenomenon was significantly inhibited by s.c. sinularin (80 mg/kg) or indomethacin (20 mg/kg). Each point in all figures represents the mean ± standard error of the mean (SEM) of 6 rats per group. * P < 0.05 between i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) group compared with the same time points in i.p.l. carrageenan plus s.c. vehicle (dimethyl sulfoxide [DMSO]) group; #P < 0.05 between i.p.l. carrageenan plus s.c. indomethacin (20 mg/kg) group compared with the same time points in i.p.l. carrageenan plus s.c. vehicle group.
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marinedrugs-10-01899-f004: Time-courses of analgesic effects of subcutaneous (s.c.) sinularin (80 mg/kg) or indomethacin (20 mg/kg) on intraplantar (i.p.l.) carrageenan-induced nociceptive behaviors, including thermal hyperalgesia (A) mechanical allodynia; (B) cold allodynia; (C) and hindpaw weight-bearing deficits; (D) We used 20 mg/kg indomethacin as a positive control. Carrageenan-induced nociceptive behaviors peaked at 3–6 h and persisted for at least 24 h. This phenomenon was significantly inhibited by s.c. sinularin (80 mg/kg) or indomethacin (20 mg/kg). Each point in all figures represents the mean ± standard error of the mean (SEM) of 6 rats per group. * P < 0.05 between i.p.l. carrageenan plus s.c. sinularin (80 mg/kg) group compared with the same time points in i.p.l. carrageenan plus s.c. vehicle (dimethyl sulfoxide [DMSO]) group; #P < 0.05 between i.p.l. carrageenan plus s.c. indomethacin (20 mg/kg) group compared with the same time points in i.p.l. carrageenan plus s.c. vehicle group.
Mentions: No significant differences in the baselines were observed for paw withdrawal latency (PWL), paw withdrawal threshold (PWT), acetone response score, or change in hind paw weight distribution among the experimental groups before carrageenan injection. Average baselines for PWL, PWT, acetone response score, and changes in hind paw weight distribution were 28.59 ± 0.45 s (n = 18), 12.50 ± 0.52 g (n = 18), 16.75 ± 0.66 points (n = 18), and −0.29 ± 1.10 g (n = 18), respectively. As expected, thermal hyperalgesia (PWL = 10.69 ± 1.72 s; n = 6), mechanical allodynia (PWT = 1.20 ± 0.26 g; n = 6), cold allodynia (acetone response score = 3.33 ± 0.79 points; n = 6), and hindpaw weight-bearing deficits (change in hind paw weight distribution = 84.63 ± 1.50 g; n = 6) of the carrageenan-injected paw peaked at 3–6 h after i.p.l. carrageenan injection; these nociceptive behaviors of inflammatory pain persisted for at least 24 h (Figure 4). Figure 4 presents the time course of analgesic effects of s.c. 80 mg/kg sinularin: anti-thermal hyperalgesia (Figure 4A, anti-mechanical allodynia (Figure 4B), anti-cold allodynia (Figure 4C, and anti-weight-bearing deficits (Figure 4D), respectively. Sinularin groups exhibited extended antinociceptive effects until at least 24 h after i.p.l. carrageenan injection, while s.c. injection of vehicle (100% DMSO) did not affect carrageenan-induced nociceptive behaviors. Additionally, s.c. indomethacin (20 mg/kg) also significantly inhibited these i.p.l. carrageenan-induced nociceptive behaviors until at least 24 h after i.p.l. carrageenan injection. In the present study, carrageenan plus s.c. sinularin-treated rats (20 and 80 mg/kg) did not exhibit any obvious side effects regarding external behavior, including locomotor function, during treatment. We then focused on the period of 24 h after s.c. 80 mg/kg of sinularin to determine whether inhibition of spinal neuroinflammatory processes are consistent with the antinociceptive effects of sinularin based on two primary considerations. First, these four i.p.l. carrageenan-induced nociceptive behaviors continued to 24 h after carrageenan injection. Second, s.c. administration of 80 mg/kg sinularin at 24 h after carrageenan injection retained antinociceptive efficacy.

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