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ABSTRACT: The hematopoietic growth factor, granulocyte colony-stimulating factor (G-CSF), has become one of the few growth factors approved for clinical use. It has therapeutic potential for numerous neurodegenerative diseases; however, at present the cellular effects of G-CSF on the central nervous system remain unclear and in need of investigation. In the present study, we used spinal cord ischemia, a neurodegenerative model, to examine the effects of intrathecal (i.t.) G-CSF on glial cell (microglia and astrocyte) activation and neuroprotective factor expression, including glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor A (VEGF-A) protein expression. Our results indicate that i.t. G-CSF could enhance ischemia-induced microglia activation and inhibit ischemia-induced astrocyte activation. Both GDNF and VEGF-A are upregulated after injury, and i.t. G-CSF could enhance GDNF and VEGF-A expression after injury. Interestingly, our results indicate that performing i.t. G-CSF alone on normal animals could have the effect of microglial and astrocyte activation and enhanced GDNF and VEGF-A expression. Furthermore, through laser scanning confocal microscopy, we found that astrocytes may contribute the majority of GDNF and VEGF-A expression of G-CSF after spinal cord ischemia. Overall, this G-CSF-induced upregulation suggests that activation of endogenous neuroprotective mechanisms could resist neurodegenerative insults. These observations demonstrate the cellular mechanism of i.t. G-CSF after spinal cord ischemia and confirm the neuroprotective effect of G-CSF after spinal cord ischemia injury.
Neuroscience 03/2013; · 3.38 Impact Factor
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ABSTRACT: An acute gout attack manifests in the joint as dramatic inflammation. To date, the clinical use of medicinal agents has typically led to undesirable side effects. Numerous efforts have failed to create an effective and safe agent for the treatment of gout. Lemnalol-an extract from Formosan soft coral-has documented anti-inflammatory and anti-nociceptive properties. In the present study, we attempt to examine the therapeutic effects of lemnalol on intra-articular monosodium urate (MSU)-induced gouty arthritis in rats. In the present study, we found that treatment with lemnalol (intramuscular [im]), but not colchicine (oral [po]), significantly attenuated MUS-induced mechanical allodynia, paw edema and knee swelling. Histomorphometric and immunohistochemistry analysis revealed that MSU-induced inflammatory cell infiltration, as well as the elevated expression of c-Fos and pro-inflammatory proteins (inducible nitric oxide synthase and cyclooxygenase-2) observed in synovial tissue, were significantly inhibited by treatment with lemnalol. We conclude that lemnalol may be a promising candidate for the development of a new treatment for gout and other acute neutrophil-driven inflammatory diseases.
Marine Drugs 01/2013; 11(1):99-113. · 3.85 Impact Factor
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ABSTRACT: We previously demonstrated that intrathecal IL-1β caused thermal hyperalgesia in rats. This study was conducted to examine the effects and cellular mechanisms of glial inhibitors on IL-1β-induced nociception in rats. The effects of minocycline (20 μg), fluorocitrate (1 nmol), and SB203580 (5 μg) on IL-1β (100 ng) treatment in rats were measured by nociceptive behaviors, western blotting of p38 mitogen-activated protein kinase (MAPK) and inducible nitric oxide synthase (iNOS) expression, cerebrospinal fluid nitric oxide (NO) levels, and immunohistochemical analyses. The results demonstrated that intrathecal IL-1β activated microglia and astrocytes, but not neurons, in the dorsal horn of the lumbar spinal cord, as evidenced by morphological changes and increased immunoreactivity, phosphorylated p38 (P-p38) MAPK, and iNOS expression; the activation of microglia and astrocytes peaked at 30 min and lasted for 6 h. The immunoreactivities of microglia and astrocytes were significantly increased at 30 min (6.6- and 2.7-fold, respectively) and 6 h (3.3- and 4.0-fold, respectively) following IL-1β injection, as compared with saline controls at 30 min (all P < 0.01). IL-1β induced P-p38 MAPK and iNOS expression predominantly in microglia and less in astrocytes. Minocycline, fluorocitrate, or SB203580 pretreatment suppressed this IL-1β-upregulated P-p38 MAPK mainly in microglia and iNOS mainly in astrocytes; minocycline exhibited the most potent effect. Minocycline and fluorocitrate pretreatment abrogated IL-1β-induced NO release and thermal hyperalgesia in rats. In conclusion, minocycline, fluorocitrate, and SB203580 effectively suppressed the IL-1β-induced central sensitization and hyperalgesia in rats. © 2012 Wiley Periodicals, Inc.
Glia 09/2012; 60(12):2004-17. · 4.82 Impact Factor
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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.
