LF 16-0687 Ms, a bradykinin B2 receptor antagonist, reduces ischemic brain injury in a murine model of transient focal cerebral ischemia.
1. Bradykinin promotes neuronal damage and brain edema through the activation of the B(2) receptor. The neuroprotective effect of LF 16-0687 Ms, a B(2) receptor antagonist, has been described when given prior to induction of transient focal cerebral ischemia in rat, but there are no data regarding the consequence of a treatment when given after injury. Therefore, in a murine model of transient middle cerebral artery occlusion (MCAO), we evaluated the effect of LF 16-0687 Ms given prior to and/or after the onset of ischemia on neurological deficit, infarct volume and inflammatory responses including cerebral edema, blood-brain barrier (BBB) disruption and neutrophil accumulation. 2. LF 16-0687 Ms (1, 2 and 4 mg kg(-1)) administered 0.5 h before and, 1.25 and 6 h after MCAO, decreased the infarct volume by a maximum of 33% and significantly improved the neurological recovery. 3. When given at 0.25 and 6.25 h after MCAO, LF 16-0687 Ms (1.5, 3 and 6 mg kg(-1)) decreased the infarct volume by a maximum of 25% and improved the neurological score. 4. Post-treatment with LF 16-0687 Ms (1.5 mg kg(-1)) significantly decreased brain edema (-28%), BBB disruption (-60%) and neutrophil accumulation (-65%) induced by ischemia. Physiological parameters were not modified by LF 16-0687 Ms. 5. These data emphasize the role of bradykinin B(2) receptor in the development of infarct lesion, neurological deficit and inflammatory responses resulting from transient focal cerebral ischemia. Therefore, B(2) receptor antagonist might represent a new therapeutic approach in the pharmacological treatment of stroke.
Ding-Zhou
Li
L
UPRES EA 2510, Laboratoire de Pharmacologie, Université René Descartes, 4 Avenue de l'Observatoire, 75006 Paris, France.
Margaill
Isabelle
I
Palmier
Bruno
B
Pruneau
Didier
D
Plotkine
Michel
M
Marchand-Verrecchia
Catherine
C
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D065094:Bradykinin B2 Receptor Antagonists; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects; D011804:Quinolines / Q000627:therapeutic use*
D065094:Bradykinin B2 Receptor Antagonists; C403051:LF 16-0687; D011804:Quinolines