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John M. Stewart - One of the best experts on this subject based on the ideXlab platform.
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strong cytotoxic effect of the Bradykinin Antagonist bkm 570 in ovarian cancer cells analysis of the molecular mechanisms of its antiproliferative action
FEBS Journal, 2010Co-Authors: Stephanie Jutras, John M. Stewart, Magdalena Bachvarova, Mamadou Keita, Jeanloup Bascands, Annemarie Mesmasson, Dimcho BachvarovAbstract:The standard chemotherapy for epithelial ovarian cancer (EOC) patients is currently a combination of taxane and platinum. However, most EOC patients still suffer relapses, and there is an immediate need for the development of novel and more effective therapeutic modalities against this deadly disease. Recently, the nonpeptide Bradykinin (BK) Antagonist 2,3,4,5,6-pentafluorocinnamoyl-(o-2,6-dichlorobenzyl)-l-tyrosine-N-(4-amino-2,2,6,6-tetramethyl-piperidyl) amide (BKM-570) was shown to cause impressive growth inhibition of lung and prostate tumors, displaying superior in vivo inhibitory effects than convential chemotherapeutic drugs. Here, we investigated BKM-570 cytotoxic effects in two EOC cell lines, derived from different EOC histopathologies: a clear cell carcinoma (TOV-21), and an endometrioid carcinoma (TOV-112). We showed that BKM-570 effectively inhibited the growth of ovarian cancer cells, as its cytotoxic effects were comparable to those of cisplatin, and were independent of the functional status of BK receptors. Moreover, BKM-570 synergized with cisplatin in inhibiting EOC cell growth. To better understand the molecular mechanisms of the antiproliferative action of this BK Antagonist in EOC cells, we performed gene expression profiling in TOV-21 and TOV-112 cells following treatment with 10 μm BKM-570 for 24 h. BKM-570 displayed similar cytotoxic effects in the two cell lines analyzed, as genes with previously shown involvement in apoptosis/antiapoptosis and cell adhesion were proportionally upregulated and downregulated in both cell lines, whereas genes involved in basic cellular mechanisms, including cell growth and maintenance, metabolism, cell cycle control, inflammatory and immune response, signal transduction, protein biosynthesis, transcription regulation, and transport, were predominantly downregulated upon treatment. Our data are indicative of the therapeutic potential of BKM-570 and related compounds in EOC management.
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Combination cancer chemotherapy with one compound: Pluripotent Bradykinin Antagonists
Peptides, 2005Co-Authors: John M. Stewart, Lajos Gera, Paul A. Bunn, Daniel C. Chan, Eunice J. York, Vitalija Simkeviciene, Laimute Taraseviciene-stewartAbstract:Abstract Lung and prostate cancers are major health problems worldwide. Treatments with standard chemotherapy agents are relatively ineffective. Combination chemotherapy gives better treatment than a single agent because the drugs can inhibit the cancer in different pathways, but new therapeutic agents are needed for the treatment of both tumor types. Bradykinin (BK) Antagonists offer advantages of combination therapy in one compound. These promising multitargeted anti-cancer compounds selectively stimulate apoptosis in cancers and also inhibit both angiogenesis and matrix metalloprotease (MMP) action in treated lung and prostate tumors in nude mice. The highly potent, metabolism-resistant Bradykinin Antagonist peptide dimer, B-9870 [SUIM-(DArg-Arg-Pro-Hyp-Gly-Igl-Ser-DIgl-Oic-Arg) 2 ] (SUIM = suberimidyl; Hyp = 4-hydroxyproline; Igl = α-(2-indanyl)glycine; Oic = octahydroindole-2-carboxylic acid) and its non-peptide mimetic, BKM-570 [2,3,4,5,6-pentafluorocinnamoyl-( o -2,6-dichlorobenzyl)- l -tyrosine- N -(4-amino-2,2,6,6-tetramethylpiperidyl)amide] are superior to the widely used but toxic chemotherapeutic drugs cisplatin and taxotere. In certain combinations, they act synergistically with standard anti-cancer drugs. Due to its structure and biological activity, BKM-570 is an attractive lead compound for derivatization and evaluation for lung and prostate cancer drugs.
