Cellular localization of kinin B1 receptor in the spinal cord of streptozotocin-diabetic rats with a fluorescent [Nα-Bodipy]-des-Arg9-bradykinin

Talbot, Sébastien; Théberge-Turmel, Patrick; Liazoghli, Dalinda; Sénécal, Jacques; Gaudreau, Pierrette; Couture, Réjean

doi:10.1186/1742-2094-6-11

Cited by 30 publications

(38 citation statements)

References 72 publications

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“…The hyperalgesic response to intrathecally injected B 1 R agonist was ascribed to the intraspinal release of NO and activation of NK-1R and NMDA-R, as previously reported following spinal activation of B 1 R in streptozotocin-diabetic rats [1]. The presence of B 1 R in spinal cord microglia is consistent with the emerging role of microglial B 1 R in pain neuropathy [29,30,49]. …”

Section: Discussionsupporting

confidence: 80%

Activation of TRPV1 by capsaicin induces functional Kinin B1 receptor in rat spinal cord microglia

Talbot

Dias

Lahjouji

et al. 2012

J Neuroinflammation

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BackgroundThe kinin B1 receptor (B1R) is upregulated by pro-inflammatory cytokines and oxydative stress, which are enhanced by transient receptor potential vanilloid subtype 1 (TRPV1) activation. To examine the link between TRPV1 and B1R in inflammatory pain, this study aimed to determine the ability of TRPV1 to regulate microglial B1R expression in the spinal cord dorsal horn, and the underlying mechanism.MethodsB1R expression (mRNA, protein and binding sites) was measured in cervical, thoracic and lumbar spinal cord in response to TRPV1 activation by systemic capsaicin (1-50 mg/kg, s.c) in rats pre-treated with TRPV1 antagonists (capsazepine or SB-366791), the antioxidant N-acetyl-L-cysteine (NAC), or vehicle. B1R function was assessed using a tail-flick test after intrathecal (i.t.) injection of a selective B1R agonist (des-Arg9-BK), and its microglial localization was investigated by confocal microscopy with the selective fluorescent B1R agonist, [Nα-bodipy]-des-Arg9-BK. The effect of i.t. capsaicin (1 μg/site) was also investigated.ResultsCapsaicin (10 to 50 mg/kg, s.c.) enhanced time-dependently (0-24h) B1R mRNA levels in the lumbar spinal cord; this effect was prevented by capsazepine (10 mg/kg, i.p.; 10 μg/site, i.t.) and SB-366791 (1 mg/kg, i.p.; 30 μg/site, i.t.). Increases of B1R mRNA were correlated with IL-1β mRNA levels, and they were significantly less in cervical and thoracic spinal cord. Intrathecal capsaicin (1 μg/site) also enhanced B1R mRNA in lumbar spinal cord. NAC (1 g/kg/d × 7 days) prevented B1R up-regulation, superoxide anion production and NF-kB activation induced by capsaicin (15 mg/kg). Des-Arg9-BK (9.6 nmol/site, i.t.) decreased by 25-30% the nociceptive threshold at 1 min post-injection in capsaicin-treated rats (10-50 mg/kg) while it was without effect in control rats. Des-Arg9-BK-induced thermal hyperalgesia was blocked by capsazepine, SB-366791 and by antagonists/inhibitors of B1R (SSR240612, 10 mg/kg, p.o.), glutamate NMDA receptor (DL-AP5, 10 μg/site, i.t.), substance P NK-1 receptor (RP-67580, 10 μg/site, i.t.) and nitric oxide synthase (L-NNA, 10 μg/site, i.t.). The B1R fluorescent agonist was co-localized with an immunomarker of microglia (Iba-1) in spinal cord dorsal horn of capsaicin-treated rats.ConclusionThis study highlights a new mechanism for B1R induction via TRPV1 activation and establishes a link between these two pro-nociceptive receptors in inflammatory pain.