Marine Drugs 09/2012; 10(9):1899-919. · 3.85 Impact Factor
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ABSTRACT: The investigators previously found that the administration of lemnalol, a natural marine compound isolated from the Formosan soft coral Lemnalia cervicorni, produced anti-inflammatory and analgesic effects in carrageenan-injected rats. Recently, several studies have demonstrated that the development and maintenance of neuropathic pain are accompanied by releasing of proinflammatory mediators from activated glial cells in the spinal cord. In this study, we investigated the antinociceptive properties of lemnalol, a potential anti-inflammatory compound, on chronic constriction injury (CCI) in a well-established rat model of neuropathic pain. Our results demonstrated that a single intrathecal administration of lemnalol (0.05-10 μg) significantly attenuated CCI-induced thermal hyperalgesia and mechanical allodynia, 14 days postsurgery. Furthermore, immunohistofluorescence analyses showed that lemnalol (10 μg) also significantly inhibits CCI-induced upregulation of microglial and astrocytic immunohistochemical activation markers in the dorsal horn of the lumbar spinal cord. Double immunofluorescent staining demonstrated that intrathecal injection of lemnalol (10 μg) markedly inhibited spinal proinflammatory mediator tumor necrosis factor-α expression in microglial cells and astrocytes in neuropathic rats. Collectively, our results indicate that lemnalol is a potential therapeutic agent for neuropathic pain, and that further exploration of the effects of lemnalol on glial proinflammatory responses is warranted.
Behavioural pharmacology 12/2011; 22(8):739-50. · 2.85 Impact Factor
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Wu-Fu Chen,
Chiranjib Chakraborty,
Chun-Sung Sung,
Chien-Wei Feng,
Yen-Hsuan Jean,
Yen-You Lin,
Han-Chun Hung,
Tzu-Yi Huang, Shi-Ying Huang,
Thung-Ming Su,
Ping-Jyun Sung,
Jyh-Horng Sheu,
Zhi-Hong Wen
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ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disease characterized by tremor, rigidity, bradykinesia, and gait impairment. So far, very few pharmacological agents have been isolated or developed that effectively inhibit the progression of PD. However, several studies have demonstrated that inflammatory processes play critical roles in PD. Therefore, anti-inflammatory agents may suppress disease progression in PD. 11-Dehydrosinulariolide was isolated from cultured soft corals. The anti-inflammatory effect of this molecule has been observed through suppression of the expression of two main pro-inflammatory proteins: inducible nitric oxide synthase and cyclooxygenase-2, in lipopolysaccharide-stimulated macrophage cells. We also found that 11-dehydrosinulariolide significantly reduced 6-hydroxydopamine (6-OHDA)-induced cytotoxicity and apoptosis in a human neuroblastoma cell line (SH-SY5Y). The pharmacological activity of this compound has been studied, and it is associated with the inhibition of 6-OHDA-induced activation of caspase-3 and translocation of nuclear factor kappa B. 11-Dehydrosinulariolide increased the activation of survival-signaling phospho-Akt but not phospho-ERK. The neuroprotective effect of 11-dehydrosinulariolide was assessed here using 6-OHDA-treated SH-SY5Y cells, wherein neuroprotection is mediated through regulation of phosphatidylinositol 3-kinase (PI3K). Furthermore, 11-dehydrosinulariolide caused a significant decrease in caspase-3/7 activity in comparison to the 6-OHDA-treated group, indicating that 11-dehydrosinulariolide has neuroprotective properties. We conclude that 11-dehydrosinulariolide is a promising candidate for the treatment of Parkinson's disease through its anti-apoptotic and anti-inflammatory action via PI3K signaling.
Archiv für Experimentelle Pathologie und Pharmakologie 11/2011; 385(3):265-75. · 2.65 Impact Factor
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ABSTRACT: Recently, the hematopoietic factor, granulocyte colony-stimulating factor (G-CSF), has been shown to exhibit neuroprotective effects in CNS injuries. Our previous study demonstrated that intrathecal (i.t.) G-CSF significantly improved neurological defects in spinal cord ischemic rats. Considerable evidence indicates that the release of excessive amounts of excitatory amino acids (EAAs) plays a critical role in neuron injury induced by ischemic insult. In the present study, we used a spinal cord ischemia-microdialysis model to examine whether i.t. G-CSF exerted antiexcitotoxicity effects in a rat model of spinal cord ischemia. I.t. catheters and a microdialysis probe were implanted in male Wistar rats. The results revealed that spinal cord ischemia-induced neurological defects were accompanied by a significant increase in the concentration of EAAs (aspartate and glutamate) in the spinal dialysates from 30 min to 2 days after reperfusion. I.t administration of G-CSF immediately after the performance of surgery designed to induce ischemia led to a significant reduction in ischemia-induced increases in the levels of spinal EAAs. Moreover, i.t. G-CSF also brought about a significant reduction in the elevation of spinal EAA concentrations induced by exogenous i.t. administration of glutamate (10 microl of 500 mM). I.t. G-CSF attenuated spinal cord ischemia-induced downregulation of expression of three glutamate transporters (GTs), glial transporter Glu-Asp transporter (GLAST), Glu transporter-1 (GLT-1), and excitatory amino acid carrier 1 (EAAC1) protein 48 h after spinal cord ischemic surgery. Immunohistofluorescent staining showed that i.t. G-CSF significantly upregulated expression of the three GTs in the gray matter of the lumbar spinal cord from 3 to 24 h after injection. We propose that i.t. G-CSF possesses an ability to reduce the extent of spinal cord ischemia-induced excitotoxicity by inducing the expression of glutamate transporters.