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Bradykinin Antagonist dimer, CU201, inhibits the growth of human lung cancer cell lines by a “biased agonist” mechanism
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Daniel Chan, Lajos Gera, John M. Stewart, Barbara Helfrich, Marileila Verella-garcia, Gary L. Johnson, Anna E. Barón, Jie Yang, Theodore Puck, Paul A. BunnAbstract:All small cell (SCLCs) and many non-small cell lung cancers (NSCLCs) have neuroendocrine features including production of neuropeptides and cell surface receptors creating autocrine and paracrine growth loops. Neuropeptides bind to a family of 7-transmembrane receptors and activate heterotrimeric G proteins consisting of Gαq and Gα12,13. Substance P derivatives (SPDs) induced apoptosis and inhibited growth of lung cancer cells by discoordinately inhibiting Gαq and stimulating Gα12,13. However, these SPDs had low potency and short half-lives. In this report we show that a Bradykinin Antagonist dimer, CU201, inhibited the growth of SCLC and NSCLC cell lines with or without multidrug-resistant proteins and was 10-fold more potent with a longer plasma half-life than SPDs. Bradykinin agonists in either monomeric or dimeric form and monomeric Bradykinin Antagonist have no effect on lung cancer cell growth. The dimeric linking moiety of the two molecules was created, requiring a sufficient number of carbon chains to provide critical spacing between the two Antagonists. CU201 inhibited intracellular Ca2+ release in response to Bradykinin, indicating blockage of the Gαq signal, and stimulated c-Jun kinases, indicating stimulation of the Gα12,13 pathway. CU201-induced apoptosis was preceded by unique changes in apparent nuclear DNA binding and by c-Jun kinase and caspase-3 activation. At the concentration at which CU201 inhibited the growth of the cancer cells, it had no effect on the growth of normal lung cells in vitro. CU201 and similar compounds offer hope of becoming a new form of targeted therapy for tumors with neuroendocrine properties.
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Bradykinin Antagonist dimer cu201 inhibits the growth of human lung cancer cell lines by a biased agonist mechanism
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Daniel Chan, Lajos Gera, John M. Stewart, Barbara Helfrich, Gary L. Johnson, Anna E. Barón, Jie Yang, Theodore Puck, Marileila VerellagarciaAbstract:All small cell (SCLCs) and many non-small cell lung cancers (NSCLCs) have neuroendocrine features including production of neuropeptides and cell surface receptors creating autocrine and paracrine growth loops. Neuropeptides bind to a family of 7-transmembrane receptors and activate heterotrimeric G proteins consisting of Gαq and Gα12,13. Substance P derivatives (SPDs) induced apoptosis and inhibited growth of lung cancer cells by discoordinately inhibiting Gαq and stimulating Gα12,13. However, these SPDs had low potency and short half-lives. In this report we show that a Bradykinin Antagonist dimer, CU201, inhibited the growth of SCLC and NSCLC cell lines with or without multidrug-resistant proteins and was 10-fold more potent with a longer plasma half-life than SPDs. Bradykinin agonists in either monomeric or dimeric form and monomeric Bradykinin Antagonist have no effect on lung cancer cell growth. The dimeric linking moiety of the two molecules was created, requiring a sufficient number of carbon chains to provide critical spacing between the two Antagonists. CU201 inhibited intracellular Ca2+ release in response to Bradykinin, indicating blockage of the Gαq signal, and stimulated c-Jun kinases, indicating stimulation of the Gα12,13 pathway. CU201-induced apoptosis was preceded by unique changes in apparent nuclear DNA binding and by c-Jun kinase and caspase-3 activation. At the concentration at which CU201 inhibited the growth of the cancer cells, it had no effect on the growth of normal lung cells in vitro. CU201 and similar compounds offer hope of becoming a new form of targeted therapy for tumors with neuroendocrine properties.
