title: LF 16-0687 Ms, a bradykinin B2 receptor antagonist, reduces brain edema and improves long-term neurological function recovery after closed head trauma in rats.
abstract: Bradykinin is an endogenous inflammatory agent that enhances vascular permeability and produces tissue edema. We investigated whether LF 16-0687 Ms, a potent nonpeptide antagonist of bradykinin type-2 (B(2)) receptor, was able to reduce brain swelling and to improve the recovery of neurological function following closed head trauma (CHT) in rats. In dose-effect studies, LF 16-0687 Ms doses of 0.75-4.5 mg/kg given 1 h after trauma significantly reduced the development of edema in the injured hemisphere by a maximum of 70%. It had no effect on the brain water content of sham-operated rats. LF 16-0687 Ms also significantly improved neurological recovery evaluated by a Neurological Severity Score (NSS) based on motor, reflex, and behavioral tests. In time-window studies LF 16-0687 Ms (2.25 mg/kg) was given 1, 2, 4, and 10 h after CHT. The extent of edema was significantly reduced when LF 16-0687 Ms was given 1 h (-45%), 2 h (-52%), and 4 h (-63%) but not 10 h (-24%) after CHT. Given at any time-point, LF 16-0687 Ms significantly improved the recovery of the NSS at 24 h. In duration of treatment studies, rats tended to recover normal neurological function over 14 days after CHT. However, time to recovery was longer in severely than in moderately injured animals, unless they were treated with LF 16-0687 Ms. This study provides further evidence that blockade of bradykinin B(2) receptors represents a potential effective approach to the treatment of focal cerebral contusions.
authors.affiliation: Department of Pharmacology, Soroka Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Jakob
authors.initials: J
authors.lastname: Kaplanski
authors.forename: Didier
authors.initials: D
authors.lastname: Pruneau
authors.forename: Ilia
authors.initials: I
authors.lastname: Asa
authors.forename: Alan A
authors.initials: AA
authors.lastname: Artru
authors.forename: Abeb
authors.initials: A
authors.lastname: Azez
authors.forename: Yulia
authors.initials: Y
authors.lastname: Ivashkova
authors.forename: Zvia
authors.initials: Z
authors.lastname: Rudich
authors.forename: Yoram
authors.initials: Y
authors.lastname: Shapira
mesh_terms: D000818:Animals; D065168:Bradykinin Receptor Antagonists; D001929:Brain Edema / Q000503:physiopathology*; D001930:Brain Injuries / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D016489:Head Injuries, Closed / Q000188:drug therapy* / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2; D020127:Recovery of Function; D013997:Time Factors; D015599:Trauma Severity Indices
chemical_list: D065168:Bradykinin Receptor Antagonists; C403051:LF 16-0687; D018696:Neuroprotective Agents; D011804:Quinolines; D043782:Receptor, Bradykinin B2