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Neuroprotective effects of a potent bradykinin B2 receptor antagonist HOE-140 on microvascular permeability, blood flow disturbances, edema formation, cell injury and nitric oxide synthase upregulation following trauma to the spinal cord
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
Bethune Int Peace Hosp, Dept Neurol, Shijiazhuang, Hebei, Peoples R China.
Univ Med & Pharm, Dept Clin Neurosci, Cluj Napoca, Romania;RoNeuro Inst Neurol Res & Diagnost, Cluj Napoca, Romania.
Univ Maryland, Dept Pathol, Baltimore, MD 21201 USA.
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2019 (English)In: New Therapeutic Strategies for Brain Edema and Cell Injury / [ed] Sharma, HS Sharma, A, Elsevier, 2019, p. 103-152Chapter in book (Refereed)
Abstract [en]

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 (2mm deep and 5mm long) into the right dorsal horn of the T10-11 segment. The animals were allowed to survive 5h after injury. A focal SCI significantly disrupted BSCB to Evans blue and I-[131]-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. 1mg to 1mg/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 2mg to 5mg/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.

Place, publisher, year, edition, pages
Elsevier, 2019. p. 103-152
Series
International Review of Neurobiology, ISSN 0074-7742 ; 146
National Category
Cell and Molecular Biology Neurology
Identifiers
URN: urn:nbn:se:uu:diva-401917DOI: 10.1016/bs.irn.2019.06.008ISI: 000501592100005PubMedID: 31349925ISBN: 978-0-12-816754-0 (print)OAI: oai:DiVA.org:uu-401917DiVA, id: diva2:1385126
Funder
Swedish Research Council, 2710Göran Gustafsson Foundation for Research in Natural Sciences and MedicineAstraZenecaNIH (National Institute of Health), R01 AG028679Available from: 2020-01-13 Created: 2020-01-13 Last updated: 2020-01-13Bibliographically approved

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Sharma, Hari ShankerSharma, Aruna

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