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Potent Bradykinin Antagonists having medical potential
Chinese Peptide Symposia, 2002Co-Authors: John M. Stewart, Lajos Gera, Eunice J. York, Daniel C. ChanAbstract:Bradykinin Antagonist peptides have been developed during the past fourteen years into extremely potent and stable molecules that offer great potential for development into drugs for serious inflammation and cancers. The great need now is for financial support for these human studies.
Lajos Gera - One of the best experts on this subject based on the ideXlab platform.
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A preclinical pharmacodynamic analysis of CU201, a novel Bradykinin Antagonist, using a calcium flux assay in lung cancer cell lines
Clinical Cancer Research, 2006Co-Authors: Glen J. Weiss, Lajos Gera, Paul A. Bunn, Karen M. Helm, Daniel C. ChanAbstract:A105 Background: Neuroendocrine features, including paracrine and autocrine growth stimulation by various neuropeptides, are characteristics of all small cell lung cancers (SCLC) and many non-small cell lung cancers (NSCLC). CU201, a novel Bradykinin Antagonist, acts as a biased agonist for neuropeptides by blocking G αq signaling and activating G α12,13 signaling (Chan DC, et al. Clin Cancer Res 2002;8:1280-1287). A pharmacodynamic test is sought to incorporate into future phase I/II studies with this compound, at feasible plasma concentrations in clinical trial participants.Methods: Cell growth was assessed using a modified tetrazolium salt (MTT) assay. Gene expression profiling was performed using Affymetrix U133A plus 2.0 microarray on SCLC cell lines (SHP77 and H69) and Affymetrix U133A microarray on NSCLC cell lines (H2126 and H1703). Cell necrosis and apoptosis was determined by flow cytometry after cells were treated with CU201 (range 0.1-10 uM) over 48 hours followed by loading with YO-PRO-1 and propidium iodide. Intracellular calcium flux was determined by flow cytometry after cells were loaded with calcium marker Indo-1-AM and were exposed to Bradykinin (range 0.1-10 uM) or CU201 (range 0.1-100 uM) followed by Bradykinin. Plasma was obtained from 3 healthy volunteers. Calcium flux was then determined using fresh, thawed, and heat-inactivated plasma, respectively. Plasma was spiked with CU201 to a final concentration of 1 uM and then heat-inactivated and frozen at -70 C for 10 days, then thawed and exposed to cell lines followed by the addition of 0.1 uM Bradykinin.Results: IC 50 (uM) values for growth inhibition were 4.0, 1.9, 3.0, and 1.2 uM and BKR2 expression signal intensities were 1460, 1267, 4.76, 10.73 in H2126, SHP77, H1703, and H69; respectively. Necrosis 50 values by the apoptosis assay was seen with 8 uM and 4.5 uM CU201 in H2126 and SHP77, respectively. Bradykinin at 0.1uM caused maximum flux (>95%) within seconds in SHP77 and H2126. No calcium flux was seen in H1703 and H69 even at 20 uM Bradykinin. CU201 alone at concentrations ranging from 0.1-10 uM did not cause calcium flux. However, at concentrations ranging from 20-100 uM, there was a rapid and persistent calcium flux >99%, as a result of rapid cell death. CU201 at 1 uM effectively blocked calcium flux after 0.1 uM Bradykinin was added to SHP77 and H2126 with over 3 minutes observation. Fresh plasma caused persistent calcium flux in seconds, while it took 2 minutes for thawed plasma to cause a persistent calcium flux. These persistent fluxes may be due to the presence of lipopolysaccharides (LPS) in plasma. Interestingly, heat-inactivated plasma alone only caused a transient calcium flux that resolved after 80 seconds. Heat-inactivated plasma with 1 uM CU201 (added at least 10 days prior) caused a transient calcium flux resolving in 15-30 seconds. After the consecutive addition of 0.1 uM Bradykinin to heat-inactivated plasma with 1 uM CU201, progressively smaller transient calcium fluxes were seen, each lasting less than 15 seconds. This suggests the Antagonistic activity of CU201 persisted after pretreatment in heat-inactivated plasma.Conclusions: CU201 inhibits calcium flux in cell lines with high BKR2 expression signal by microarray at doses less than IC 50 and 1/4 of necrosis 50 in SHP77 and H2126. CU201 alters the calcium flux pattern of heat-inactivated plasma. These results on plasma may be due to CU201 suppression of lipopolysaccharides in plasma and further testing is ongoing. Effective calcium flux blockade by CU201 is maintained in heat-inactivated plasma. Patient samples can be heat-inactivated and frozen for testing (for at least 10 days) for calcium flux inhibition in SHP77 and H2126 cell lines. Our study provides a method for analyzing the pharmacodynamic properties of CU201 in treated patients for a clinical phase I/II study.