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Section: Discussionsupporting

confidence: 80%

Activation of TRPV1 by capsaicin induces functional Kinin B1 receptor in rat spinal cord microglia

Talbot

Dias

Lahjouji

et al. 2012

J Neuroinflammation

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“…These data are in agreement with previous reports that modification at the N-terminus of B1R-targeting peptides was tolerable, and the resulting derivatives could retain good binding affinity to B1R. [39][40][41][42] Of the four [desArg 10 ]kallidin derivatives, P04168 displayed the highest B1R binding affinity. At physiological pH, the Pip linker can be protonated to confer an additional +1 charge at the Nterminus.…”

Section: As Shown Insupporting

confidence: 92%

Imaging Bradykinin B1 Receptor with⁶⁸Ga-Labeled [des-Arg¹⁰]Kallidin Derivatives: Effect of the Linker on Biodistribution and Tumor Uptake

et al. 2015

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Bradykinin B1 receptor (B1R) that is overexpressed in cancers but minimally expressed in normal healthy tissues represents an attractive biomarker for the development of cancer imaging agents. The goal of this study was to evaluate the effect of different linkers on the pharmacokinetics and tumor uptake of a B1R-targeting radio-peptide sequence, 68Ga-DOTA-linker-Lys-Arg-Pro-Hyp-Gly-Cha-Ser-Pro-Leu. Four peptides, SH01078, P03034, P04115, and P04168, with 6-aminohexanoic acid, 9-amino-4,7-dioxanonanoic acid, Gly-Gly, and 4-amino-(1-carboxymethyl)piperidine, respectively, as the linker were synthesized and evaluated. In vitro competition binding assays showed that the Ki values of SH01078, P03034, P04115, and P04168 were 27.8±4.9, 16.0±1.9, 11.4±2.5, and 3.6±0.2 nM, respectively. Imaging and biodistribution studies were performed in mice bearing both B1R-positive HEK293T::hB1R and B1R-negative HEK293T tumors. All tracers showed mainly renal excretion with excellent tumor visualization and minimal background activity except for kidneys and bladder. The average uptake of 68Ga-labeled SH01078, P03034, and P04115 in HEK293T::hB1R tumor was similar (1.96-2.17%ID/g) at 1 h postinjection. 68Ga-P04168 generated higher HEK293T::hB1R tumor uptake (4.15±1.13%ID/g) and lower background activity, leading to a >2-fold improvement in HEK293T::hB1R tumor-to-background (HEK293T tumor, blood, muscle, and liver) contrasts over those of 68Ga-labeled SH01078, P03034, and P04115. Our results indicate that the choice of linker affects binding affinity, pharmacokinetics, and tumor targeting. The use of the cationic 4-amino-(1-carboxymethyl)piperidine linker improved tumor visualization, and the resulting 68Ga-P04168 might be promising for clinical application for imaging B1R-expressing tumors with positron emission tomography.

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“…This was previously demonstrated by B1R-targeting probes for receptorbinding assays and flow cytometry (26)(27)(28) as well as by B1R antagonists that are resistant to the cleavage by aminopeptidase N (25). On the basis of this finding, we initiated the development of PET probes for in vivo imaging of B1R expression.…”

Section: Discussionmentioning

confidence: 83%

Comparative Studies of Three⁶⁸Ga-Labeled [Des-Arg¹⁰]Kallidin Derivatives for Imaging Bradykinin B1 Receptor Expression with PET

