Bradykinin antagonist decreases early disruption of the blood–spinal cord barrier after spinal cord injury in mice

doi:10.1016/S0304-3940(01)01904-8

Neuroscience Letters

Volume 307, Issue 1, 6 July 2001, Pages 25-28

https://doi.org/10.1016/S0304-3940(01)01904-8 Get rights and content

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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Acknowledgements

Supported in part by the US Army Medical Research Acquisition Activity (DAMD17–00–0113), the Department of Veterans Affairs, and NIH grant HL-25284.

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2019, International Review of Neurobiology
Citation Excerpt :
This is evident from our findings that if B2 receptors are blocked before trauma with low doses it induces neuroprotection, a feature not observed when the B2 receptors are blocked after SCI. Likewise, high doses of the B2 receptor antagonist failed to induce neuroprotection following SCI confirming the dual effects of HOE-140 (Félétou et al., 1994; Pan et al., 2001). In conclusion, our observations demonstrate that bradykinin B2 receptor antagonist HOE-140 in low doses is capable to induce neuroprotection in SCI particularly when administered 30 min before trauma.
Bradykinin is a mediator of vasogenic brain edema formation. Recent reports suggest that bradykinin interacts with nitric oxide synthase (NOS) system in the central nervous system (CNS). However, role of bradykinin in spinal cord injury (SCI) induced alterations in the blood-spinal cord barrier (BSCB), spinal cord blood flow (SCBF), edema formation and cell changes are still not well known. Our previous reports showed that SCI induces marked upregulation of neuronal NOS (nNOS) in the cord associated with BSCB disruption, edema formation and cell injury. Thus, a possibility exists that bradykinin participates in SCI induced nNOS upregulation and cord pathology. To explore this idea a potent bradykinin B2 receptor antagonist HOE-140 was used in our rat model of SCI and cord pathology. SCI was inflicted in Equithesin anesthetized rats by making a longitudinal incision (2 mm deep and 5 mm long) into the right dorsal horn of the T10-11 segment. The animals were allowed to survive 5 h after injury. A focal SCI significantly disrupted BSCB to Evans blue and ^[131]I-sodium in the traumatized and adjacent segments. Interestingly, far remote spinal cord segments C4 and T5 segments also affected within 5 h. These spinal cord segments also exhibited pronounced reductions in the SCBF (mean—30%), increased edematous swelling and profound neuronal damages. Upregulation of nNOS expression is seen in both the dorsal and ventral horns of the spinal cord exhibiting cord pathology. At the ultrastructural level, exudation of lanthanum is seen within the endothelial cell cytoplasm and occasionally in the basal lamina. Pretreatment with low doses of HOE-140 (0. 1 mg to 1 mg/kg, i.v.) 30 min prior to SCI significantly enhanced the SCBF and reduced the BSCB disruption, edema formation, nNOS upregulation and cell injury. However, HOE-140 in doses ranging from 2 mg to 5 mg/kg, i.v. did not induce significant neuroprotection. These observations are the first to suggest that bradykinin B2 receptors play an important role in BSCB permeability, SCBF, edema formation, nNOS upregulation and cell injury following acute SCI, not reported earlier.
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A dozen years ago, we noted a relatively unique pattern of upregulation of the transport system for tumor necrosis factor α (TNF) at the BBB and the associated blood–spinal cord barrier. This is seen in mouse models of spinal cord injury [44,45,48,57–59,65,67,73], traumatic brain injury [68], ischemic stroke [49], and experimental autoimmune encephalomyelitis (EAE) [46]. BBB signaling and regulatory changes are now seen in many pathophysiological conditions, including neuroAIDS [75] and inflammatory pain [9,16].
In this Festschrift, I discuss the career and guiding principles to which Abba J. Kastin has adhered during the last 20 years we worked together. I briefly describe the history of our joint laboratory group, the context of studies of peptide permeation across the blood–brain barrier (BBB), and newer developments in the BBB Group as Abba steps down after serving 35 years as the founding Editor-in-Chief for Peptides. Abba's BBB studies on peptides have contributed to concepts in the neuroendocrinology of feeding and developed information on molecular trafficking across BBB cells. The astroglial leptin signaling studies and the interactions of sleep and BBB are two major directions, whereas the long-term MIF-1 project demarcates a tortuous road on translational research.
Kinin-mediated inflammation in neurodegenerative disorders
2012, Neurochemistry International