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Combination cancer chemotherapy with one compound: Pluripotent Bradykinin Antagonists
Peptides, 2005Co-Authors: John M. Stewart, Lajos Gera, Paul A. Bunn, Daniel C. Chan, Eunice J. York, Vitalija Simkeviciene, Laimute Taraseviciene-stewartAbstract:Abstract Lung and prostate cancers are major health problems worldwide. Treatments with standard chemotherapy agents are relatively ineffective. Combination chemotherapy gives better treatment than a single agent because the drugs can inhibit the cancer in different pathways, but new therapeutic agents are needed for the treatment of both tumor types. Bradykinin (BK) Antagonists offer advantages of combination therapy in one compound. These promising multitargeted anti-cancer compounds selectively stimulate apoptosis in cancers and also inhibit both angiogenesis and matrix metalloprotease (MMP) action in treated lung and prostate tumors in nude mice. The highly potent, metabolism-resistant Bradykinin Antagonist peptide dimer, B-9870 [SUIM-(DArg-Arg-Pro-Hyp-Gly-Igl-Ser-DIgl-Oic-Arg) 2 ] (SUIM = suberimidyl; Hyp = 4-hydroxyproline; Igl = α-(2-indanyl)glycine; Oic = octahydroindole-2-carboxylic acid) and its non-peptide mimetic, BKM-570 [2,3,4,5,6-pentafluorocinnamoyl-( o -2,6-dichlorobenzyl)- l -tyrosine- N -(4-amino-2,2,6,6-tetramethylpiperidyl)amide] are superior to the widely used but toxic chemotherapeutic drugs cisplatin and taxotere. In certain combinations, they act synergistically with standard anti-cancer drugs. Due to its structure and biological activity, BKM-570 is an attractive lead compound for derivatization and evaluation for lung and prostate cancer drugs.
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Bradykinin Antagonist dimer, CU201, inhibits the growth of human lung cancer cell lines in vitro and in vivo and produces synergistic growth inhibition in combination with other antitumor agents.
