Neuroprotective effects of a postischemic treatment with a bradykinin B2 receptor antagonist in a rat model of temporary focal cerebral ischemia.
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.
Lumenta
D B
DB
Institute for Surgical Research, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Plesnila
N
N
Kläsner
B
B
Baethmann
A
A
Pruneau
D
D
Schmid-Elsaesser
R
R
Zausinger
S
S
D000704:Analysis of Variance; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome
C403051:LF 16-0687; D018696:Neuroprotective Agents; D011804:Quinolines