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Neuroprotective effects of a postischemic treatment with a bradykinin B2 receptor antagonist in a rat model of temporary focal cerebral ischemia.

Abstract
Bradykinin, an endogenous nonapeptide produced by activation of the kallikrein-kinin system, promotes neuronal tissue damage as well as disturbances in blood-brain barrier function through activation of B2 receptors. In a rat model of focal cerebral ischemia, blockade of B2 receptors before initiation of ischemia with the B2 receptor antagonist, LF 16-0687 Ms, afforded substantial neuroprotection. In order to assess the potential clinical value of this approach, we evaluated the effect of LF 16-0687 Ms given at reperfusion following focal cerebral ischemia on local cerebral blood flow (LCBF), neurological outcome, and infarct size. Sprague-Dawley rats were subjected to MCA occlusion for 90 min by an intraluminal filament. Animals were assigned to one of four treatment arms (n = 7 each): (1) vehicle, (2) LF 16-0687 Ms (1.0 mg/kg/day), (3) LF 16-0687 Ms (3.0 mg/kg/day), or (4) LF 16-0687 Ms (10.0 mg/kg/day) given at reperfusion and repetitively over 2 days. Neurological recovery was examined daily, and infarct volume was assessed histologically on day 7 after ischemia. Physiological parameters and local CBF were not influenced by the treatment. Significant improvement of neurological outcome was observed on postischemic day 3 in animals receiving 1.0 and 3.0 mg/kg/day of LF 16-0687 Ms (P < 0.05). Inhibition of B2 receptors significantly reduced infarct volume in all treated animals predominantly in the cortex. B2 receptor blockade with LF 16-0687 Ms showed neuroprotective effectiveness even when therapy was initiated upon reperfusion, i.e. 90 min after induction of ischemia. Therefore, blockade of B2 receptors seems to be a promising therapeutic approach after focal cerebral ischemia, which deserves further experimental and clinical evaluation.
AuthorsD B Lumenta, N Plesnila, B Kläsner, A Baethmann, D Pruneau, R Schmid-Elsaesser, S Zausinger
JournalBrain research (Brain Res) Vol. 1069 Issue 1 Pg. 227-34 (Jan 19 2006) ISSN: 0006-8993 [Print] Netherlands
PMID16378603 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • LF 16-0687
  • Neuroprotective Agents
  • Quinolines
Topics
  • Analysis of Variance
  • Animals
  • Brain Ischemia (drug therapy, pathology, physiopathology)
  • Cerebral Infarction (etiology, pathology, prevention & control)
  • Cerebrovascular Circulation (drug effects)
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Laser-Doppler Flowmetry (methods)
  • Male
  • Neuroprotective Agents (therapeutic use)
  • Quinolines (therapeutic use)
  • Rats
  • Rats, Sprague-Dawley
  • Recovery of Function (drug effects)
  • Time Factors
  • Treatment Outcome

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