Clinical Cancer Research, 2002Co-Authors: Daniel C. Chan, Lajos Gera, Barbara Helfrich, John Stewart, Tom L. M. Zhao, Wan Yong Feng, Kenneth K. Chan, Joseph M. Covey, Paul A. BunnAbstract:Small cell lung cancers (SCLCs), many non-SCLCs, andother cancers have neuroendocrine features, including paracrineand autocrine growth stimulation by various neuropeptides. Interference with this pathway is an attractive target for novel therapies. We developed a novel Bradykinin Antagonist dimer, CU201 (B9870), that acts as a “biased agonist” for neuropeptides by blocking G αq signaling and activating G α12,13 signaling. CU201 induced apoptosis and complete growth inhibition in various lung cancer and other cancer cell lines. CU201 was 10-fold more potent than substance P derivatives and was stable in serum for >7 days. In this study, we evaluated the ability of CU201 to produce additive or synergistic growth inhibition in combination with various antitumor agents used in lung cancer therapy. We found that CU201 produced additive or synergistic growth inhibition when combined with doxorubicin, etoposide, cisplatin, vinorelbine, and paclitaxel for SCLC lines and with paclitaxel and ZD1839, an epidermal growth factor receptor tyrosine kinase inhibitor, for non-SCLC cell lines. Pharmacokinetic parameters associated with the i.v. administration of CU201 were evaluated in normal mice, and the effects of CU201 on the growth of human lung cancer xenografts were evaluated in athymic nude mice. In CD2F1 mice given an i.v. bolus infusion of 5 mg/kg, the c max was 5773 ng/ml (5 μm), and the decay was biexponential. When fitted to a two-compartment model, the t 1/2α was 14.4 min, and the t 1/2β was 44.3 h, indicating a long terminal half-life consistent with the prolonged in vitro effects. CU201 inhibited the growth of human lung cancers in athymic nude mice by the intratumoral, s.c., and i.p. routes at a dose of 5 mg/kg/day. This dose is >10-fold less than the dose of substance P derivatives used to inhibit SCLC xenografts in nude mice. We conclude that CU201 should undergo further preclinical toxicology studies in its development as a novel targeted therapy for the treatment of lung cancers with neuroendocrine features. These studies are in progress through the NCI RAID mechanism.
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Bradykinin Antagonist dimer, CU201, inhibits the growth of human lung cancer cell lines by a “biased agonist” mechanism
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Daniel Chan, Lajos Gera, John M. Stewart, Barbara Helfrich, Marileila Verella-garcia, Gary L. Johnson, Anna E. Barón, Jie Yang, Theodore Puck, Paul A. BunnAbstract:All small cell (SCLCs) and many non-small cell lung cancers (NSCLCs) have neuroendocrine features including production of neuropeptides and cell surface receptors creating autocrine and paracrine growth loops. Neuropeptides bind to a family of 7-transmembrane receptors and activate heterotrimeric G proteins consisting of Gαq and Gα12,13. Substance P derivatives (SPDs) induced apoptosis and inhibited growth of lung cancer cells by discoordinately inhibiting Gαq and stimulating Gα12,13. However, these SPDs had low potency and short half-lives. In this report we show that a Bradykinin Antagonist dimer, CU201, inhibited the growth of SCLC and NSCLC cell lines with or without multidrug-resistant proteins and was 10-fold more potent with a longer plasma half-life than SPDs. Bradykinin agonists in either monomeric or dimeric form and monomeric Bradykinin Antagonist have no effect on lung cancer cell growth. The dimeric linking moiety of the two molecules was created, requiring a sufficient number of carbon chains to provide critical spacing between the two Antagonists. CU201 inhibited intracellular Ca2+ release in response to Bradykinin, indicating blockage of the Gαq signal, and stimulated c-Jun kinases, indicating stimulation of the Gα12,13 pathway. CU201-induced apoptosis was preceded by unique changes in apparent nuclear DNA binding and by c-Jun kinase and caspase-3 activation. At the concentration at which CU201 inhibited the growth of the cancer cells, it had no effect on the growth of normal lung cells in vitro. CU201 and similar compounds offer hope of becoming a new form of targeted therapy for tumors with neuroendocrine properties.