The mediatory role of kinins in both acute and chronic inflammation within nervous tissues has been widely described. Bradykinin, the major representative of these bioactive peptides, is one of a few mediators of inflammation that directly stimulates afferent nerves due to the broad expression of specific kinin receptors in cell types in these tissues. Moreover, kinins may be delivered to a site of injury not only after their production at the endothelium surface but also following their local production through the enzymatic degradation of kininogens at the surface of nerve cells. A strong correlation between inflammatory processes and neurodegeneration has been established. The activation of nerve cells, particularly microglia, in response to injury, trauma or infection initiates a number of reactions in the neuronal neighborhood that can lead to cell death after the prolonged action of inflammatory substances. In recent years, there has been a growing interest in the effects of kinins on neuronal destruction. In these studies, the overexpression of proteins involved in kinin generation or of kinin receptors has been observed in several neurologic disorders including neurodegenerative diseases such Alzheimer’s disease and multiple sclerosis as well as disorders associated with a deficiency in cell communication such as epilepsy. This review is focused on recent findings that provide reliable evidence of the mediatory role of kinins in the inflammatory responses associated with different neurological disorders. A deeper understanding of the role of kinins in neurodegenerative diseases is likely to promote the future development of new therapeutic strategies for the control of these disorders. An example of this could be the prospective use of kinin receptor antagonists.
D-Arg-[Hyp3, IgI5, D-IgI7, Oic8]Bradykinin
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A fluorescent version of the bradykinin B<inf>2</inf> receptor antagonist B-9430: Pharmacological characterization and use in live cell imaging
2008, Peptides
B-9430 (d-Arg-[Hyp³, Igl⁵, D-Igl⁷, Oic⁸]-bradykinin), where Hyp is trans-4-hydroxyproline, Igl is α-(2-indanyl)glycine and Oic is (3as, 7as)-octahydroindol-2-yl-carbonyl is a high affinity bradykinin B₂ receptor antagonist with effects extended to the B₁ receptors at high concentrations. The N-terminus of B-9430 has been extended with d-biotinyl (B-10330) or 5(6)-carboxyfluorescein-ɛ-aminocaproyl (B-10380) to derive fluorescent receptor probes. The pharmacological profile of B-10380 was similar to that of B-9430 with a minor loss of potency (a competitive antagonist of bradykinin at the B₂ receptors of the human isolated umbilical vein, pA₂ 6.83; an insurmountable antagonist at the B₂ receptors in the rabbit jugular vein; a weak competitive antagonist of the B₁ receptors in the rabbit aorta, pA₂ 5.95). B-10330 and B-10380 displaced the binding of [³H]bradykinin from rabbit B₂ receptors with a potency slightly inferior to that of B-9430 (larger gap at the rat B₂ receptor). Treatment with B-10330 and fluorescent streptavidin did not support imaging of recombinant B₂ receptors. However, the plasma membrane of HEK 293a cells that transiently expressed recombinant rabbit B₂ receptors, but not B₁ receptors, was labeled with 5–50 nM B-10380 (epifluorescence microscopy). B-10380 staining was not observed in nontransfected cells and was abolished by co-treating receptor-expressing cells with a nonpeptide antagonist. The N-terminal extension of a potent peptide antagonist of the bradykinin B₂ receptor with a fluorophore produced a fluorescent probe suitable for live cell imaging and other applications at the expense of a minor loss of affinity.
Bradykinin preconditioning induces protective effects on the spinal cord ischemic injury of rats
2008, Neuroscience Letters
The study was performed to investigate the effects of bradykinin preconditioning on spinal cord ischemic injury using an in vivo transient spinal cord ischemia model in rats. Prior to ischemia, bradykinin was infused continuously via the left femoral artery starting 15 min before ischemia. Neurological functions were evaluated for 7 days postoperatively using modified Tarlov's scores. Tarlov's score outcomes showed a marked improvement in the bradykinin group compared to the ischemia group. The blood-spinal cord barrier (BSCB) permeability was also decreased by bradykinin preconditioning after 72 h reperfusion focal spinal cord in rats, which was greatly reversed by B9430 (bradykinin B2 receptor antagonist). Immunohistochemical and Western blot analysis of spinal cords revealed a significant increase in basic fibroblast growth factor protein (bFGF) levels. The study demonstrated that bradykinin preconditioning induces protection against spinal cord ischemic injury, and this protection is likely due to the protection of the vasculature of the spinal cord and the promotion of neuronal survival.

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Bradykinin antagonist decreases early disruption of the blood–spinal cord barrier after spinal cord injury in mice

Abstract

Section snippets

Acknowledgements

Neuron

J. Neuroimmunol.

Neurosci. Biobehav. Rev.

Exp. Neurol.

J. Neuroimmunol.

Neurosci. Biobehav. Rev.

Brain Res.

Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulation

Proc. Natl. Acad. Sci. USA

Transendothelial vesicular transport of protein following compression injury to the spinal cord

Lab. Invest.