Neuroscience 11/2009; 165(4):1217-32. · 3.38 Impact Factor
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ABSTRACT: Natural compounds obtained from marine organisms have received considerable attention as potential sources of novel drugs for treatment of human inflammatory diseases. Capnellene, isolated from the marine soft coral Capnella imbricate, 4,4,6a-trimethyl-3-methylene-decahydro-cyclopenta[]pentalene-2,3a-diol (GB9) exhibited anti-inflammatory actions on activated macrophages in vitro. Here we have assessed the anti-neuroinflammatory properties of GB9 and its acetylated derivative, acetic acid 3a-hydroxy-4,4,6a-trimethyl-3-methylene-decahydro-cyclopenta[]pentalen-2-yl ester (GB10).
Effects of GB9 or GB10 on the expression of inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in interferon-gamma (IFN-gamma)-stimulated mouse microglial BV2 cells were measured by Western blot. The in vivo effects of these compounds were examined in the chronic constriction injury (CCI) rat model of neuropathic pain, measuring thermal hyperalgesia, and microglial activation and COX-2 protein in lumbar spinal cord, by immunohistochemistry.
In BV2 cells, GB9 and GB10 inhibited the expression of iNOS and COX-2, stimulated by IFN-gamma. Intrathecal administration of GB9 and GB10 inhibited CCI-induced nociceptive sensitization and thermal hyperalgesia in a dose-dependent manner. Intraperitoneal injection of GB9 inhibited CCI-induced thermal hyperalgesia and also inhibited CCI-induced activation of microglial cells and up-regulation of COX-2 in the dorsal horn of the lumbar spinal cord ipsilateral to the injury.
Taken together, these data indicate that the marine-derived capnellenes, GB9 and GB10, had anti-neuroinflammatory and anti-nociceptive properties in IFN-gamma-stimulated microglial cells and in neuropathic rats respectively. Therefore, capnellene may serve as a useful lead compound in the search for new therapeutic agents for treatment of neuroinflammatory diseases.
British Journal of Pharmacology 09/2009; 158(3):713-25. · 4.41 Impact Factor
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ABSTRACT: Recently, we found that intrathecal (i.t.) pertussis toxin (PTX) injection produces thermal hyperalgesia and is associated with increasing concentrations of excitatory amino acids (EAAs) in spinal cerebrospinal fluid (CSF) dialysates; a reduction in the antinociceptive effects of morphine and glutamate transporters (GTs) was also observed. The reduction in the morphine-induced analgesic effects is directly related to increased extracellular EAA levels, which are maintained by GTs at physiological levels. In this study, we aimed to examine the role of GT isoforms in thermal hyperalgesia, determine the EAA concentrations in CSF dialysates, and elucidate the role of N-methyl-d-aspartate (NMDA) receptors in PTX-induced reduction in the antinociceptive effects of morphine. Two i.t. catheters and one microdialysis probe were inserted into male Wistar rats: one catheter was used for PTX (1 microg) and morphine (10 microg) injection and the other was connected to an osmotic pump for NMDA receptor antagonist d-2-amino-5-phosphonopentanoic acid (d-AP5; 2 microg/h for 4 days) continuous infusion. The microdialysis probe was used to collect CSF dialysates for EAA measurements by high-performance liquid chromatography. Intrathecal morphine failed to produce antinociceptive effects in PTX-treated rats, and d-AP5 coinfusion prevented the PTX-induced reduction in the antinociceptive effect and associated downregulation of the GTs. We conclude that NMDA receptor suppression inhibits EAA excitation and reduces the morphine-induced antinociception in PTX-treated rats.