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Bradykinin Antagonist dimer cu201 inhibits the growth of human lung cancer cell lines by a biased agonist mechanism
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Daniel Chan, Lajos Gera, John M. Stewart, Barbara Helfrich, Gary L. Johnson, Anna E. Barón, Jie Yang, Theodore Puck, Marileila VerellagarciaAbstract:All small cell (SCLCs) and many non-small cell lung cancers (NSCLCs) have neuroendocrine features including production of neuropeptides and cell surface receptors creating autocrine and paracrine growth loops. Neuropeptides bind to a family of 7-transmembrane receptors and activate heterotrimeric G proteins consisting of Gαq and Gα12,13. Substance P derivatives (SPDs) induced apoptosis and inhibited growth of lung cancer cells by discoordinately inhibiting Gαq and stimulating Gα12,13. However, these SPDs had low potency and short half-lives. In this report we show that a Bradykinin Antagonist dimer, CU201, inhibited the growth of SCLC and NSCLC cell lines with or without multidrug-resistant proteins and was 10-fold more potent with a longer plasma half-life than SPDs. Bradykinin agonists in either monomeric or dimeric form and monomeric Bradykinin Antagonist have no effect on lung cancer cell growth. The dimeric linking moiety of the two molecules was created, requiring a sufficient number of carbon chains to provide critical spacing between the two Antagonists. CU201 inhibited intracellular Ca2+ release in response to Bradykinin, indicating blockage of the Gαq signal, and stimulated c-Jun kinases, indicating stimulation of the Gα12,13 pathway. CU201-induced apoptosis was preceded by unique changes in apparent nuclear DNA binding and by c-Jun kinase and caspase-3 activation. At the concentration at which CU201 inhibited the growth of the cancer cells, it had no effect on the growth of normal lung cells in vitro. CU201 and similar compounds offer hope of becoming a new form of targeted therapy for tumors with neuroendocrine properties.
Weihong Pan - One of the best experts on this subject based on the ideXlab platform.
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Bradykinin Antagonist decreases early disruption of the blood–spinal cord barrier after spinal cord injury in mice
Neuroscience Letters, 2001Co-Authors: Weihong Pan, Lajos Gera, Abba J. Kastin, John M. StewartAbstract:Abstract Bradykinin is one of the key molecules involved in the disruption of the blood–brain barrier and blood–spinal cord barrier occurring after spinal cord injury (SCI). Previously we have shown a biphasic opening of the blood–spinal cord barrier as well as increased transport of tumor necrosis factor-α (TNFα) after SCI by compression of the lumbar spinal cord in mice. To evaluate the role of Bradykinin in the two phases of blood–spinal cord barrier disruption, we pretreated mice with a potent Bradykinin Antagonist, the decapeptide B9430, before SCI. Our results show that B9430 decreased the general blood–spinal cord barrier disruption occurring immediately after SCI but failed to affect the delayed opening of the blood–spinal cord barrier observed 72 h after SCI. By contrast, the entry of TNFα after SCI was not affected by B9430 treatment. We conclude that Bradykinin is involved in the early phase of blood–spinal cord barrier disruption, with B9430 non-selectively blocking this early disruption without affecting the selective transport system for TNFα. This indicates the therapeutic potential of Bradykinin Antagonists in ameliorating tissue damage induced by SCI.
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Bradykinin Antagonist decreases early disruption of the blood spinal cord barrier after spinal cord injury in mice
Neuroscience Letters, 2001Co-Authors: Weihong Pan, Lajos Gera, Abba J. Kastin, John M. StewartAbstract:Abstract Bradykinin is one of the key molecules involved in the disruption of the blood–brain barrier and blood–spinal cord barrier occurring after spinal cord injury (SCI). Previously we have shown a biphasic opening of the blood–spinal cord barrier as well as increased transport of tumor necrosis factor-α (TNFα) after SCI by compression of the lumbar spinal cord in mice. To evaluate the role of Bradykinin in the two phases of blood–spinal cord barrier disruption, we pretreated mice with a potent Bradykinin Antagonist, the decapeptide B9430, before SCI. Our results show that B9430 decreased the general blood–spinal cord barrier disruption occurring immediately after SCI but failed to affect the delayed opening of the blood–spinal cord barrier observed 72 h after SCI. By contrast, the entry of TNFα after SCI was not affected by B9430 treatment. We conclude that Bradykinin is involved in the early phase of blood–spinal cord barrier disruption, with B9430 non-selectively blocking this early disruption without affecting the selective transport system for TNFα. This indicates the therapeutic potential of Bradykinin Antagonists in ameliorating tissue damage induced by SCI.