et al. 2015

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Bradykinin B1 receptor (B1R) is a G-protein-coupled receptor that is overexpressed in a variety of cancers. B1R is not expressed in healthy tissues, making it an attractive cancer imaging marker. Previously, we reported selective uptake of 68 Ga-P03034 ( 68 Ga-DOTA-dPEG2-LysArg-Pro-Hyp-Gly-Cha-Ser-Pro-Leu) in B1R-positive (B1R1) HEK293T:: hB1R tumor xenografts in mice. In this study, we compare 68 Ga-P03034 with 68 Ga-labeled P04158 ( 68 Ga-DOTA-dPEG2-Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic) and Z02090 ( 68 Ga-DOTAdPEG2-Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg) derived from 2 potent B1R antagonists, B9858 and B9958, respectively, for imaging B1R expression with PET. Methods: Peptide sequences were assembled on solid-phase. Cold standards were prepared by incubating DOTA-conjugated peptides with GaCl 3 . Binding affinity was measured via competition binding assays using hB1R-expressing Chinese hamster ovary-K1 cell membranes. 68 Ga labeling was performed in N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) buffer with microwave heating and purified by high-performance liquid chromatography. Imaging/biodistribution studies were performed in mice bearing wild-type HEK293T (B1R−) and B1R1 HEK293T:: hB1R tumors. Results: P03034, P04158, and Z02090 bound B1R with high affinity, with K i values at 16.0 ± 2.9, 1.5 ± 1.9, and 1.1 ± 0.8 nM, respectively. 68 Ga-labeled P03034, P04159, and Z02090 were obtained in greater than 50% decay-corrected radiochemical yields with more than 99% radiochemical purity. Biodistribution studies showed that all three 68 Ga-labeled tracers cleared rapidly from the blood and normal tissues, with excretion mainly via the renal pathway. At 1 h after injection, only the kidneys, bladders, and B1R1 HEK293T::hB1R tumors were clearly visualized in PET images. Uptake values of 68 Ga-labeled P03034, P04158, and Z02090 in B1R1 tumors were 2.17 ± 0.49, 19.6 ± 4.50, and 14.4 ± 1.63 percentage injected dose per gram, respectively. Uptake ratios of B1R1 to B1R− tumor, blood, and muscle were 6.23 ± 1.69, 5.72 ± 2.20, and 25.5 ± 13.1 for 68 Ga-P03034; 34.5 ± 10.5, 19.2 ± 8.21, and 66.1 ± 17.0 for 68 Ga-P04158; and 29.3 ± 9.68, 29.9 ± 5.58, and 124 ± 28.1 for 68 Ga-Z02090, respectively. Conclusion: All three 68 Ga-labeled B1R-targeting peptides generated specific and high-contrasted images of B1R1 tumors xenografted in mice. With significantly higher tumor uptake and target-to-nontarget ratios, 68 Ga-labeled P04158 and Z02090 are superior to P03034 for imaging B1R expression with PET.

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Cellular localization of kinin B1 receptor in the spinal cord of streptozotocin-diabetic rats with a fluorescent [Nα-Bodipy]-des-Arg9-bradykinin

Cited by 30 publications

References 72 publications

Activation of TRPV1 by capsaicin induces functional Kinin B1 receptor in rat spinal cord microglia

Activation of TRPV1 by capsaicin induces functional Kinin B1 receptor in rat spinal cord microglia

Imaging Bradykinin B1 Receptor with⁶⁸Ga-Labeled [des-Arg¹⁰]Kallidin Derivatives: Effect of the Linker on Biodistribution and Tumor Uptake

Comparative Studies of Three⁶⁸Ga-Labeled [Des-Arg¹⁰]Kallidin Derivatives for Imaging Bradykinin B1 Receptor Expression with PET

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Cellular localization of kinin B1 receptor in the spinal cord of streptozotocin-diabetic rats with a fluorescent [Nα-Bodipy]-des-Arg9-bradykinin

Cited by 30 publications

References 72 publications

Activation of TRPV1 by capsaicin induces functional Kinin B1 receptor in rat spinal cord microglia

Activation of TRPV1 by capsaicin induces functional Kinin B1 receptor in rat spinal cord microglia

Imaging Bradykinin B1 Receptor with68Ga-Labeled [des-Arg10]Kallidin Derivatives: Effect of the Linker on Biodistribution and Tumor Uptake

Comparative Studies of Three68Ga-Labeled [Des-Arg10]Kallidin Derivatives for Imaging Bradykinin B1 Receptor Expression with PET

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Imaging Bradykinin B1 Receptor with⁶⁸Ga-Labeled [des-Arg¹⁰]Kallidin Derivatives: Effect of the Linker on Biodistribution and Tumor Uptake

Comparative Studies of Three⁶⁸Ga-Labeled [Des-Arg¹⁰]Kallidin Derivatives for Imaging Bradykinin B1 Receptor Expression with PET