Brain research bulletin 06/2009; 80(1-2):69-74. · 2.18 Impact Factor
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ABSTRACT: Lemnalol (8-isopropyl-5-methyl-4-methylene-decahydro-1,5-cyclo-naphthalen-3-ol) is a natural compound isolated from the marine soft coral Lemnalia cervicorni. In the present study, the anti-inflammatory and anti-nociceptive properties of lemnalol were investigated in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and carrageenan-injected rats, respectively. Our results demonstrate that lemnalol significantly inhibited the expression of the pro-inflammatory proteins, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in LPS-stimulated RAW 264.7 cells. An in vivo inflammation model was induced by intraplantar injection of carrageenan into rat hind paws. An intramuscular injection of lemnalol (15 mg/kg) 10 min before carrageenan injection resulted in significant inhibition of carrageenan-induced rat paw edema and thermal hyperalgesia behavior. Western blot experiments revealed that the carrageenan-induced expression of iNOS and COX-2 in paw tissue was significantly down-regulated by lemnalol. Moreover, post-intrathecal injection of lemnalol produced a dose-dependent anti-nociceptive effect in carrageenan-injected rats (1 and 5 microg). The present results indicate that the marine-derived compound lemnalol had anti-inflammatory and analgesic effects in LPS-stimulated RAW 264.7 cells and carrageenan-injected rats, respectively. In addition, inhibition of elevated iNOS and COX-2 protein expression as well as neurophil infiltration of carrageenan-injected paws may be involved in the beneficial effects of lemnalol.
European Journal of Pharmacology 02/2008; 578(2-3):323-31. · 2.52 Impact Factor
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ABSTRACT: This study was performed to determine the serum concentrations of interleukin-6 (IL-6) during the early course of bacterial infections disease in children, and to evaluate the usefulness of IL-6 as a diagnostic test alone and in combination with C-reactive protein (CRP).
We measured serum IL-6 values in 3 groups of children on their first day of admission, from January 2001 to December 2001: group 1, patients with clinical and microbiological evidence of sepsis (n = 13); group 2, patients with clinical and chest radiographical evidence of pneumonia (n = 18); and group 3, patients with no signs of infection (control group) (n = 16). Kruskal-Wallis tests were used to compare the difference of IL-6 values between groups and control subjects.
IL-6 values were significantly higher in groups 1 and 2 compared with those in the control group (p < 0.001). No significant differences were found between the groups 1 and 2. As a diagnostic test, IL-6 (> or = 20 pg/mL) alone yielded a sensitivity of 68%, a specificity of 88%, a positive predictive value of 71%, and a negative predictive value of 58%. A combined parameter of IL-6 (> or = 20 pg/mL) and CRP (> or = 1 mg/dL) yielded a sensitivity of 94%, a specificity of 63%, a positive predictive value of 79%, and a negative predictive value of 87%.
IL-6 levels increase in children with sepsis. In combination with CRP, IL-6 seems to be a valuable parameter in the early diagnosis of pediatric infections.
Journal of the Chinese Medical Association 09/2003; 66(9):523-7. · 0.79 Impact Factor
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ABSTRACT: Coagulase-negative staphylococci (CoNS) are the most common microorganisms isolated from blood cultures in childern, and determining whether there is true bacteremia or merely contamination is a clinical dilemma. A total of 67 episodes of CoNS-positive blood cultures in pediatric and neonatal intensive care units were evaluated during a 3-year period in order to find the possible risk factors involved and the antimicrobial susceptibility of CoNS isolates. In this study, 37 episodes were judged to be infections as opposed to 30 that were not. In comparison with individuals without infection, patients with true infection of CoNS stayed longer in the hospital (32 +/- 32.9 vs 10.7 +/- 9.3 days, p = 0.001), had more surgical procedures (32.4% vs 6.7%, p = 0.014), received more antibiotic treatments in the recent 2 weeks (37.8% vs 0%, p < 0.001), underwent more central venous catheter insertions (86.4% vs 10%, p < 0.001), received more parenteral nutrition (37.8% vs 3.3%, p = 0.001), had higher C-reactive protein profiles (4.8 +/- 5.4 vs 0.6 +/- 0.9 mg/dL, p < 0.001), and had higher neutrophil proportion (58.1% vs 44.3%, p = 0.001). However, there were no significant differences in corticosteroid therapy, hemoglobin level, total leukocyte count, and platelet count. All strains of the infection group were resistant to cefazolin, cefotaxime, penicillin, and erythromycin. Nonetheless, all isolates were susceptible to vancomycin. The percentage of multiple-resistant CoNS in the infection group was 96.9%. Empirical therapy with vancomycin for CoNS bacteremia in critically ill children is therefore recommended.
Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi 03/2003; 36(1):51-5. · 0.99 Impact Factor