Abba J. Kastin - One of the best experts on this subject based on the ideXlab platform.
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Bradykinin Antagonist decreases early disruption of the blood–spinal cord barrier after spinal cord injury in mice
Neuroscience Letters, 2001Co-Authors: Weihong Pan, Lajos Gera, Abba J. Kastin, John M. StewartAbstract:Abstract Bradykinin is one of the key molecules involved in the disruption of the blood–brain barrier and blood–spinal cord barrier occurring after spinal cord injury (SCI). Previously we have shown a biphasic opening of the blood–spinal cord barrier as well as increased transport of tumor necrosis factor-α (TNFα) after SCI by compression of the lumbar spinal cord in mice. To evaluate the role of Bradykinin in the two phases of blood–spinal cord barrier disruption, we pretreated mice with a potent Bradykinin Antagonist, the decapeptide B9430, before SCI. Our results show that B9430 decreased the general blood–spinal cord barrier disruption occurring immediately after SCI but failed to affect the delayed opening of the blood–spinal cord barrier observed 72 h after SCI. By contrast, the entry of TNFα after SCI was not affected by B9430 treatment. We conclude that Bradykinin is involved in the early phase of blood–spinal cord barrier disruption, with B9430 non-selectively blocking this early disruption without affecting the selective transport system for TNFα. This indicates the therapeutic potential of Bradykinin Antagonists in ameliorating tissue damage induced by SCI.
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Bradykinin Antagonist decreases early disruption of the blood spinal cord barrier after spinal cord injury in mice
Neuroscience Letters, 2001Co-Authors: Weihong Pan, Lajos Gera, Abba J. Kastin, John M. StewartAbstract:Abstract Bradykinin is one of the key molecules involved in the disruption of the blood–brain barrier and blood–spinal cord barrier occurring after spinal cord injury (SCI). Previously we have shown a biphasic opening of the blood–spinal cord barrier as well as increased transport of tumor necrosis factor-α (TNFα) after SCI by compression of the lumbar spinal cord in mice. To evaluate the role of Bradykinin in the two phases of blood–spinal cord barrier disruption, we pretreated mice with a potent Bradykinin Antagonist, the decapeptide B9430, before SCI. Our results show that B9430 decreased the general blood–spinal cord barrier disruption occurring immediately after SCI but failed to affect the delayed opening of the blood–spinal cord barrier observed 72 h after SCI. By contrast, the entry of TNFα after SCI was not affected by B9430 treatment. We conclude that Bradykinin is involved in the early phase of blood–spinal cord barrier disruption, with B9430 non-selectively blocking this early disruption without affecting the selective transport system for TNFα. This indicates the therapeutic potential of Bradykinin Antagonists in ameliorating tissue damage induced by SCI.
J Knolle - One of the best experts on this subject based on the ideXlab platform.
