Effect of LF 16-0687MS, a new-nonpeptide bradykinin B2 receptor antagonist, in a rat model of closed head trauma

Didier Pruneau, Ilia Chorny, Vadim Benkovitz, Alan Artru, Leonid Roitblat, Yoram Shapira

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    43 Scopus citations

    Abstract

    Bradykinin is an endogenous nonapeptide which potently dilates the cerebral vasculature and markedly increases vascular permeability. These effects are mediated by B2 receptors located on the vascular endothelium. Previous experimental studies have shown that blockade of the kallikreinkinin system, which mediates the formation of bradykinin, afforded a reduction of the brain edema that developed following a cryogenic cortical lesion. In the present study, we investigated the effect of LF 16-0687MS, a novel nonpeptide B2 receptor antagonist, on cerebral edema and neurological severity score (NSS) after closed head injury to rats. LF 16-0687MS or its vehicle (NaCl 0.9%) was continuously infused at 10, 30, and 100 μg/kg/min over 23 h starting 1 h after a focal trauma to the left hemisphere was induced using a weight-drop device. The extent of edema formation was evaluated 24 h after trauma from left and right hemispheres samples by measurement of specific gravity and water content. In a separate study, a neurological severity score based on scoring of behavioural and motor functions was evaluated 1 h and over 1 week after trauma. LF 16-0687MS at 100 μg/kg/min markedly reduced the development of brain edema as indicated by a 68% increase in specific gravity (p < 0.05) and a 64% decrease of water content (p < 0.05) in the left hemisphere. In addition the recovery of neurological function was significantly improved by 100 μg/kg/min LF 16-0687MS from day 3 to day 7 after CHT. In a separate experiment, we also showed that LF 16-0687MS at 100 μg/kg/min given either 1 h before or 30 min after CHT did not affect mean arterial blood pressure. These results show that blockade of bradykinin B2 receptors is in effective approach to reduce cerebral edema and to improve neurological outcome after a focal contusion to the cranium.

    Original languageEnglish
    Pages (from-to)1057-1065
    Number of pages9
    JournalJournal of Neurotrauma
    Volume16
    Issue number11
    DOIs
    StatePublished - 1 Jan 1999

    Keywords

    • B receptors
    • Bradykinin
    • Brain edema
    • Closed head trauma
    • Neurological status
    • Nonpeptide antagonists
    • Rat

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