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

Hari Shanker Sharma*, Lianyuan Feng, Dafin Fior Muresanu, Rudy J. Castellani, Aruna Sharma

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapter

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Title of host publicationNew Therapeutic Strategies for Brain Edema and Cell Injury
EditorsHari Shanker Sharma, Aruna Sharma
PublisherAcademic Press Inc
Pages103-152
Number of pages50
ISBN (Print)9780128167540
DOIs
StatePublished - 2019

Publication series

NameInternational Review of Neurobiology
Volume146
ISSN (Print)0074-7742
ISSN (Electronic)2162-5514

Keywords

  • B2 receptor
  • Blood-spinal cord barrier
  • Bradykinin
  • Cell injury
  • Edema formation
  • Evans blue
  • HOE-140
  • I-sodium
  • Lanthanum
  • Neuronal nitric oxide synthase
  • Spinal cord blood flow
  • Ultrastructure

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this