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hoe 140 a new potent and long acting Bradykinin Antagonist in vivo studies
British Journal of Pharmacology, 1991Co-Authors: Klaus Wirth, Gerhard Breipohl, Wolfgang Linz, Wolfgang König, Franz Hock, Udo Dr Albus, H G Alpermann, H Anagnostopoulos, St Henke, J KnolleAbstract:1 Hoe 140 (d-Arg-[Hyp3, Thi5, d-Tic7, Oic8]Bradykinin) is a new Bradykinin (BK)-Antagonist. It was tested in several in vitro assays and compared with d-Arg-[Hyp2, Thi5,8,d-Phe7]BK. 2 In receptor binding studies in guinea-pig ileum preparations, Hoe 140 showed an IC50 of 1.07 × 10−9mol l−1 and a KI value of 7.98 × 10−10 mol l−1. 3 In isolated organ preparations Hoe 140 and d-Arg-[Hyp2, Thi5,8, d-Phe7]BK inhibited Bradykinin-induced contractions concentration dependently, with IC50-values in the guinea-pig ileum preparation of 1.1 × 10−8 mol l−1 and 3 × 10−5 mol l−1, respectively. pA2 values in this tissue were 8.42 and 6.18, respectively. In the rat uterus preparation the IC50 value was 4.9 × 10−9 mol l−1 for Hoe 140. d-Arg-[Hyp2, Thi5,8, d-Phe7]BK showed an IC50 of 4.0 × 10−6 mol l−1. The IC50 values in the guinea-pig isolated pulmonary artery were 5.4 × 10−9 mol l−1 and 6.4 × 10−6 mol l−1, respectively. In the rabbit aorta no inhibitory effects on Des-Arg9-BK induced contractions were observed. 4 In cultured bovine endothelial cells, Hoe 140 antagonized (IC50 = 10−8 mol l−1) Bradykinin-induced endothelium-derived relaxing factor (EDRF) release and the Bradykinin-induced increase in cytosolic free calcium (IC50 = 10−9 mol l−1). 5 Hoe 140 (10−7 mol l−1) totally suppressed the Bradykinin-induced (10−8 to 10−4mol l−1) prostacyclin (PGI2) release from cultured endothelial cells of bovine aorta. d-Arg-[Hyp2, Thi5,8, d-Phe7]BK (10−7 mol l−1) showed a weaker antagonism. 6 Taken together these results show that Hoe 140 is a highly potent Bradykinin Antagonist. It was two to three orders of magnitude more potent than d-Arg-[Hyp2, Thi5,8, d-Phe7]BK.
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Hoe 140 a new potent and long acting Bradykinin-Antagonist: in vitro studies.
British journal of pharmacology, 1991Co-Authors: F J Hock, Klaus Wirth, Udo Dr Albus, St Henke, W Linz, H J Gerhards, G Wiemer, G Breipohl, W König, J KnolleAbstract:1. Hoe 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]Bradykinin) is a new Bradykinin (BK)-Antagonist. It was tested in several in vitro assays and compared with D-Arg-[Hyp2,Thi5,8,D-Phe7]BK. 2. In receptor binding studies in guinea-pig ileum preparations, Hoe 140 showed an IC50 of 1.07 x 10(-9) mol l-1 and a KI value of 7.98 x 10(-10) mol l-1. 3. In isolated organ preparations Hoe 140 and D-Arg-[Hyp2,Thi5,8, D-Phe7]BK inhibited Bradykinin-induced contractions concentration dependently, with IC50-values in the guinea-pig ileum preparation of 1.1 x 10(-8) mol l-1 and 3 x 10(-5) mol l-1, respectively. pA2 values in this tissue were 8.42 and 6.18, respectively. In the rat uterus preparation the IC50 value was 4.9 x 10(-9) mol l-1 for Hoe 140. D-Arg-[Hyp2, Thi5,8, D-Phe7]BK showed an IC50 of 4.0 x 10(-6) mol l-1. The IC50 values in the guinea-pig isolated pulmonary artery were 5.4 x 10(-9) mol l-1 and 6.4 x 10(-6) mol l-1, respectively. In the rabbit aorta no inhibitory effects on Des-Arg9-BK induced contractions were observed. 4. In cultured bovine endothelial cells, Hoe 140 antagonized (IC50 = 10(-8) mol l-1) Bradykinin-induced endothelium-derived relaxing factor (EDRF) release and the Bradykinin-induced increase in cytosolic free calcium (IC50 = 10(-9) mol l-1). 5. Hoe 140 (10 -7mol I1) totally suppressed the Bradykinin-induced (10 8 to 10- mol I') prostacyclin (PGI2) release from cultured endothelial cells of bovine aorta. D-Arg-[Hyp2, Thi5'8, D-Phe7]BK (10- 7 mol I1- ) showed a weaker antagonism. 6. Taken together these results show that Hoe 140 is a highly potent Bradykinin Antagonist. It was two to three orders of magnitude more potent than D-Arg-[Hyp2, Thi5 8, D-Phe7]BK.