LF 16-0687 Ms, a bradykinin B2 receptor antagonist, reduces ischemic brain injury in a murine model of transient focal cerebral ischemia

Abstract

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.

Figure 1

Effect of pre- and postischemic treatment with LF 16-0687 Ms on (a) grip test and (b) infarct volume 48 h after MCAO. Vehicle and LF 16-0687 Ms at 1, 2 and 4 mg kg⁻¹ were given (s.c.) 0.5 h before, 1.25 and 6 h after MCAO. Experimental groups consisted of 9–11 mice. Values are means±s.e.m. †††P<0.001 versus non-operated mice, ^*P<0.05 and ^**P<0.01 versus vehicle-treated mice.

Figure 2

Effect of postischemic treatment with LF 16-0687 Ms on (a) grip test and (b) infarct volume 48 h after MCAO. Vehicle and LF 16-0687 Ms at 1.5, 3 and 6 mg kg⁻¹ were given (s.c.) 0.25 and 6.25 h after MCAO. Experimental groups consisted of 10–15 mice. Values are means±s.e.m. †††P<0.001 versus non-operated mice, ^*P<0.05, ^**P<0.01 and ^***P<0.001 versus vehicle-treated mice.

Figure 3

Effect of LF 16-0687 Ms on the brain water content (BWC) measured 24 h after MCAO. LF 16-0687 Ms (1.5 mg kg⁻¹) was given (s.c.) 0.25 and 6.25 h after MCAO. Experimental groups consisted of 10 mice. Values are means±s.e.m. †††P<0.001 versus sham-operated mice, ^*P<0.05 versus vehicle-treated mice.

Figure 4

Effect of LF 16-0687 Ms on Evans blue extravasation measured 24 h after MCAO. LF 16-0687 Ms (1.5 mg kg⁻¹) was given (s.c.) 0.25 and 6.25 h after MCAO. Experimental groups consisted of 9–11 mice. Values are means±s.e.m. †††P<0.001 versus sham-operated mice, ^*P<0.05 versus vehicle-treated mice.

Figure 5

Effect of LF 16-0687 Ms on myeloperoxidase activity (MPO) measured 48 h after MCAO. LF 16-0687 Ms (1.5 mg kg⁻¹) was given (s.c.) 0.25 and 6.25 h after MCAO. Experimental groups consisted of 14–15 mice. Values are means±s.e.m. †††P<0.001 versus sham-operated mice, ^***P<0.001 versus vehicle-treated mice.