Abstract
Bradykinin, following activation of the Kinin-Kallikrein cascade in acute spinal cord injury (ASCI), acts on the B2 receptors of blood vessels and neurons causing vasogenic edema, inflammation and neuronal death. This study explores the effect of CP0597, a B2 bradykinin receptor antagonist, and B9430, a B2/B1 bradykinin receptor antagonist on functional outcome following impact injury in an adult rat ASCI model. A randomized double blind placebo controlled study of selective Bradykinin receptor antagonists was performed on 99 male Sprague-Dawley rats (500 g) in experimental ACSI. A moderate ASCI was created using a dropped weight technique (NYU-SCI) following laminectomy at the T12 level (n=99). CP-0597 (300ng/kg/min for 7 days), B9430 (35ng/kg/min for 7 days) or placebo was administered using an osmotic pump. Functional outcome was determined by the Tarlov’s scores, Inclined Plane ability and Opto-Varimex 3D activity at 28 days postinjury. All animals underwent significant improvement from baseline. Although mean scores for all three groups were similar, CP-0597 exhibited the greater mean percentage improvement in ambulation from day 1 baseline [CP-0597 - 813%, B9430 - 671%, placebo - 366%, p = 0.0356]. This suggests that the B2 bradykinin receptor antagonist is more effective than the B2/B1 bradykinin receptor antagonist in improving independent ambulation following ASCI. Therefore, B2 bradykinin receptor antagonists may be a possible therapeutic role for these agents following ACSI.